Assessment of Mucosal Activity to Improve the Prognosis of Patients With Crohn's Disease Treated With Immunosuppressants (ADACAL)

This study has been terminated.
(Not enough patient population according to selection criteria to complete the study)
Sponsor:
Collaborators:
Abbott
TFS Trial Form Support
Information provided by (Responsible Party):
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
ClinicalTrials.gov Identifier:
NCT01562951
First received: March 13, 2012
Last updated: March 15, 2015
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Crohn's Disease
Mucosal Inflammation
Drug: ADALIMUMAB
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa:

Primary Outcome Measures:
  • The primary efficacy endpoint is the rate of therapeutic failure up to week 48 [ Time Frame: Every 12 weeks up to Week 48 ] [ Designated as safety issue: No ]

    The therapeutic failure is defined as any of following cases:

    1. CDAI > 220 with at least 70-point increase from baseline over two consecutive visits 12 weeks apart or CDAI > 300 at any time point during the study;
    2. need of any change in therapy for CD except the ones planned per protocol in each group of the study;
    3. need of surgery related to CD or of stricture endoscopic dilatation.


Secondary Outcome Measures:
  • The rate of therapeutic failure (see the definition of primary endpoint) up to week 24 [ Time Frame: up to week 24 ] [ Designated as safety issue: No ]
  • Change in CDEIS from baseline to week 48 [ Time Frame: up to week 48 ] [ Designated as safety issue: No ]
    CDEIS = Crohn's Disease Endoscopic Index of Severity.

  • The rate of mucosal healing (CDEIS=0) at week 48 [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
    CDEIS = Crohn's Disease Endoscopic Index of Severity

  • The rate of CDEIS remission (CDEIS<=3) at week 48 [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
    CDEIS = Crohn's Disease Endoscopic Index of Severity

  • The rate of CDEIS response, which is defined as a decrease of at least 4 points in CDEIS from baseline to week 48 [ Time Frame: from baseline up to week 48 ] [ Designated as safety issue: No ]
    CDEIS = Crohn's Disease Endoscopic Index of Severity

  • Change in CDAI from baseline to week 12, 24, 36 and 48 [ Time Frame: from baseline to week 12, 24, 36 and 48 ] [ Designated as safety issue: No ]
    CDAI = Crohn's Disease Activity Index.

  • Change in the global score based on IBDQ from baseline to week 12, 24, 36, and 48. [ Time Frame: from baseline to week 12, 24, 36, and 48. ] [ Designated as safety issue: No ]
    IBDQ = Inflammatory Bowel Disease Questionnaire.

  • Area Under the Curve (AUC) over 48 weeks for CDAI [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • The number of surgical interventions related to CD up to 24 and 48 weeks [ Time Frame: up to 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  • The rate of hospital admissions related to the disease, to the treatment side effects or other causes up to weeks 24 or 48 [ Time Frame: up to weeks 24 or 48 ] [ Designated as safety issue: Yes ]
  • The rate of serious AEs between the two strategies up to 24 and 48 weeks [ Time Frame: up to 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  • The rate of serious AEs requiring the cessation of the ongoing treatment between the two strategies up to 24 and 48 weeks. [ Time Frame: up to 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  • The accuracy of calprotectin/hsCRP to predict therapeutic failure 12 weeks in advance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The correlation between calprotectin, hsCRP and CDAI at any time points during the study. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Pearson Product-Moment Correlation will be used to evaluate correlations between calprotectin, hsCRP and CDAI at all scheduled visits.

  • The correlation between calprotectin/hsCRP and CDEIS or mucosal healing at Baseline and Week 48. [ Time Frame: at Baseline and Week 48. ] [ Designated as safety issue: No ]
    Pearson Product-Moment Correlation will also be used to evaluate between calprotectin (and hsCRP) and CDEIS at Baseline and Week 48.

