Center for Pediatric Inflammatory Bowel Disease

Clinical Studies: Treatment Approaches

• Metronidazole with ciprofloxacin for treating mild to moderate pediatric Crohn's flares
• Anti-TNF chimeric monoclonal antibody (Infliximab) in the treatment of active Crohn's disease
• Comparison of Option One Optimental and a polymeric enteral feeding
• Efficacy of intravenous loading of azathioprine in children and adolescents with inflammatory bowel disease
• Complementary and alternative medicine use among pediatric patients with inflammatory bowel disease
• Laparoscopy versus open laparotomy for bowel resection in pediatric Crohn's disease
• Safety and efficacy of iron dextran infusions with inflammatory bowel disease and iron deficiency anemia
• Safety and efficacy of ISIS 2303 in steroid-dependent Crohn's disease
• Safety and pharmacokinetics of CDP571 in pediatric patients with Crohn's disease

Metronidazole in combination with ciprofloxacin for treating mild to moderate pediatric Crohn's flares

W.C. Jeshion, D.A. Piccoli and R.N. Baldassano

Background

Numerous recent studies suggest that bacteria playa role in the pathogenesis and/or symptoms of Crohn's disease. Metronidazole and ciprofloxacin have been shown to be efficacious for treating perianal disease. A recent study in adults demonstrated that metronidazole in combination with ciprofloxacin can be used as a possible alternative to steroid therapy to treat Crohn's flares.

Aim

To evaluate whether there is a role for metronidazole in combination with cirpofloxacin for treating mild to moderate pediatric Crohn's flares.

Methods

All Crohn's patients between 6-22 years old with signs and symptoms of active disease and a Pediatric Crohn's Disease Activity (PCDAI) between 20-42.5 were recruited for the study. Patients were excluded if in the past month they had 1) received antibiotics 2) received steroids at a dose greater than 10mg QD for patients (35 kg or 5 mg QD for patients <35 kg or 3) an increase in their steroid dose. All patients were treated with both metronidazole and cirpofloxacin for 12 wks, without any other changes in their medical care. Patients were followed prospectively for 12 wks and PCDAIs determined at the initial visit, wk4, wk8 and at the end of the 12-wk study period.</p/>

Results

Nine patients were included in the study. Two patients were withdrawn from the study (one at 3wks, one at 8 wks) after showing clinical deterioration. All of the remaining 7 patients who completed the study showed clinical improvement which was defined as an improvement of standard deviation or greater between the baseline and post-treatment PCDAI scores. 6/7 (86%) had an improvement of greater than 1 standard deviation between baseline and post-treatment PCDAI scores. The mean PCDAI, sedimentation rate (ESR), albumin and hematocrit were determined at baseline in all 9 patients and compared after 12 wks of therapy (or when the 2 patients were withdrawn from the study). The paired t-test was used to determine statistical significance (p<0.05) between baseline and post-treatment values. The mean PCDAI was 31.1 ( 5.9 at baseline and 13.6 ( 10.6 at the end of therapy (p=0.001). The improvements in mean ESR and hematocrit were also found to be statistically significant (p=0.04, p=0.02); whereas the improvement in mean albumin was NS. Because of the small sample size and potentially skewed layout of the data, nonparametric statistics were also performed; the results were consistent with the paired t-test. Side effects of the antibiotics included Clostridium difficile infection in 1 patient following a three-month course of antibiotics, a peripheral neuropathy in 1 patient which resolved once the metronidazole dose was lowered and diarrhea in several patients that subsequently resolved with a decrease in ciprofloxacin dose.

Conclusions

1. Metronidazole and ciprofloxacin are useful in treating mild to moderate Crohn's flares.
2. 7/9 (78%) of pediatric patients had clinical improvement.
3. There was a significant improvement in mean PCDAI, ESR and hematocrit when comparing baseline with post-treatment values. NASPGN Abstracts. J. of Pediatric Gastroenterology and Nutrition. May 1998.

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A multicenter study of anti-TNF( chimeric monoclonal antibody (Infliximab) in the treatment of pediatric patients with active Crohn's disease

R. Baldassano, E. Vasiliauskis, C. Braegger, M. Sinaasappel, J. Escher, C. Wagner, K. DeWoody, R. Livingston, G. Ferry, B. Kirschner, D. Turck, C. Hadigan and H. Winter

Background

The important role played by TNF( in the pathogenesis of Crohn's disease has been confirmed by open-label and controlled clinical trials in adults which have shown that a monoclonal anti-TNF( antibody (Infliximab) is an effective short-term treatment for many patients with moderate to severe treatment-resistant Crohn's disease (van Dullemen et al., Gastroenterology 1995; 109-129; Targan et al., NEJM 1997; 337:1029).

Aim

To evaluate the safety, efficacy and pharmacokinetic properties of infliximab in pediatric patients with active Crohn's disease.

Methods

We conducted a multicenter, double-blind, single infusion, does-ranging trial of infliximab in pediatric patients (age range from 8-17 years) with treatment-resistant, moderate to severe Crohn's disease defined by Crohn's Disease Activity Index (PCDAI) (30. Patients were randomized in equal proportions to receive an IV infusion of infliximab at a dose of 1mg/kg, 5 mg/kg or 10 mg/kg. In this preliminary report of the first 12 patients, all dose groups were combined to determine CDAI, PCDAI and ESR at baseline, 1 week, 2 weeks and 4 weeks after infusion and laboratory and clinical safety data were reviewed. Remission was defined as PCDAI < 10 or CDAI (modified) <150.</span/>

Results

Among these first twelve patients treated with varying doses of infliximab, median age was 15.5 years (3F/9M, range 11 to 17 years). Remission at any point during the first 4 weeks following infusion was achieved by 5 patients. Median values (minimum, maximum) for CDAI, PCDAI and ESR are shown:

No significant adverse experience occurred and laboratory parameters (hematology, blood chemistry and urinalysis) continued at pre-infusion levels for the first four weeks of the study.

Conclusions

A single infusion of infliximab appeared to be an effective and safe treatment in these 12 children with moderate to severe treatment-resistant Crohn's disease. The optimal dose of infliximab in children remains to be determined; these preliminary pooled data may be influenced by dose effects. Complete efficacy, safety and 12-week pharmacokinetic profiling by dose group will be presented on the entire study population (n(25). This research was funded by Centocor, Inc., Malvern, PA USA. AGA Abstracts. Gastroenterology. May 1999.

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Comparison of Option One (Optimental() and a polymeric enteral feeding: attainment of remission in Crohn's disease

Research is sponsored by Ross Pharmaceuticals, Inc. Columbus OH USA

Background

Sole source enteral nutrition using formulated food has emerged as an alternative means of treating Crohn's disease. Response rates to enteral nutrition have been consistently greater than observed placebo-response rates in other controlled clinical trials. While comparative randomized controlled trials involving exclusively children have been few, enteral nutrition is particularly important in the pediatric age group because of its beneficial effect on growth.

Aim

To compare the efficacy of Option One (Optimental () versus a polymeric control formula in the attainment of remission in active Crohn's disease in children.

Methods

Steroid-dependent patients (<20 mg on alternate days or <10 mg per day) from age 6 to 17 years diagnosed with active Crohn's disease (either newly diagnosed or in relapse) and who meet inclusion criteria are recruited for this double-blinded, randomized study. The Crohn's Disease Activity Index must be/>150 and ( 450 in order to qualify for the study. Patients are randomly assigned to elemental or polymeric nutrition according to the stratification of CDAI score, new diagnosis or relapse, disease site, and study site. The formula is the sole source of nutrition for 28 days. A clear fluid diet may be permitted after the first week if the disease symptoms appear to be improving. Patients are followed on a weekly basis for one month. On Day 1 and Day 28, the patient is seen in the clinic for physician assessment and lab work. During the interim, telephone interviews are conducted.

Results

Ongoing trial

Discussion

Due to the blinding of this ongoing trial, the control and experimental products are not identified. Preliminary data suggests that enteral formula taken by the patient promotes growth and an abatement of disease symptoms. To date, the CDAI scores for patients who participated at this site dropped below 150 by Day 28, which suggests a remission of the disease. In addition, most patients have complained of less abdominal pain and, in some cases, a complete absence of abdominal discomfort. Furthermore, although the majority of patients ingest most of the formula through nasogastric tube feeds, several have been able to ingest all of the formula orally. This would imply that the taste of the formula was, at the very least, tolerable. Ross plans to keep the trial open for at least one more year at which time more conclusive results will be available. Therefore, recruitment of patients will continue until the trial closes.

