Clinical trial NCT01562951: Assessment of Mucosal Activity to Improve the Prognosis of Patients With Crohn's Disease Treated With Immunosuppressants
Official title: cAlprotectin and hsCRP as Markers of a New Diagnostic-therapeutic strAtegy That Assesses muCosal Activity to individuaLize Treatment and Improve the Prognosis of Patients With Crohn's Disease Treated With Immunosuppressants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Crohn's Disease
Mucosal Inflammation
Keywords: Crohn's disease
mucosal inflammation
lesions
Lead sponsor: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
Sponsor class: OTHER
Collaborators: name: Abbott
name: TFS Trial Form Support
First posted: 2012-03-26
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will test that individualized treatment in patients with Crohn's Disease in remission or mild clinical activity under immunosuppressants may improve prognosis, rather than just treating flares.

Detailed description: Patients will be prescreened for inclusion criteria one week before the start of screening at Visit 0 (Prescreening Visit). Patients must be on stable doses of azathioprine/mercaptopurine. Patients will be given a diary to record their CD symptoms for the seven days prior to Visit 1. At Visit 1 (Screening Visit 1), patients will have their CDAI score assessed based upon their diary information. Patients with CDAI ≤ 220 will then have both calprotectin and hsCRP testing done. Patients with calprotectin \> or = 250µg/g and/or hsCRP \> or = 5mg/L will be notified and told to schedule Visit 2 within three weeks. At Visit 2 (Screening Visit 2), patients will undergo a colonoscopy. A Crohn's Disease Endoscopic Index of Severity (CDEIS) will be used to determine the endoscopic activity. Patients with significant endoscopic lesions will be notified and asked to enroll in the study.

Patients will be randomized into the study at Visit 3 (Randomization Visit, same day of Visit 2 in results available). Due to the cost and invasiveness of the colonoscopy, the Screening Visit 2 colonoscopy will serve as the baseline for the study, should the patient be enrolled. Drug will also be dispensed at this visit. Eligible patients will be randomized in a 1:1 ratio to receive either adalimumab or placebo during the treatment period, along with continuing their current immunosuppressive maintenance treatment at a stable dose. Treatment in both arms will be induction at 160/80mg and maintenance on 40 mg every other week.

Patients will return for follow up visits every 12 weeks until the final follow-up visit at 48 weeks (Visit 7), where another colonoscopy will be performed. Patients who terminate early from the study for any reason will be asked to return for a follow-up visit, where Visit 7 procedures will be performed.

Before week 48, if a patient has an increase of more than 50% in either calprotectin and/or hsCRP over baseline and above the thresholds at any regular visit, a follow-up visit will be performed two weeks later. If the 50% increase is still observed another colonoscopy will be performed, within two weeks of the follow-up visit. If patients still have significant endoscopic lesions, study product will be intensified to 40 mg weekly. This will include patients on placebo in order to preserve the double-blind aspect of the study.

Eligibility criteria: Inclusion Criteria:

* Age 18-75 years old- Patients with CD diagnosis confirmed by colonoscopy
* Patients with inflammatory CD of terminal ileal, colonic or ileocolonic location
* Maintenance treatment with at least 2 mg/kg/day for azathioprine/ 1 mg/kg/day for mercaptopurine or the highest dosage tolerated in patients who could not tolerate this dosage, at least 6 months.
* Willingness to sign informed consent
* If female of childbearing age, be post-menopausal, surgically sterile, or willing to use a reliable form of birth control for the duration of the study (such as physical barrier \[patient and partner\], contraceptive pill or patch, spermicide and barrier, or intrauterine device)and for at least five months after the last adalimumab treatment.
* Able to comply with the requirements of the study.
* CDAI score ≤ 220.
* Calprotectin \> or = 250µg/g and/or hsCRP \> or = 5mg/L.
* Significant lesions seen during colonoscopy, as defined by CDEIS.

Exclusion Criteria:

* Patients with an ostomy, or ileoanal pouch (subject with previous ileo-rectal anastomosis are not excluded), draining fistula, abscess
* Patients who had intestinal resection within one year.
* Symptomatic stricture either diagnosed by colonoscopy or clinically suspected and confirmed by imaging techniques.
* Prior treatment with any anti-tumor necrosis factor (TNF) drug.
* Patients receiving rectal treatment 1 month before inclusion
* Signs of active infection
* Previous history of active untreated or inadequately treated tuberculosis (TB) or latent TB. Patients should be screened for latent TB as per local guidelines or clinical practice in the country of study conduct. Patients with latent TB should be treated with standard antimycobacterial therapy (for at least 4 weeks) before initiating biologic therapy and have a negative CRX for active TB at screening
* Subjects with a poorly controlled medical condition such as: uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association \[NYHA\] class III or IV), recent cerebrovascular accident, or any other condition which, in the opinion of the Investigator or the sponsor, would put the subject at risk by participation in the protocol
* Signs of colon cancer or dysplasia
* Signs of severe or unstable renal, hepatic, gastrointestinal, cardiovascular, respiratory, neurological, psychiatric, or hematological disease
* Signs of cancer in the past five years, except for localized and treated basal cell skin cancer or cervical cancer
* Patients who are pregnant or nursing
* Concomitant treatment with:

  * Live vaccines.
  * 5-ASA compounds: Rectal 5-ASA should be discontinued at least 4 weeks before study inclusion. Oral 5-ASA must be at a stable dose for at least 4 weeks before study inclusion. If oral 5-ASA has recently been discontinued, 4 weeks should pass before study inclusion.
  * Oral corticosteroids (eg., Prednisone, budesonide) should be discontinued for 3 months before study inclusion.
  * Antibiotics for CD. Only antibiotics used to treat a concurrent infection are allowed.
  * Immunomodulators:

Patients receiving therapy with azathioprine/mercaptopurine must have been on a stable dose for at least 12 weeks before inclusion and must continue with the same dose during the study.