  • Change in the scores based on WPAI from baseline to week 12, 24, 36 and 48 [ Time Frame: from baseline to week 12, 24, 36 and 48 ] [ Designated as safety issue: No ]
    WPAI = Work Productivity and Activity Impairment Questionnaire

  • The change in calprotectin and hsCRP from baseline to week 12, 24, 36, and 48 [ Time Frame: from baseline to week 12, 24, 36, and 48 ] [ Designated as safety issue: No ]

Enrollment: 15
Study Start Date: October 2012
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: PLACEBO
Treatment with placebo
Drug: Placebo
PLACEBO at 160/80 mg and maintained on 40 mg eow until next colonoscopy performed at week 48. If before week 48, an increase of more than 50% is observed in calprotectin and/or hsCRP from baseline, over two consecutive follow up visits 2 weeks apart, the colonoscopy will be performed earlier. If patients have still significant endoscopic lesions, adalimumab or adalimumab placebo will be intensified to 40 mg weekly
Active Comparator: ADALIMUMAB
Treatment with Adalimumab
Drug: ADALIMUMAB
Adalimumab at 160/80 mg and maintained on 40 mg eow until next colonoscopy performed at week 48. If before week 48, an increase of more than 50% is observed in calprotectin and/or hsCRP from baseline, over two consecutive follow up visits 2 weeks apart, the colonoscopy will be performed earlier. If patients have still significant endoscopic lesions, adalimumab or adalimumab placebo will be intensified to 40 mg weekly.
Other Name: HUMIRA

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

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01562951

Locations
Belgium
Imeldaziekenhuis Bonheiden
Bonheiden, Belgium, 2820
Hospital Erasme Bruxelles
Bruxelles, Belgium, 1070
Hospital Saint Luc Bruxelles
Bruxelles, Belgium, 1200
Hospital University Gent
Gent, Belgium, 9000
Centre Hospitalier Universitaire de Liege
Liege, Belgium, 4000
Heiling Hartzieknhuis Roeselare
Roeselare, Belgium, 8800
France
CHU Bordeaux - Hospital Haut-Leveque
Pessac, Bordeaux, France, 33604
CHU Nancy - Hospital de Brabois Adultes
Vandoeuvre Les Nancy, Nancy, France, 54500
CHU Tours - Hospital Trousseau
Chambray, Tours, France, 76031
CHU Amiens - Hospital Nord
Amiens, France, 80054
Hospital Beaujon
Clichy, France, 92110
CHRU Lille - Hospital Claude Huriez
Lille, France, 59037
CHU Lyon Sud
Lyon, France, 69495
CHU Nantes
Nantes, France, 44093
Hospital Saint Louis
Paris, France, 75010
CHRU Reims - Hospital Robert Debre
Reims, France, 51092
CHU Rouen - Hospital Charles Nicolle
Rouen, France, 76031
CH Saint Etienne - Hospital Nord
Saint Etienne, France, 42270
Spain
Complejo Hospitalario Santiago de Compostela
Santiago de Compostela, A coruña, Spain
Hospital Universitario Reina Sofia
Córdoba, Andalucía, Spain, 14004
Hospital Germans Trias i Pujol
Badalona, Barcelona, Spain
Hospital Doctor Negrin
Las Palmas de Gran Canarias, Canarias, Spain, 35010
Hospital de Manises
Manises, Valencia, Spain, 46940
Hospital Santa Creu i Sant Pau
Barcelona, Spain, 08025
Hospital Gregorio Marañón
Madrid, Spain, 28007
Hospital Ramón y Cajal
Madrid, Spain, 28034
Hospital Universitario La Princesa
Madrid, Spain, 28005
Hospital Virgen del Rocío
Sevilla, Spain, 41013
Hospital Clínico de Valencia
Valencia, Spain, 46010
Hospital Lozano Blesa
Zaragoza, Spain
Sponsors and Collaborators
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
Abbott
TFS Trial Form Support
Investigators
Principal Investigator: VALLE GARCÍA, MD Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
  More Information

No publications provided

Responsible Party: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
ClinicalTrials.gov Identifier: NCT01562951     History of Changes
Other Study ID Numbers: A12-771
Study First Received: March 13, 2012
Last Updated: March 15, 2015
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
Belgium: Federal Agency for Medicinal Products and Health Products
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa:
Crohn's disease
mucosal inflammation
lesions

Additional relevant MeSH terms:
Crohn Disease
Inflammation
Mucositis
Digestive System Diseases
Gastroenteritis
Gastrointestinal Diseases
Inflammatory Bowel Diseases
Intestinal Diseases
Mouth Diseases
Pathologic Processes
Stomatognathic Diseases
Adalimumab
Immunosuppressive Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 25, 2015