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Trial registered on ANZCTR


Registration number
ACTRN12612000129886
Ethics application status
Approved
Date submitted
11/11/2010
Date registered
30/01/2012
Date last updated
30/01/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Atorvastatin for treatment of acute inflammation in newly diagnosed children with Crohn’s disease
Scientific title
Randomised controlled trial of eight weeks treatment with Atorvastatin versus conventional treatment (Prednisolone) as an agent of induction of disease remission measured by the paediatric disease activity index (PCDAI) in children with newly diagnosed crohn’s disease aged 8-17 years
Secondary ID [1] 279813 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Crohn's disease 258636 0
Condition category
Condition code
Oral and Gastrointestinal 258777 258777 0 0
Crohn's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Oral Atorvastatin (less than 50 kg = 20 mg daily; 50 kg and greater = 40 mg daily) for eight weeks with no dose adjustment.
Intervention code [1] 257594 0
Treatment: Drugs
Comparator / control treatment
Comparator: Conventional treatment starting with oral Prednisolone at diagnosis (2mg/kg/day with maximum dose of 60 mg daily) to be weaned over a 6-8 weeks period as clinically indicated. Weaning of Prednisolone is as per clinical disease status. The atorvastatin group will not receive Prednisolone.
Control group
Active

Outcomes
Primary outcome [1] 259641 0
Primary outcome: Percentage of children with Paediatric Crohn's Disease Activity Index (PCDAI) < 30 and reduction of at 6 weeks at least 10 points from baseline at 8 weeks. PCDAI < 30 is generally classified as moderate disease.
Timepoint [1] 259641 0
0, 2, 4, 6, 8 weeks
Secondary outcome [1] 266303 0
-Markers of inflammation including inflammatory cytokines, faecal calprotectin over the 8 weeks.
Markers of inflammation all with blood samples except calprotectin which is assayed using a stool sample
- Blood analysis and stools
Timepoint [1] 266303 0
0, 2, 4, 6, 8 weeks
Secondary outcome [2] 294022 0
-Quality of life using the IMPACT-III (validated paediatric inflammatory bowel disease quality of life score) over the 8 weeks.
Timepoint [2] 294022 0
0, 2, 4, 6, 8 weeks
Secondary outcome [3] 294023 0
Markers of bone formation and resorption (bone alkaline phosphatase and CTX) over the 8 weeks
Timepoint [3] 294023 0
0, 2, 8 weeks
Secondary outcome [4] 294024 0
Linear growth and pubertal development over the 8 weeks
- Height and weight measurements
- Pubertal assessment by clinician assessment according to method of Tanner and patient self assessment
Timepoint [4] 294024 0
Height at 0, 2, 4, 6, 8 weeks and pubertal staging at 0 and 8 weeks
Secondary outcome [5] 294025 0
Markers of GH secretion (IGF1, IGFBP3)
- Blood analysis
Timepoint [5] 294025 0
0, 2, 8 weeks
Secondary outcome [6] 294026 0
Creatine kinase
- Blood analysis
Timepoint [6] 294026 0
0, 2, 4, 6, 8 weeks
Secondary outcome [7] 294027 0
Lipid profile
- Blood analysis
Timepoint [7] 294027 0
0, 4, 8 weeks

Eligibility
Key inclusion criteria
-Male or females aged 8 to 17 years
-Diagnosis of crohn’s diease confirmed on clinical,radiological,endoscopic and/or histological criteria and yet to receive treatment
Minimum age
8 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Age <8 or > than 17
- Previously treated CD
- Newly diagnosed CD but already commenced any form of therapy for induction of remission including any form of steroid therapy.
- Any underlying chromosomal disorders eg Down’s syndrome, Turner’s syndrome
-Any underlying autoimmune diagnosis eg juvenile arthritis, connective tissue disease, coeliac disease, type 1 diabetes mellitus, addison’s disease, hypothyroidism, hyperthyroidism, polyglandular endocrinopathy.
- Primary bone disorder eg osteogenesis imperfecta
- A secondary chronic medical diagnosis that may have an impact on linear growth and bone health
- Previous adverse reaction to statins
- Current pregnancy or sexually active and not using a medically acceptable form of birth control. (All girls who are menarchal or > 14 years of age will need to undego a pregnancy test before being eligible for the study).
- History of clinically significant organic or psychiatric disease or findings on physical examination, which in the opinion of the Investigator would prevent the patient from completing the study.
- Ongoing use of oral corticosteroid for a different medical condition prior to diagnosis
- Ongoing use of immunomodulators eg azathioprine, methotrexate; biologics eg anti TNF therapy for a different medical condition (to exclude patients with another known chronic inflammatory condition)
- Ongoing use of growth hormone, sex steroid, thyroxine and/or steroid replacement (hydrocortisone, prednisolone, dexamathasone) for an underlying endocrine diagnosis (to exclude conditions like growth hormone deficiency, hypopituitarism)
- Ongoing use of cyclosporine, fibrates, CYP3A4 inhibitors, itraconazole, HIV protease inhibitors (concurrent medication absolutely contraindicated with atovarstatin).
- AST or ALT > 2 x upper limit of normal from investigations performed in the last 4 weeks.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Primary clinicians will alert the research team of patients with suspected crohn’s disease either when first seen in the outpatient clinic or when attending the hospital for endoscopy. The research team will discuss the study with the patient and family at that time and provide study information sheets. Once the diagnosis is confirmed and after at least 72 hours has lapsed from the time the study was discussed with the patient/family, the research team will approach the patient/family of their willingness to participate in the study.
Randomization will be performed by members of the Clinical Epidemology and Biostatistics Unit (CEBU),Royal Children’s Hospital Melbourne and are not involved in the study directly. Members of CEBU will also not be involved in recruiting patients to the study. Allocation concealment is performed using a web based computer generated randomization list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computerised sequence generation will be used for randomization. Stratification will be performed for disease severity based on PCDAI (Severe: PCDAI > 40; moderate PCDAI equals or less than 40).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 258276 0
Hospital
Name [1] 258276 0
Royal Children's Hospital
Country [1] 258276 0
Australia
Primary sponsor type
Hospital
Name
Royal Children's Hospital
Address
Flemington Road, Parkville,
Melbourne,
3052
VIC
Country
Australia
Secondary sponsor category [1] 257230 0
None
Name [1] 257230 0
Address [1] 257230 0
Country [1] 257230 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260038 0
Human Research Ethics Committee (HREC 31031A)
Ethics committee address [1] 260038 0
Royal Children's Hospital
Flemington Road
Parkville
3052
VIC
Ethics committee country [1] 260038 0
Australia
Date submitted for ethics approval [1] 260038 0
01/02/2011
Approval date [1] 260038 0
30/05/2011
Ethics approval number [1] 260038 0