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A prospective randomized double-blind placebo controlled study to assess the efficacy of intravenous loading of azathioprine in children and adolescents with inflammatory bowel disease

H.A. Kader, Y. Theoret, V. Tolia, C.A. Liacouras, D.A. Piccoli and R.N. Baldassano

Background

Oral azathioprine (AZA) is used to treat corticosteroid (CS) refractory and dependent IBD. The mean onset of action is delayed and occurs at 4 months.

Aims

1. To determine the value of IV AZA loading
2. To identify the safety profile for IV and oral AZA
3. To determine the utility of measuring AZA metabolites

Methods

Patients were randomized to receive an IV infusion of AZA, Group 1; or placebo,group 2, after confirming a high or normal TPMT activity, 13.8-25.1 U/mL RBC. An IV AZA dose of 30 mg/m2/hr (maximum 50 mg/hr) for 24 hours was used. Patients began oral AZA, 2 mg/kg/day, after completion of the IV infusion. CS were weaned by weekly increments until discontinued or disease recurred. Disease activity was determined serially by the PCDAI or Seoactivity index. Blood samples for AZA metabolites were obtained concurrently. AZA metabolite assays were performed as described by Cuffari et al. (Gut 1996; 39: 401-406). 6-TGN analysis was performed for study days 42 through 84.

Results

Fifteen patients with IBD were enrolled: 11 with Crohn's disease & 4 with ulcerative colitis. Eight patients received IV AZA and 7 patients received placebo. Two patients from each group were excluded from analysis for protocol violation as were 1 patient in Group 2 who went to surgery and another in Group 2 who developed pancreatitis. Mean age was 13.1 ( 4.5 yrs old, range 6-19 yrs old.) Mean disease duration was 30.3 ( 22.4 months) Mean CS dose was 26.3 ( 12.6 mg. Mean TPMT activity was 18.1 ( 3.5 U/mL RBC. Complete remission (normal disease activity index and off CS) occurred in 4/9 (44.4%) patients: 3/6 (50.0%) in Group 1 and 1/3 (33.3%) in Group 2. Median time to complete remission was 3 months. Patients who achieved complete remission had a mean 6-TGN level of 224 ( 74 pmol/8x10⁸ RBC while patients who failed had a mean 6-TGN level of194 ( 59 pmol/8x10⁸ RBC, p=ns.) Significant adverse events occurred in 5/13 (38.5%) patients and were reversible. One patient with a median 6-MMP level of 6589 pmol/8x10⁸ RBC developed hepatitis but 3 patients did not with median 6-MMP levels of 6728, 6860 & 7443 pmol/8x10⁸ RBC. Two patients developed leukopenia with 6-TGN levels of 598 and 302pmol/8x10⁸RBC, respectively.

Conclusions

1. IV loading of AZA does not accelerate the efficacy of AZA.
2. AZA related adverse events are reversible.
3. There may be a trend towards complete remission with higher 6-TGN levels, but a larger trial is needed.

(Funded by GCRC grant M01-RR00240). Submitted-AGA abstracts. May 2000.

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Complementary and alternative medicine use among pediatric patients with inflammatory bowel disease

J.E. Markowitz, K. Culton, P. Mamula, R.N. Baldassano and B.L. Strom

Background and aims

Complementary and alternative medicine (CAM) use has become prominent in the United States, especially with regard to chronic illnesses. There is evidence that CAM use is particularly prevalent among patients with inflammatory bowel disease (IBD). CAM therapies are generally considered safe when used in isolation, but their effects when used with other medications are not well understood. Because patients with IBD are frequently on medications with dose-related immune mediating side effects, further research into the use of CAM is warranted. We sought to investigate the degree of CAM usage among patients with IBD, aged 6 to 16 years, with special attention to the medications they were being treated with.

Methods

A structured questionnaire was mailed to the families of patients identified as having IBD, aged 6 to 16 years, and living within the greater Philadelphia area as defined by home postal code. The questionnaire consisted of 19 items to assess demographic data, measures of disease severity and chronicity, and usage of traditional and complementary therapies for IBD over the previous 12 months. A series of mailings at predetermined intervals was used to maximize response rate.

Results

The families of patients with IBD completed 258 of 363 questionnaires (71.1%). 54% had Crohn's disease, 34% had ulcerative colitis, and 12% were unsure of their type of IBD. 50.4% of patients used CAM for IBD, as defined by the use of at least one of the following: nutritional supplements (43%), special diets (22%), alternative health systems (8%), or herbal medications (5%). CAM use did not increase if patients had been admitted to the hospital or had surgery within the previous 12 months. CAM use was higher among patients receiving immunomodulatory therapy (OR 2.1 [95% C.I. 1.2-3.7]) and biologic therapy (OR 3.7 [1.7-22.0]).

Conclusions

Over 50% of patients surveyed used CAM, most commonly nutritional supplements, for IBD. CAM use was higher among patients receiving immunomodulatory and biologic therapy, raising concern over the potential for drug-CAM interactions. Future research may need to focus on the interactions of CAM with these types of medications.

95% C>I> [.0442-.0566]

Presented at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting, San Antonio, 2002

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Laparoscopy versus open laparotomy for bowel resection in pediatric Crohn's disease

A. York, J. Markowitz, D. von Allmen and R.Baldassano

Background and aims

Laparoscopy is an increasingly utilized technique for abdominal surgery. It may offer the advantages of reduced post-operative pain and faster recovery. We sought to compare laparoscopy and open laparotomy for bowel resection in pediatric patients with Crohn's disease.

Methods

Retrospective review of patients who underwent bowel resection for Crohn's disease between March 1997 and March 2002. Subjects were divided into groups based on type of surgery (laparoscopic versus laparotomy). The primary outcome was length of post-operative hospital stay (in days). Secondary outcomes included days of parenteral pain medications, time to full diet, and duration of anesthesia. Comparisons were made using the Mann-Whitney U test for non-parametric data.

Results

16 patients underwent open laparotomy for resection during the 5-year study, while 12 patients underwent laparoscopic resection. Post-operative length of stay was shorter in the laparoscopic surgery (LAP) group (median 5.5 d., range 4-26) than the open laparotomy (OPEN) group (median 11.5 d., range 5-36) p.<0.01. Duration of parenteral pain medication usage was shorter in the LAP group (median 3 d., range 1-7) than the OPEN group (median 3 d., range 2-5) than the OPEN group (median 5 d., range 2-18), p=0.01. Time to full diet was shorter in the LAP group (median 3 d., range 2-5) than the OPEN group (median 5 d., range 3-27), p<0.01. Duration of anesthesia was shorter in the LAP group (median 166 min., range 135-388) than the OPEN group (median 185.5 min., range 148-328), p=0.04.</p/>

Conclusions

Laparoscopy offers advantages over open laparatomy for bowel resection in pediatric patients with Crohn's disease, including shorter hospital stay and anesthesia time, faster resumption of regular diet, and reduced used of parenteral pain medications.

Presented at the American Academy of Pediatrics National Conference & Exhibition, October 19-23, 2002, Boston

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Safety and efficacy of iron dextran infusions in children with inflammatory bowel disease and iron deficiency anemia

S.N. Peck, D.A. Piccoli and R.N. Baldassano

Background

Iron-deficiency anemia is a frequent complication in children with inflammatory bowel disease (IBD). Clinicians may avoid the use of intravenous iron-dextran (IVFeDx) due to the risk of anaphylaxis. Halpin et al. (JPEN 6:9-11, 1982) reported the use of single dose infusions of Imferon® (Merrell-National Laboratories) IVFeDx in 6 children with severe IBD. IVFeDx preparations are now available from many manufacturers including INFeD® (Schein Pharmaceutical, Inc.) and Dexferrum® (American Regent Laboratories, Inc.).

Aims

To determine the safety of IVFeDx in children with IBD. To determine the efficacy of single dose IVFeDx in correcting Fe deficiency anemia.

Methods

Prospective trial of Fe replacement in 28 children with IBD and Fe deficiency anemia. 51 infusions were given between 1988 and 1998. A test dose of 25mg was given prior to the IVFeDx infusion. The test dose and infusion were administered by an advanced practice nurse (APN) who observed for adverse events (AE) such as coughing, respiratory distress, facial flushing, chills, rigors and back pain. Infusion doses were calculated using the formula described by Halpin. INFeD( was used from 1988 to October 1996. Dexferrum® was used from October 1996 to January 1997, at which time INFeD® was restarted.

Results

In 51 infusions of IVFeDx, 9 AE to the test dose terminated therapy. There were 4 AE during 44 (9%) INFeD® infusions and 5AE during 7 (74%) Dexferrum® infusions. All AE responded to IV Benadryl (1mg/kg) and IV fluids. 11 patients received multiple IVFeDX with INFeD® without AE. 3 patients who had AE to Dexferrum® subsequently received INFeD® without adverse sequelae. Hemoglobin pre-infusion was 9.4 ± 1.4 g/dl and post-infusion was 12.2 ± 1.5 g/dl (p Conclusions Infusion of INFeD® is a safe and effective therapy. Clinicians must recognize that the rate of AE may vary widely depending on FeDx formulation. NASPGN Abstract. J. of Pediatric Gastroenterology and Nutrition. May 1999.

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A six or a twelve month, randomized, double-masked, placebo controlled, three arm study to evaluate the safety and efficacy of ISIS 2302 in steroid-dependent Crohn's disease

This trial is being sponsored by Isis Pharmaceuticals, Inc. Carlsbad, CA USA

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract. The prevalence of Crohn's disease in the US has been estimated at 24 to 40 cases per 100,000 population and the incidence appears to be increasing, particularly in western Europe and North America. The underlying cause of the disease is unknown. Predisposing genetic factors appear to interact with exogenous triggers and modifying factors to result in a spontaneously relapsing and remitting inflammatory process in which tissue injury is mediated by the immune system.

Manufactured by Isis Pharmaceuticals, Inc., ISIS 2302 is a chemically-synthesized antisense oligonucleotide designed to bind, by complementary base-pairing, to the 3' untranslated region of human mRNA for intercellular adhesion molecule-1 (ICAM-1) and thereby inhibits synthesis of the protein. Numerous studies have demonstrated an increase in ICAM-1 expression within tissues obtained from patients suffering from disease with an inflammatory component. Examples of disease in which increased ICAM-1 expression has been documented include graft rejection, rheumatoid arthritis, inflammatory bowel disease, acute and chronic hepatitis, multiple sclerosis, psoriasis and contact dermatitis.

The present trial is being conducted to definitively assess the efficacy and tolerability of repeated courses of ISIS 2302 in steroid-dependent patients with Crohn's disease.

This clinical trial was granted full approval by the Institutional Review Board for the Protection of Human Subjects at The Children's Hospital of Philadelphia but enrollment has been closed to new study participants by Isis Pharmaceuticals, Inc.

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Safety and pharmacokinetics of CDP571 in pediatric patients with Crohn's disease

P. Mamula1, J. Patel2, R.N. Baldassano, and Pediatric Inflammatory Bowel Disease Consortium

1The Children's Hospital of Philadelphia 2Celltech R & D, Slough, United Kingdom

Aim

This is the first trial of CDP571, a humanized monoclonal antibody against TNF- á in pediatric patients with Crohn's disease (CD). The primary aim of this study was to examine the plasma profile and safety of a single intravenous (IV) dose of CDP571 in pediatric patients with CD. The secondary aim was to obtain a preliminary assessment of efficacy.

Methods

Pediatric patients with active CD defined by Pediatric Crohn's Disease Activity Index (PCDAI) score >20 points were recruited to this multicenter, open-label study. Patients received a single IV dose of CDP571 (10mg/kg) over 2 hours, and were followed over a period of 12 weeks. Patients were stratified according to their age in two groups: 6-13 years or 14-17 years.

Results

A total of 20 patients were enrolled, nine in the 6-13 years group and 11 in the 14-17 years group. The median PCDAI at the time of enrollment was 37.5 (6-13y) and 32.5 (14-17y). Eight patients were withdrawn from the study due to disease progression or non-improvement. CDP571 plasma concentrations were highest on the day of infusion, decreased at each subsequent visit thereafter, and were similar to those observed in adults in previous studies. CDP571 was well tolerated. Fourteen patients experienced a total of 59 adverse events (AEs) during the study, the majority of which were mild or moderate in intensity. One patient experienced an infusion reaction manifested by skin rash, dizziness, and shortness of breath, which resolved with acetaminophen and anti-histamine treatment. The most frequently reported AEs were sore throat (n=3), pyrexia (n=2), and dermatitis (n=2). Six patients experienced seven serious adverse events, which were exacerbation of CD and/or intercurrent infection, none considered related to the study treatment. By week 2, seven patients (78%) in the 6-13 year age group, and 6 patients (55%) in the 14-17 year age group had responded to treatment (reduction in PCDAI score >10 points). Overall, 6 patients (30%) were in remission (PCDAI

Conclusions

The anti-TNF-á antibody CDP571 (10 mg/kg) was well tolerated among pediatric patients with CD. Plasma concentration profile was similar to that in adults. Preliminary efficacy data are encouraging and warrant further investigation.

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