Crohn's Disease
Conditions
Keywords
Pediatric Crohn's disease, Pediatric, Crohn's Disease
Brief summary
The purpose of this study is to determine whether taking a growth hormone (GH) drug called somatropin causes the intestine of a person with Crohn's Disease (CD) to heal faster when compared to a person with Crohn's Disease that does not receive growth hormone drug.
Detailed description
The optimal treatment goals in childhood CD include: 1) clinical remission in conjunction with mucosal healing and 2) restoration of normal growth and development. Current therapy in most cases includes induction of remission with corticosteroids followed by maintenance of remission with 6-mercaptopurine (6-MP) or mesalamine. With this approach, the goals of achieving mucosal healing with normalization of growth are not achieved in a significant number of children. GH therapy is now used in several chronic childhood diseases which are complicated by growth failure despite adequate GH secretion. These include chronic renal failure (CRF), juvenile rheumatoid arthritis (JRA), and Turner's syndrome. However, despite a comparable frequency and magnitude of permanent growth failure, the efficacy of GH therapy in this respect has not yet been determined in a controlled trial for CD. Moreover, whether GH therapy may also directly reduce disease activity and promote intestinal healing is not known. This represents a significant clinically unmet need in this patient population. Therefore, new therapeutic approaches are needed to both improve final adult height and enhance intestinal mucosal healing in children with CD. The primary objective of this study is to determine the effect of growth hormone (GH) therapy upon colon mucosal healing in a 12 week randomized trial in children with Crohn's Disease (CD). Children with active CD will be randomized to GH + prednisone (GP) or prednisone alone (P) for a 12 week period. This study also involves a 52 week extension phase where all participants that meet eligibility will be given the opportunity to take or continue taking growth hormone for 52 weeks.
Interventions
DRUGgrowth hormone
Nutropin AQ 0.075mg/kg/day subcutaneously daily
DRUGcortecosteroid
As prescribed by the referring gastroenterologist
Sponsors
Genentech, Inc.
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to provide written informed consent * Age ≥ 5 years. * Diagnosis of Crohn's disease (CD) with ileo-colonic involvement as determined by standard clinical, radiological, and pathological criteria. * Moderate to severely active CD as defined by a PCDAI (Pediatric Crohn's Disease Activity Index) ≥ 30. * Currently taking Prednisone or Budesonide at starting dose (not tapering) * May continue stable doses of AZA/6-MP, methotrexate, and/or mesalamine at entry. * For the 52 week extension, baseline bone age ≤ 12 years for girls and ≤ 13 years for boys. * For the 52 week extension phase, remission or mild Crohn's disease as determined by a PCDAI \< 30.
Exclusion criteria
* Acute critical illness * Active neoplasia * Diabetes mellitus * History of intracranial lesion and/or neoplasia * Severe disease requiring hospitalization for treatment * Current therapy with infliximab as this may independently rapidly reduce clinical disease activity and promote mucosal healing * Use of prednisone or budesonide and in tapering phase * Family history of colorectal cancer before age 50 * Personal or familial history of familial polyposis syndrome * Pregnancy (positive pregnancy test) prior to randomization * Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated * Participation in another simultaneous medical investigation or trial other than the Pediatric IBD (Inflammatory Bowel Disease) registry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Crohn's Disease Histologic Index of Severity (CDHIS) | Baseline and 12 weeks | The CDHIS was developed and validated in order to determine the effect of therapies upon histologic disease activity in Crohn's Disease. It has been used to assess mucosal healing in response to infliximab and 6-MP/AZA.It contains eight items which reflect epithelial injury, mucosal inflammation, and the extent of involvement. Scores range from 0-16, with patients with moderate to severely active CD typically having scores of 6-12. It was computed by a GI pathologist. The higher the score indicates worsening of disease, the lowest score is 0 and highest possible is 16 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IMPACT III Score | Baseline, 12 weeks, 24 weeks | Health-related quality of life (QOL)was assessed using the IMPACT 111 questionnnaire. It is a self-administered 35 item questionnaire which typically takes 10-15 minutes to complete. Scores range from 0-350, with higher scores reflecting better perceived quality of life. |