Summary
Brief summary
Crohn’s disease is a lifelong condition with symptoms of abdominal pain, diarrhoea, lethargy, vomiting due to an underlying inflammation of the gastrointestinal tract. This is thought to be mediated via elevation of compounds called inflammatory cytokines. There are other health effects not localised to the gut like growth problems and poor bone health (osteoporosis) which may be a consequence of the underlying disease process itself or the use of medication to treat the disease.

Often potent steroid medication like Prednisolone are used to control the disease. Whilst this is an effective form of treatment, steroids can have a range of side effects. Growth failure leading to significant short stature, poor bone health with cases of fractures with little or no injury and fracture in the spine have been reported in these groups of children. These of course lead to significant morbidity in the growing years.

Statins like atorvastatin have been shown to have a potent effect in lowering cholesterol levels and preventing heart disease from large scale adult studies. Statins have also been used to treat paediatric patients with inherited reason for their high cholesterol. There is some suggestion that statins may have an effect directly at the inflammatory process independent of the level of lowering of cholesterol level. It is thought that statins can lower the level of inflammatory cytokines. As inflammatory cytokine levels are elevated in crohn’s disease and if statins may lower inflammatory cytokine levels, there maybe a role of statins in the treatment of crohn’s disease in children. There are already animal studies and some adult trials that show that statins may help in crohn’s disease and other inflammatory disease like arthritis.

In our study, we aim to recruit 60 children with newly diagnosed crohn’s disease (30 in each group) aged between 8-17 years, randomly assigned to either receive atorvastatin or Prednisolone (which is the usual form of treatment in our centre).The study is for a period of 8 weeks. The study aims to show that atorvastatin is no worse than Prednisolone as a medication for induction of remission in reducing actue inflammation in newly diagnosed children with crohn's disease.

Patients will attend the study follow-up at baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks after diagnosis. At all of those time points, blood tests will be obtained to assess the inflammatory process, growth factors and bone markers. Faeces will be collected to look at the level of inflammation in the gut. At all those time points, the paediatric crohn’s disease activity index will be obtained and also a quality of life score specific for this population of children. IMPACT-III. At baseline and 8 weeks, an assessment of the child’s state of development (puberty) will also be done. Children will also be asked to self assess their development (puberty) based on validated forms.

We hypothesis that statin has an effect on the inflammatory process and will be no worse compared with Prednisolone treatment.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 31903 0
Address 31903 0
Country 31903 0
Phone 31903 0
Fax 31903 0
Email 31903 0
Contact person for public queries
Name 15150 0
A/Prof Margaret Zacharin
Address 15150 0
Department of Endocrinology,
Royal Children’s Hospital,
Flemington Road, Parkville,
Melbourne,
3052, VIC
Country 15150 0
Australia
Phone 15150 0
+61 3 93454214
Fax 15150 0
+61 3 9347 7763
Email 15150 0
[email protected]
Contact person for scientific queries
Name 6078 0
A/Prof Margaret Zacharin
Address 6078 0
Department of Endocrinology,
Royal Children’s Hospital,
Flemington Road, Parkville,
Melbourne,
3052, VIC
Country 6078 0
Australia
Phone 6078 0
+61 3 93454214
Fax 6078 0
+61 3 9347 7763
Email 6078 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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