Cystic Fibrosis - Insulin Deficiency, Early Action

Study Overview
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Brief Summary
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Cystic Fibrosis (CF) is the most common life-threatening genetic condition affecting Australian children. As well as repeated lung infections, children with CF develop insulin deficiency and eventually diabetes. The CF-IDEA trial (Cystic Fibrosis - Insulin Deficiency, Early Action) will determine whether starting insulin treatment before the onset of diabetes (earlier than current practice) will improve the health of children with CF by improving body weight and lung function.

Detailed Description
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As well as progressive lung disease, patients with Cystic Fibrosis (CF) suffer pancreatic destruction, leading to slow but progressive insulin deficiency. Deficiency of insulin, a powerful anabolic hormone, causes accelerated decline of weight and lung function (important predictors of early mortality in CF). We analysed Oral Glucose Tolerance Tests sampled every 30 mins and defined stages of CF Insulin Deficiency (CFID) as early glucose abnormalities, CFID1 (BGmax >=8.2 and <11.1mmol/L) and CFID2 (BGmax >=11.1 and BG120min <11.1), progressing to diabetes without fasting hyperglycaemia (CFID3), and finally to diabetes with fasting hyperglycaemia (CFID4). Currently insulin treatment is standard only for CFID3 and 4, but we have data showing that the earlier stages (CFID1 and 2) are also associated with declining weight and lung function. In the CF-IDEA Trial, subjects with CF aged >=5 years with early glucose abnormalities (CFID1 or 2) will be randomised to once-daily insulin detemir (Levemir) for 12 months, or to observation only. We aim to determine whether starting insulin earlier than current practice will prevent decline in weight and lung function, reduce frequency of hospitalisation, improve quality of life, and slow progression through CFID categories. Our pilot studies using once-daily Levemir in children with CFID1 and 2 found that this simple insulin regimen (rather than multiple daily injections) was well accepted by patients, with minimal hypoglycaemia, and resulted in significant weight gain and improved lung function (compared with 12 months prior to insulin). Sample size calculations for the CF-IDEA Trial are based on our pilot studies. When 70-80% of patients have completed the protocol, the study statistician will perform an interim analysis (blinded to the other investigators) to check the original power calculations. Stages of CF Insulin Deficiency: CFID1 Peak BG on OGTT >=8.2mmol/L and <11.1mmol/l. CFID2 Peak BG on OGTT >=11.1mmol/L and 120 minute BG <11.1. CFID3 120 minute BG on OGTT >=11.1mmol/L. CFID4 Fasting hyperglycemia (Fasting BG >=7mmol/L).

Official Title
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Cystic Fibrosis - Insulin Deficiency, Early Action

Conditions
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Cystic Fibrosis, Diabetes

Intervention / Treatment
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* Drug: Once-daily insulin detemir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with CF aged >=5 yrs attending one of the study sites. CFID1 or CFID2 (defined as BGmax >=8.2 and BG120 <11.1mmol/l on OGTT performed within the last 6 months, when respiratory function stable as judged by the treating respiratory team, not taking fluoroquinolone antibiotics, and not taking systemic glucocorticoids). Exclusion Criteria: Cystic Fibrosis Related Diabetes, defined as CFID3 (BG120 >11.1mmol/L) or CFID4 (fasting BG >7mmol/L). Such patients will be offered insulin treatment as standard clinical care. Unstable respiratory disease (hospital admission for treatment of respiratory exacerbation within the last month). Treatment with systemic glucocorticoids of more than 1 month duration, within the last 12 months.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>Observation only. Does not receive once-daily insulin detemir. | |
| Experimental: Once-daily insulin detemir<br>Once-daily insulin detemir | Drug: Once-daily insulin detemir<br>* Insulin detemir is a long-acting insulin analog. Starting dose 0.1 units/kg/day (titrated according to the results of home blood glucose monitoring).<br>* Other names: Levemir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight SDS (Standard Deviation Score) |  | 12 months | 
| Change in lung function (FEV1, FVC) |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduced rate of decline in glycaemic category, comparing OGTT at baseline and 12 months. | OGTT = Oral Glucose Tolerance Test | 12 months | 
| Reduced frequency of hospitalisation for acute respiratory illness |  | 12 months | 
| Change in glycaemic status assessed by HbA1c and CGM | CGM = Continuous Glucose Monitoring | 12 months | 
| Body composition by DEXA. Patients at CHW will also have pQCT. | DEXA = Dual Energy X-ray Absorptiometry pQCT = peripheral Quantitative Computed Tomography | 12 months | 
| Change in Grip-strength |  | 12 months | 
| Improved quality of life, measured by a validated CF QOL questionnaire |  | 12 months | 
| Bacterial colonisation of sputum |  | 12 months | 
| Change in effort-dependent lung function: MIP, MEP, SnIP | MIP = Mouth Inspiratory Pressure MEP = Mouth Expiratory Pressure SnIP = Sniff Nasal Inspiratory Pressure | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatrics, Pancreas