Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment (PAILOT) Trial

September 25, 2021 updated by: Amit Assa, Schneider Children's Medical Center, Israel
Objectives: To examine the effect of drug level-based personalized treatment of adalimumab in children with Crohn's disease. Design: A prospective, randomized, open label study. Setting: Pediatric gastroenterology centers. Participants: Children 6 year to 17 years who are diagnosed with CD and are planned to receive adalimumab treatment. Main outcome measures: Pediatric Crohn's Activity Index (PCDAI) at 48 and 72 weeks. Secondary outcome measures: Corticosteroids free remission rates and on adalimumab at 48 and 72 weeks. The effect of routine adalimumab drug monitoring-based treatment on trough levels and anti-adalimumab antibodies during therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The efficacy of adalimumab in inducing and maintaining remission in both adults and children with moderate-to-severe Crohn's Disease has been demonstrated in multiple clinical trials. Despite efforts to optimize treatment, approximately 40% of patients who initially respond to anti-TNF ultimately lose response. Measurement of adalimumab (ADA) drug levels and antibodies to adalimumab (ATAs) in patients has been shown to assist decision making in patients who have lost response during the course of treatment. This approach is based on the observations showing that higher ADA concentrations are associated with higher treatment efficacy and that loss of response is primarily attributed to either undetectable drug levels or to the presence of high titers of ATAs. Existing data is mostly based on retrospective cohort studies, nevertheless, the concept of routine therapeutic drug monitoring in-order to improve efficacy is still evolving. Recently, preliminary results of the Trough level Adapted infliXImab Treatment (TAXIT) study, performed in adult IBD patients, have failed to demonstrate superiority of level-based treatment over clinically-based treatment regarding rates of response over time. Nevertheless, it is premature to conclude that patients do not benefit from a tailored approach as the reported abstract did not stratify patients according to type of disease (CD vs. ulcerative colitis) and as some significant advantages such as reduced rate of antibodies and reduction of CRP were described in the level-based arm. Anti-TNF treatment in pediatric patients may differ from adults due to a higher risk for developing the rare hepatosplenic T cell lymphomas (HSCTL) in young males treated with combination therapy including thiopurines and anti-TNF agents. Concomitant therapy (using immunomodulators, mainly azathioprine) which has demonstrated superiority over mono-therapy has become a standard of care in moderate to severe CD in adults. In-view of the concerns of pediatric gastroenterologist from concomitant therapy-induced adverse events the option to improve efficacy of mono-therapy by guiding it according to drug monitoring is further appealing. Therefore, our aim is to assess the efficacy of routine therapeutic drug monitoring based treatment in pediatric CD patients in a prospective randomized control trial. We hope that this study will further contribute to the understanding of the potential benefits of therapeutic drug monitoring based management in pediatric patients treated with anti-TNF agents.Hypothesis:

We hypothesize that by routine measuring of ADA trough levels and ATAs titers we will achieve higher and stable trough levels resulting in greater corticosteroid free remission rates and decreased LOR rates. We assume that this will be associated with lower frequencies of ATAs. We further assume that the intervention will reduce the need for alteration of treatment schemes by adding immunomodulators or by switching treatment within class or out of class.

Objectives:

This is ADA therapy optimization study in patients starting or receiving ADA due to active disease.

  1. Primary Efficacy Objective: To evaluate the effect of routine ADA drug monitoring-based treatment, in comparison to clinically-based monitoring on disease activity.
  2. Secondary Objective: To evaluate the effect of routine ADA drug monitoring-based treatment on trough levels and ATAs during therapy.

Study Type

Interventional

Enrollment (Actual)

82

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Israel
      • Petach Tikva, Israel, 4920235
        • Schneider Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 17 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Crohn's disease
  2. Age 6-17 (inclusive)
  3. Naïve to biologics
  4. Informed consent
  5. Neg. TB-Test, negative HBV- S Ag
  6. Negative stool culture, parasites and clostridium toxin

Inclusion criteria Comments:

  1. Patients receiving corticosteroids may be included if on taper-down scheduled to be completed by week 10.
  2. Partial enteral nutrition, accounting for less than 50% of daily required calories, may be supplied as needed.
  3. Patients receiving antibiotics must cease use of antibiotics within the 14 days of receiving the first injection. Excluding immunomodulators (azathioprine/6MP and methotrexate), any other targeted therapy for crohn's disease (i.e 5-ASA) must be stopped prior to ADA first injection. Immunomodulators will be required to be stopped either prior to first ADA injection or at 6 months following ADA initiation.