| Pediatric Crohn's Disease Activity Index (PCDAI) | Baseline, 12 and 24 weeks | The PCDAI is a previously validated measure of clinical disease activity for children with CD. It contains three self-report items which reflect patient abdominal pain, diarrhea, and general well being; three laboratory values; height and weight velocity; and three physical examination parameters reflecting abdominal tenderness, perirectal disease, and extra-intestinal manifestations. Scores may range from 0-100. Remission is defined as 0-10, mild disease as 10-30, and moderate to severe disease as greater than 30. |
| Total Corticosteroid Use | 12 weeks | The total corticosteroid use over 12 weeks between groups, using the unpaired t test. |
| Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Baseline, 12 weeks, 24 weeks | Elevated serum IGF-1 levels have been implicated in the development of colorectal cancer, both in the general population and in patients with an excess of growth hormone production. The serum IGF-1 levels were monitored to maintain them in the physiologic range during growth hormone therapy to reduce the risk of tumorigenesis. The levels are reported as a z score, a statistical way of standardizing data. The standard deviation is the unit of measurement of the z-score. Each z score corresponds to a point in a normal distribution, describing how much a point deviates from a mean. |
| Height Velocity | Baseline, week 12, 24 and 48 | Height velocity was computed every 12 weeks up to week 64 and then yearly during the Maintenance study. Since 40 to 80% of children with Crohn's disease have significant growth failure at diagnosis, height velocity is used to track for changes in height. It is calculated by measuring height at two points of time and then dividing the change by the amount of time. |
| Fecal Calprotectin | At 24 and 64 weeks | Fecal calprotectin is a previously validated stool marker of intestinal inflammation in Crohn's Disease. |
| Crohn's Disease Endoscopic Index of Severity (CDEIS) | Baseline and 12 weeks | Measure of mucosal disease at baseline and week 12 obtained during colonoscopy. The CDEIS score generally ranges from 0-30. A higher score indicates more severe mucosal inflammation. |
Countries
United States
Participant flow
Recruitment details
98 subjects were assessed for eligibility, 76 did not meet inclusion criteria, 21 refused to participate
Pre-assignment details
21 subjects enrolled, one withdrew consent prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Growth Hormone Plus Corticosteroid (CTX) Growth Hormone (nutropin AQ 0.075 mg/kg/day subcutaneously daily) | 10 |
| Corticosteroid (CTX) Subjects took corticosteroid as prescribed by their physician | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Growth Hormone Plus Corticosteroid (CTX) | Corticosteroid (CTX) | Total |
|---|---|---|---|
| Age, Continuous | 12 years STANDARD_DEVIATION 3 | 13 years STANDARD_DEVIATION 3 | 13 years STANDARD_DEVIATION 3 |
| Age, Customized <=18 years | 10 participants | 10 participants | 20 participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 17 / 17 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 | 2 / 17 |
Outcome results
Primary
Crohn's Disease Histologic Index of Severity (CDHIS)
The CDHIS was developed and validated in order to determine the effect of therapies upon histologic disease activity in Crohn's Disease. It has been used to assess mucosal healing in response to infliximab and 6-MP/AZA.It contains eight items which reflect epithelial injury, mucosal inflammation, and the extent of involvement. Scores range from 0-16, with patients with moderate to severely active CD typically having scores of 6-12. It was computed by a GI pathologist. The higher the score indicates worsening of disease, the lowest score is 0 and highest possible is 16
Time frame: Baseline and 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Crohn's Disease Histologic Index of Severity (CDHIS) | Baseline | 7 scores on a scale |
| Growth Hormone Plus Corticosteroid (CTX) | Crohn's Disease Histologic Index of Severity (CDHIS) | Week 12 | 6 scores on a scale |
| Corticosteroid (CTX) | Crohn's Disease Histologic Index of Severity (CDHIS) | Baseline | 8 scores on a scale |
| Corticosteroid (CTX) | Crohn's Disease Histologic Index of Severity (CDHIS) | Week 12 | 8 scores on a scale |
Secondary
Crohn's Disease Endoscopic Index of Severity (CDEIS)
Measure of mucosal disease at baseline and week 12 obtained during colonoscopy. The CDEIS score generally ranges from 0-30. A higher score indicates more severe mucosal inflammation.
Time frame: Baseline and 12 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Crohn's Disease Endoscopic Index of Severity (CDEIS) | Baseline | 9 Scores on a scale |
| Growth Hormone Plus Corticosteroid (CTX) | Crohn's Disease Endoscopic Index of Severity (CDEIS) | Week 12 | 3 Scores on a scale |
| Corticosteroid (CTX) | Crohn's Disease Endoscopic Index of Severity (CDEIS) | Baseline | 8 Scores on a scale |
| Corticosteroid (CTX) | Crohn's Disease Endoscopic Index of Severity (CDEIS) | Week 12 | 6 Scores on a scale |
Secondary
Fecal Calprotectin
Fecal calprotectin is a previously validated stool marker of intestinal inflammation in Crohn's Disease.
Time frame: At 24 and 64 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Fecal Calprotectin | Baseline | 863 micrograms per gram (microg/g) |
| Growth Hormone Plus Corticosteroid (CTX) | Fecal Calprotectin | Week 12 | 868 micrograms per gram (microg/g) |
| Corticosteroid (CTX) | Fecal Calprotectin | Baseline | 904 micrograms per gram (microg/g) |
| Corticosteroid (CTX) | Fecal Calprotectin | Week 12 | 656 micrograms per gram (microg/g) |
Secondary
Height Velocity
Height velocity was computed every 12 weeks up to week 64 and then yearly during the Maintenance study. Since 40 to 80% of children with Crohn's disease have significant growth failure at diagnosis, height velocity is used to track for changes in height. It is calculated by measuring height at two points of time and then dividing the change by the amount of time.
Time frame: Baseline, week 12, 24 and 48
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Height Velocity | Baseline | 5 cm/year | Standard Error 1 |
| Growth Hormone Plus Corticosteroid (CTX) | Height Velocity | Week 12 | 8 cm/year | Standard Error 1 |
| Growth Hormone Plus Corticosteroid (CTX) | Height Velocity | Week 24 | 9 cm/year | Standard Error 1 |
| Corticosteroid (CTX) | Height Velocity | Baseline | 3 cm/year | Standard Error 1 |
| Corticosteroid (CTX) | Height Velocity | Week 12 | 3 cm/year | Standard Error 1 |
| Corticosteroid (CTX) | Height Velocity | Week 24 | 7 cm/year | Standard Error 1 |
Secondary
IMPACT III Score
Health-related quality of life (QOL)was assessed using the IMPACT 111 questionnnaire. It is a self-administered 35 item questionnaire which typically takes 10-15 minutes to complete. Scores range from 0-350, with higher scores reflecting better perceived quality of life.
Time frame: Baseline, 12 weeks, 24 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | IMPACT III Score | Baseline | 134 Scores on a scale |
| Growth Hormone Plus Corticosteroid (CTX) | IMPACT III Score | Week 12 | 143 Scores on a scale |
| Corticosteroid (CTX) | IMPACT III Score | Baseline | 132 Scores on a scale |
| Corticosteroid (CTX) | IMPACT III Score | Week 12 | 136 Scores on a scale |
Secondary
Pediatric Crohn's Disease Activity Index (PCDAI)
The PCDAI is a previously validated measure of clinical disease activity for children with CD. It contains three self-report items which reflect patient abdominal pain, diarrhea, and general well being; three laboratory values; height and weight velocity; and three physical examination parameters reflecting abdominal tenderness, perirectal disease, and extra-intestinal manifestations. Scores may range from 0-100. Remission is defined as 0-10, mild disease as 10-30, and moderate to severe disease as greater than 30.
Time frame: Baseline, 12 and 24 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Baseline | 32 Scores on a scale |
| Growth Hormone Plus Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Week 12 | 8 Scores on a scale |
| Growth Hormone Plus Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Week 24 | 9 Scores on a scale |
| Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Baseline | 33 Scores on a scale |
| Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Week 12 | 22 Scores on a scale |
| Corticosteroid (CTX) | Pediatric Crohn's Disease Activity Index (PCDAI) | Week 24 | 6 Scores on a scale |
p-value: 0.02Mixed Models Analysis
Secondary
Serum IGF-1 (Insulin-like Growth Factor 1)z Score
Elevated serum IGF-1 levels have been implicated in the development of colorectal cancer, both in the general population and in patients with an excess of growth hormone production. The serum IGF-1 levels were monitored to maintain them in the physiologic range during growth hormone therapy to reduce the risk of tumorigenesis. The levels are reported as a z score, a statistical way of standardizing data. The standard deviation is the unit of measurement of the z-score. Each z score corresponds to a point in a normal distribution, describing how much a point deviates from a mean.
Time frame: Baseline, 12 weeks, 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Baseline | -0.4 Z score | Standard Error 0.6 |
| Growth Hormone Plus Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Week 12 | 1.8 Z score | Standard Error 1 |
| Growth Hormone Plus Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Week 24 | 3.3 Z score | Standard Error 1.5 |
| Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Baseline | -0.7 Z score | Standard Error 0.3 |
| Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Week 12 | -1 Z score | Standard Error 0.3 |
| Corticosteroid (CTX) | Serum IGF-1 (Insulin-like Growth Factor 1)z Score | Week 24 | 3.8 Z score | Standard Error 1 |
Secondary
Total Corticosteroid Use
The total corticosteroid use over 12 weeks between groups, using the unpaired t test.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Growth Hormone Plus Corticosteroid (CTX) | Total Corticosteroid Use | prednisone | 22 mg | Standard Error 8 |
| Growth Hormone Plus Corticosteroid (CTX) | Total Corticosteroid Use | budesonide | 7 mg | Standard Error 4 |
| Corticosteroid (CTX) | Total Corticosteroid Use | prednisone | 28 mg | Standard Error 10 |
| Corticosteroid (CTX) | Total Corticosteroid Use | budesonide | 8 mg | Standard Error 3 |