ANZCTR - Registration

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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]

Nil

Universal Trial Number (UTN)

Nil

Trial acronym

Nil

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Crohn's disease

Condition category

Condition code

Oral and Gastrointestinal

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]

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]

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]

0, 2, 4, 6, 8 weeks

Secondary outcome [1]

-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]

0, 2, 4, 6, 8 weeks

Secondary outcome [2]

-Quality of life using the IMPACT-III (validated paediatric inflammatory bowel disease quality of life score) over the 8 weeks.

Timepoint [2]

0, 2, 4, 6, 8 weeks

Secondary outcome [3]

Markers of bone formation and resorption (bone alkaline phosphatase and CTX) over the 8 weeks

Timepoint [3]

0, 2, 8 weeks

Secondary outcome [4]

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]

Height at 0, 2, 4, 6, 8 weeks and pubertal staging at 0 and 8 weeks

Secondary outcome [5]

Markers of GH secretion (IGF1, IGFBP3)
- Blood analysis

Timepoint [5]

0, 2, 8 weeks

Secondary outcome [6]

Creatine kinase
- Blood analysis

Timepoint [6]

0, 2, 4, 6, 8 weeks

Secondary outcome [7]

Lipid profile
- Blood analysis

Timepoint [7]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Royal Children's Hospital

Address [1]

Flemington Road, Parkville,
Melbourne,
3052
VIC

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Children's Hospital

Address

Flemington Road, Parkville,
Melbourne,
3052
VIC

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee (HREC 31031A)

Ethics committee address [1]

Royal Children's Hospital
Flemington Road
Parkville
3052
VIC

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/02/2011

Approval date [1]

30/05/2011

Ethics approval number [1]

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

Address

Country

Phone

Fax

Contact person for public queries

Name

A/Prof Margaret Zacharin

Address

Department of Endocrinology,
Royal Children’s Hospital,
Flemington Road, Parkville,
Melbourne,
3052, VIC

Country

Australia

Phone

+61 3 93454214

Fax

+61 3 9347 7763

margaret.zacharin@rch.org.au

Contact person for scientific queries

Name

A/Prof Margaret Zacharin

Address

Department of Endocrinology,
Royal Children’s Hospital,
Flemington Road, Parkville,
Melbourne,
3052, VIC

Country

Australia

Phone

+61 3 93454214

Fax

+61 3 9347 7763

margaret.zacharin@rch.org.au

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

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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