Exclusion Criteria:

  1. Pregnancy.
  2. Renal Failure.
  3. Current abscess or perforation of the bowel.
  4. Small bowel obstruction within the last 6 months.
  5. Fixed non inflammatory stricture with related symptoms.
  6. Complicated or heavily draining perianal fistula (indolent non draining or minimally draining fistula are not an exclusion criteria).
  7. Prior treatment with infliximab or adalimumab.
  8. Previous malignancy.
  9. Sepsis or active bacterial infection.
  10. Surgery related to Crohn's disease in the previous 8 weeks.
  11. Positive Hepatitis B surface antigen or evidence for TB.
  12. IBD unclassified.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Interventional
Adalimumab levels and antibodies will be obtained with every laboratory examination (every 2 months, except for the first 2 visits). Dose or interval adjustment will be performed as followed:when trough levels results taken prior to ADA injection are above 5 µg/ml no change in dosing is required. Detectable levels below 5 µg/ml will result in interval decrease to every week. If levels are still below 5 µg/ml dose will be increased to 40 mg (in patients receiving less than 40 mg). Undetectable levels below 0.3µg/ml will be followed by antibodies (ATAs) measurement. If ATAs are persistently above 8 µg/ml the patient will discontinue the study. If ATAs are below 8 µg/ml ADA intervals will be decreased to every week.
Drug: Adalimumab
Eligible patients are those who are planned to start Adalimumab (ADA). Patients will be randomized at the first screening visits to either group 1 (interventional) or group 2 (clinical). Eligible patients, will start induction treatment (weeks 0,2) with ADA (> 40kg 160/80/40 mg every 2 weeks or < 40 kg 100/50/25 mg for m2 body surface area every 2 weeks). Interventions will start from the 4th injection for responding patients only (based on levels taken prior to the third injection). Responding patients will continue to the maintenance phase in which they will receive ADA every 2 weeks, either 40 mg or 25 mg/m2. At screening, and every 2 months all patients will be examined and have height, weight, PCDAI performed as well as comprehensive laboratory examinations.
Other Names:
  • Humira
No Intervention: Clinical

Adalimumab levels and antibodies will be requested based on physician judgment when there are signs of loss of response (LOR). Dose and interval adjustment will be performed according to clinical measures: Following physician decision trough levels and ATAs will be collected and further adjustment may be considered according to results. Interval adjustment will be performed as described for the interventional arm.

LOR is defined as PCDAI equal or higher than 10 or CRP higher than 0.5 mg/dl (5mg/l) and/or Fecal calprotectin higher than 150 mcg/gr (If lower than 150 at randomization).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Loss of response (LOR) during treatment.
Time Frame: Week 72
Patients with loss of response are defined as those with a good initial clinical response to anti-TNFα, with a later clinical and biochemical relapse defined as PCDAI≥10 (for patients in remission) or an increase of 15 points PCDAI from post induction baseline and CRP> 0.5mg/dl and/or calprotectin>150µgr/gr
Week 72

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Corticosteroids free complete clinical remission, on ADA,
Time Frame: 48 and 72 weeks
Patients with PCDAI<10, and quiescent disease by physician global assessment (PGA).
48 and 72 weeks
Trough levels
Time Frame: 8, 16, 32, 48, 72 weeks
Mean adalimumab trough levels
8, 16, 32, 48, 72 weeks
Antibodies to adalimumab
Time Frame: 8, 16, 32, 48, 72 weeks
Presence of antibodies to adalimumab (ATAs)
8, 16, 32, 48, 72 weeks
Anthropometric indices
Time Frame: 0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
Anthropometric indices (weight, height, BMI) and growth assessment during scheduled visits
0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
Laboratory markers
Time Frame: 0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
Laboratory surrogate markers (CBC, ESR, CRP, albumin, fecal calprotectin) during scheduled visits
0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
Adverse events
Time Frame: 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
Medication associated adverse events
4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
The need for treatment modification during therapy
Time Frame: Week 72
Addition of immunomodulator, switch within/out of class
Week 72
Disease activity defined by PCDAI
Time Frame: 48 and 72 weeks
Pediatric Crohn's Disease Activity Index
48 and 72 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Schneider Children's Medical Center, Israel

Investigators

  • Study Chair: Raanan Shamir, MD, Tel Aviv University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2015

Primary Completion (Actual)

January 31, 2019

Study Completion (Actual)

January 31, 2019

Study Registration Dates

First Submitted

September 26, 2014

First Submitted That Met QC Criteria

September 30, 2014

First Posted (Estimate)

October 3, 2014

Study Record Updates

Last Update Posted (Actual)

September 28, 2021

Last Update Submitted That Met QC Criteria

September 25, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PAILOT

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Crohn's Disease

Clinical Trials on Adalimumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Suriname

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe