Clinical trial NCT02256462: Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment (PAILOT) Trial
Official title: Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment (PAILOT) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Crohn's Disease
Lead sponsor: Schneider Children's Medical Center, Israel
Sponsor class: OTHER
First posted: 2014-10-03
Enrollment: 82
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Loss of response (LOR) during treatment.
timeFrame: Week 72
Secondary outcomes:
measure: Corticosteroids free complete clinical remission, on ADA,
timeFrame: 48 and 72 weeks
measure: Trough levels
timeFrame: 8, 16, 32, 48, 72 weeks
measure: Antibodies to adalimumab
timeFrame: 8, 16, 32, 48, 72 weeks
measure: Anthropometric indices
timeFrame: 0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
measure: Laboratory markers
timeFrame: 0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
measure: Adverse events
timeFrame: 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, weeks
measure: The need for treatment modification during therapy
timeFrame: Week 72
measure: Disease activity defined by PCDAI
timeFrame: 48 and 72 weeks
Other outcomes:
Locations:
city: Petach Tikva
country: Israel
facility: Schneider Children's Hospital
Study officials:
affiliation: Tel Aviv University
name: Raanan Shamir, MD
role: STUDY_CHAIR
References:
citation: Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006 Feb;130(2):323-33; quiz 591. doi: 10.1053/j.gastro.2005.11.030.
citation: Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007 Jan;132(1):52-65. doi: 10.1053/j.gastro.2006.11.041. Epub 2006 Nov 29.
citation: Karmiris K, Paintaud G, Noman M, Magdelaine-Beuzelin C, Ferrante M, Degenne D, Claes K, Coopman T, Van Schuerbeek N, Van Assche G, Vermeire S, Rutgeerts P. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology. 2009 Nov;137(5):1628-40. doi: 10.1053/j.gastro.2009.07.062. Epub 2009 Aug 5.
citation: Paul S, Moreau AC, Del Tedesco E, Rinaudo M, Phelip JM, Genin C, Peyrin-Biroulet L, Roblin X. Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014 Jul;20(7):1288-95. doi: 10.1097/MIB.0000000000000037.
citation: Matar M, Shamir R, Lev-Zion R, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Assa A. The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial. J Pediatr Gastroenterol Nutr. 2020 Aug;71(2):237-242. doi: 10.1097/MPG.0000000000002728.
citation: Matar M, Shamir R, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Ben-Horin S, Assa A. Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial. Inflamm Bowel Dis. 2020 Oct 23;26(11):1627-1635. doi: 10.1093/ibd/izz294.
citation: Assa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Shamir R. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring. Gastroenterology. 2019 Oct;157(4):985-996.e2. doi: 10.1053/j.gastro.2019.06.003. Epub 2019 Jun 10.