No treatment with other known immunomodulators (eg. methotrexate, 6-thioguanine \[6-TG\], cyclosporine, tacrolimus, sirolimus, ustekinumab, pentoxifylline, or mycophenolate mofetil) or experimental drugs (eg., factor colony stimulating granulocyte macrophage \[GM-CSF\]) within 6 months

* Monoclonal antibodies or anti-TNF drugs.
* Aspirin or Non-steroidal anti-inflammatory drugs (NSAIDs). Treatment with aspirin and/or NSAIDS should not occur for more than 15 consecutive days before collecting of the stool sample for Calprotectin and performing the colonoscopy.

  - Screening laboratory and other analyses show any of the following abnormal results:
* Aspartate transaminase (AST) or alanine transaminase (ALT) \> 2 x the upper limit of the reference range;
* Total bilirubin ≥ 3 mg/dL (51 μmol/L);
* Serum creatinine \> 1.6 mg/dL (144 μmol/L)

  * History of any drug or alcohol abuse in the past 2 years
  * Receipt of other study product within 3 months of inclusion in this study
  * Patients employed by the sponsor or in any relationship of dependence with the sponsor and/or investigator
  * Staff at the study center
  * Hypersensitivity to the active substance or to any of the excipients

Primary outcomes:
measure: The primary efficacy endpoint is the rate of therapeutic failure up to week 48
timeFrame: Every 12 weeks up to Week 48
Secondary outcomes:
measure: The rate of therapeutic failure (see the definition of primary endpoint) up to week 24
timeFrame: up to week 24
measure: Change in CDEIS from baseline to week 48
timeFrame: up to week 48
measure: The rate of mucosal healing (CDEIS=0) at week 48
timeFrame: at week 48
measure: The rate of CDEIS remission (CDEIS<=3) at week 48
timeFrame: at week 48
measure: The rate of CDEIS response, which is defined as a decrease of at least 4 points in CDEIS from baseline to week 48
timeFrame: from baseline up to week 48
measure: Change in CDAI from baseline to week 12, 24, 36 and 48
timeFrame: from baseline to week 12, 24, 36 and 48
measure: Change in the global score based on IBDQ from baseline to week 12, 24, 36, and 48.
timeFrame: from baseline to week 12, 24, 36, and 48.
measure: Area Under the Curve (AUC) over 48 weeks for CDAI
timeFrame: 48 weeks
measure: The number of surgical interventions related to CD up to 24 and 48 weeks
timeFrame: up to 24 and 48 weeks
measure: The rate of hospital admissions related to the disease, to the treatment side effects or other causes up to weeks 24 or 48
timeFrame: up to weeks 24 or 48
measure: The rate of serious AEs between the two strategies up to 24 and 48 weeks
timeFrame: up to 24 and 48 weeks
measure: The rate of serious AEs requiring the cessation of the ongoing treatment between the two strategies up to 24 and 48 weeks.
timeFrame: up to 24 and 48 weeks
measure: The accuracy of calprotectin/hsCRP to predict therapeutic failure 12 weeks in advance
timeFrame: 12 weeks
measure: The correlation between calprotectin, hsCRP and CDAI at any time points during the study.
timeFrame: 48 weeks
measure: The correlation between calprotectin/hsCRP and CDEIS or mucosal healing at Baseline and Week 48.
timeFrame: at Baseline and Week 48.
measure: Change in the scores based on WPAI from baseline to week 12, 24, 36 and 48
timeFrame: from baseline to week 12, 24, 36 and 48
measure: The change in calprotectin and hsCRP from baseline to week 12, 24, 36, and 48
timeFrame: from baseline to week 12, 24, 36, and 48
Other outcomes:
Locations:
city: Bonheiden
country: Belgium
facility: Imeldaziekenhuis Bonheiden
city: Bruxelles
country: Belgium
facility: Hospital Erasme Bruxelles
city: Bruxelles
country: Belgium
facility: Hospital Saint Luc Bruxelles
city: Gent
country: Belgium
facility: Hospital University Gent
city: Liege
country: Belgium
facility: Centre Hospitalier Universitaire de Liege
city: Roeselare
country: Belgium
facility: Heiling Hartzieknhuis Roeselare
city: Pessac
country: France
facility: CHU Bordeaux - Hospital Haut-Leveque
state: Bordeaux
city: Vandoeuvre Les Nancy
country: France
facility: CHU Nancy - Hospital de Brabois Adultes
state: Nancy
city: Chambray
country: France
facility: CHU Tours - Hospital Trousseau
state: Tours
city: Amiens
country: France
facility: CHU Amiens - Hospital Nord
city: Clichy
country: France
facility: Hospital Beaujon
city: Lille
country: France
facility: CHRU Lille - Hospital Claude Huriez
city: Lyon
country: France
facility: CHU Lyon Sud
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hospital Saint Louis
city: Reims
country: France
facility: CHRU Reims - Hospital Robert Debre
city: Rouen
country: France
facility: CHU Rouen - Hospital Charles Nicolle
city: Saint Etienne
country: France
facility: CH Saint Etienne - Hospital Nord
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Santiago de Compostela
state: A coruña
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
state: Andalucía
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Las Palmas de Gran Canarias
country: Spain
facility: Hospital Doctor Negrin
state: Canarias
city: Manises
country: Spain
facility: Hospital de Manises
state: Valencia
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Zaragoza
country: Spain
facility: Hospital Lozano Blesa
Study officials:
affiliation: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
name: VALLE GARCÍA, MD
role: PRINCIPAL_INVESTIGATOR
References: