Effect of Increlex® on Children With Crohn Disease
| Status: | Terminated |
|---|---|
| Conditions: | Gastrointestinal, Crohns Disease |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 5 - 15 |
| Updated: | 4/17/2018 |
| Start Date: | October 2008 |
| End Date: | May 2010 |
Patients with Crohn disease often have poor weight gain and short stature, yet the etiology
of the poor growth is not well defined. Studies in chronically ill patients who do not have
Crohn disease have suggested that inflammation causes IGF-1 deficiency due to inadequate
IGF-1 generation. Previous studies of GH use in Crohn patients have demonstrated improvement
in linear growth, weight and bone mineralization. However, GH can cause glucose intolerance
in chronically ill children, particularly those who require treatment with corticosteroids.
Recently the FDA has approved recombinant IGF-1 (rhIGF) for treatment of IGF-1 deficient
short stature. This medication has not been studied in Crohn disease. The purpose of this
study is to test the hypothesis that poor growth in Crohn disease is associated abnormal
IGF-1 generation which leads to poor linear growth, decreased weight and osteoporosis and
that replacement of IGF-1 with rhIGF will correct growth and improve bone density. To test
our hypothesis we will recruit 20 patients with Crohn disease from our pediatric
gastroenterology practice. Each will have been previously diagnosed with Crohn disease for a
minimum of one year and will be studied at baseline and six month intervals for one year
while on treatment with Increlex.
of the poor growth is not well defined. Studies in chronically ill patients who do not have
Crohn disease have suggested that inflammation causes IGF-1 deficiency due to inadequate
IGF-1 generation. Previous studies of GH use in Crohn patients have demonstrated improvement
in linear growth, weight and bone mineralization. However, GH can cause glucose intolerance
in chronically ill children, particularly those who require treatment with corticosteroids.
Recently the FDA has approved recombinant IGF-1 (rhIGF) for treatment of IGF-1 deficient
short stature. This medication has not been studied in Crohn disease. The purpose of this
study is to test the hypothesis that poor growth in Crohn disease is associated abnormal
IGF-1 generation which leads to poor linear growth, decreased weight and osteoporosis and
that replacement of IGF-1 with rhIGF will correct growth and improve bone density. To test
our hypothesis we will recruit 20 patients with Crohn disease from our pediatric
gastroenterology practice. Each will have been previously diagnosed with Crohn disease for a
minimum of one year and will be studied at baseline and six month intervals for one year
while on treatment with Increlex.
1. Subjects. We will recruit 20 established Crohn patients from our gastroenterology (GI)
referral practice at Nationwide Children's Hospital in Columbus, Ohio. Each will have
previously undergone a complete diagnostic workup and classification of disease.
Information on disease activity, location and behavior are routinely recorded at each
follow up visit. Medical records will be assessed for this information. These patients
will be followed every three months. All of these patients will be assigned to receive
rhIGF therapy for 12 months and results will be compared to medical record data. We will
recruit 10 per year.
2. Assessment of growth and IGF-1 generation. Each subject will undergo IGF-1 generation
testing using standard published "high-dose: protocol and interpreted according to
guidelines of Blum. Briefly, GH will be given as a one time per day subcutaneous
injection in a dose of 0.05mg/kg/dy. IGF-1 will be measured at baseline and again after
7 days. Inadequate generation will be interpreted by an IGF-1 increase < 15 ng/dl after
7 days of GH. We will also measure baseline random GH and IGFBP-3 levels. The IGF-1, GH
and IGFBP-3 levels will be measured by Esoterix laboratory (Calabasas Hills, CA). IGF-1
levels will also be measured every six months and with disease exacerbation. All
patients will have a single radiological film of the left hand and wrist to determine
bone age by Greulich and Pyle standards, and routine examination by the PI to determine
Tanner staging.
3. Anthropometric measures. Patients will be seen every three months. At every visit, we
will evaluate linear growth using a calibrated stadiometer and weight with a
standardized scale. Longitudinal data will be used to calculate height and weight
velocity. Height velocity will be annualized for each visit compared to baseline data.
All growth information, including velocity will be converted to standard deviation
scores (SDS, Z score) using GenenCalc (Genentech, San Francisco, CA).
4. Nutrition. To assess for low nutritional intake as the cause for poor growth (and low
IGF-1 levels), each patient will complete a 3 day food journal at every visit and
results will be assessed by Nutrition Pro software. We will evaluate our findings in
both pubertal and prepubertal children. For this reason we will carefully measure Tanner
stage as breast in girls and testicular volume in boys. We will measure testosterone
levels in boys and estradiol in girls (Esoterix). Sex steroid levels will be correlated
with Tanner staging and tempo of pubertal progression.
5. Treatment with rhIGF (Increlex, Tercica). Patients will be followed as above for 12
months while on Increlex therapy. Increlex (rhIGF) will be administered per the
following schema: First 2 weeks: 40 mcg/kg BID; Weeks 3 and 4: 80 mcg/kg BID; Subsequent
weeks: 120 mcg/kg BID. Each parent and patient will be carefully trained in injection
technique by the same skilled personnel. Compliance will be assessed by having subjects
return empty vials to the study site.
6. Bone mineral content and bone turnover. All subjects will undergo DXA scan (Lunar
Prodigy) at baseline and every six months. Measurements will be compared to age- and
gender- matched normals and converted to Z scores (www.bcm.edu/bodycomplab). To
determine bone turnover, blood and urine will be collected at baseline and every six
months. These labs will be run by Esoterix according to their methods: N-Telopeptides
(reverse transcriptase PCR, urine), osteocalcin (double antibody RIA, blood), bone
specific alkaline phosphatase activity (ICMA, blood), and deoxypyridinoline (ELISA,
urine). Although the typical patient treated with GH demonstrates initial bone loss
during the first six months, our group has documented improvement in bone mineral
content within six months of starting GH therapy.
7. Cytokines. We will measure the cytokines TNF-α, IL-1, and IL-6 at the initiation of the
study, at 6 months and 12 months. This will better help us understand the role of
cytokines on disease course, activity, and the growth hormone axis.
8. Biomarkers for rhIGF-1 dosing efficacy. We will draw BL, 6 mos and 12 mos levels of
IGF-1, IGFBP3 and ALS levels. The baseline level will be collected prior to the 1st dose
of Increlex. At six months patients will be instructed to take their Increlex the
morning of their visit and the sample will be drawn within 2 hours of dosing which will
represent peak biomarker levels. The 12 month level will be obtained in the morning the
day after the patient completes his/her final dose and will represent a trough level.
9. Measures of Disease Activity. At each protein turnover measure we will ask subjects to
bring stool samples which will be evaluated for fecal calprotectin. We will complete the
Pediatric Crohn Disease Activity Index (PCDAI), a reliable and valid index for disease
activity in clinical research. Subjects will complete the IMPACT-III, a valid and
reliable measure of quality of life in pediatric Crohn disease.
referral practice at Nationwide Children's Hospital in Columbus, Ohio. Each will have
previously undergone a complete diagnostic workup and classification of disease.
Information on disease activity, location and behavior are routinely recorded at each
follow up visit. Medical records will be assessed for this information. These patients
will be followed every three months. All of these patients will be assigned to receive
rhIGF therapy for 12 months and results will be compared to medical record data. We will
recruit 10 per year.
2. Assessment of growth and IGF-1 generation. Each subject will undergo IGF-1 generation
testing using standard published "high-dose: protocol and interpreted according to
guidelines of Blum. Briefly, GH will be given as a one time per day subcutaneous
injection in a dose of 0.05mg/kg/dy. IGF-1 will be measured at baseline and again after
7 days. Inadequate generation will be interpreted by an IGF-1 increase < 15 ng/dl after
7 days of GH. We will also measure baseline random GH and IGFBP-3 levels. The IGF-1, GH
and IGFBP-3 levels will be measured by Esoterix laboratory (Calabasas Hills, CA). IGF-1
levels will also be measured every six months and with disease exacerbation. All
patients will have a single radiological film of the left hand and wrist to determine
bone age by Greulich and Pyle standards, and routine examination by the PI to determine
Tanner staging.
3. Anthropometric measures. Patients will be seen every three months. At every visit, we
will evaluate linear growth using a calibrated stadiometer and weight with a
standardized scale. Longitudinal data will be used to calculate height and weight
velocity. Height velocity will be annualized for each visit compared to baseline data.
All growth information, including velocity will be converted to standard deviation
scores (SDS, Z score) using GenenCalc (Genentech, San Francisco, CA).
4. Nutrition. To assess for low nutritional intake as the cause for poor growth (and low
IGF-1 levels), each patient will complete a 3 day food journal at every visit and
results will be assessed by Nutrition Pro software. We will evaluate our findings in
both pubertal and prepubertal children. For this reason we will carefully measure Tanner
stage as breast in girls and testicular volume in boys. We will measure testosterone
levels in boys and estradiol in girls (Esoterix). Sex steroid levels will be correlated
with Tanner staging and tempo of pubertal progression.
5. Treatment with rhIGF (Increlex, Tercica). Patients will be followed as above for 12
months while on Increlex therapy. Increlex (rhIGF) will be administered per the
following schema: First 2 weeks: 40 mcg/kg BID; Weeks 3 and 4: 80 mcg/kg BID; Subsequent
weeks: 120 mcg/kg BID. Each parent and patient will be carefully trained in injection
technique by the same skilled personnel. Compliance will be assessed by having subjects
return empty vials to the study site.
6. Bone mineral content and bone turnover. All subjects will undergo DXA scan (Lunar
Prodigy) at baseline and every six months. Measurements will be compared to age- and
gender- matched normals and converted to Z scores (www.bcm.edu/bodycomplab). To
determine bone turnover, blood and urine will be collected at baseline and every six
months. These labs will be run by Esoterix according to their methods: N-Telopeptides
(reverse transcriptase PCR, urine), osteocalcin (double antibody RIA, blood), bone
specific alkaline phosphatase activity (ICMA, blood), and deoxypyridinoline (ELISA,
urine). Although the typical patient treated with GH demonstrates initial bone loss
during the first six months, our group has documented improvement in bone mineral
content within six months of starting GH therapy.
7. Cytokines. We will measure the cytokines TNF-α, IL-1, and IL-6 at the initiation of the
study, at 6 months and 12 months. This will better help us understand the role of
cytokines on disease course, activity, and the growth hormone axis.
8. Biomarkers for rhIGF-1 dosing efficacy. We will draw BL, 6 mos and 12 mos levels of
IGF-1, IGFBP3 and ALS levels. The baseline level will be collected prior to the 1st dose
of Increlex. At six months patients will be instructed to take their Increlex the
morning of their visit and the sample will be drawn within 2 hours of dosing which will
represent peak biomarker levels. The 12 month level will be obtained in the morning the
day after the patient completes his/her final dose and will represent a trough level.
9. Measures of Disease Activity. At each protein turnover measure we will ask subjects to
bring stool samples which will be evaluated for fecal calprotectin. We will complete the
Pediatric Crohn Disease Activity Index (PCDAI), a reliable and valid index for disease
activity in clinical research. Subjects will complete the IMPACT-III, a valid and
reliable measure of quality of life in pediatric Crohn disease.
Inclusion Criteria:
- Moderate to severe Crohn Disease (PCDAI > 30)
- Chronological age 5-15 years old
- Tanner 1 - 3
- Bone age less than or equal to 13 in females and 14 in males
Exclusion Criteria:
- Identified infectious etiology
- Immunological disorder (excluding Crohn disease)
- Associated severe concomitant chronic illnesses (CF, liver failure, etc)
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