Effect of Postprandial Insulin Administration of Faster-acting Insulin Analogue Versus Pre-prandial Administration of Acting-insulin Analogue in Cystic Fibrosis Related Diabetes

Study Overview
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Brief Summary
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Cystic fibrosis related diabetes (CFRD) is a major factor of morbidity and mortality at all disease stages. Insulin deficiency has serious clinical consequences by increasing malnutrition, since protein and lipid catabolism is accelerated in chronic infections. Traditionally, insulin is injected before a meal. Yet, in these patients with highly varied and often staggered nutritional intakes, insulin injection can result in an increased risk of postprandial hypoglycaemia, all the more so as CF patients exhibit decreased glucagon secretion. Recent progress in the development of new insulins mimicking the physiological secretion more closely has led to ultra-fast insulins (fast aspart), allowing for postprandial hyperglycaemia to be better controlled. In Type 1 diabetics treated with basal-bolus, faster-acting aspart insulin injected after a meal enabled metabolic control comparable to injection of aspart insulin prior to the meal. Fast apart insulin is of particular interest with regard to CFRD, wherein postprandial hyperglycaemia occurs early. In CFRD, these insulins are likewise advantageous in that they can be injected after the meal, thus permitting more flexibility in patients with highly varied diets. Moreover, the insulin dose can be adapted depending on dietary intake, thus preventing hypoglycaemia secondary to highly-varied carbohydrate intakes. Due to its flexibility, this insulin therapy is likely to be better accepted by patients with cystic fibrosis.

Detailed Description
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The investigators hypothesis that post prandial administration of Insulin faster-acting aspart insulin in patients with CFRD may contribute to a better metabolic control with a decrease of hypoglycaemia and facilitate insulin administration according to the real food intake. The use of Insulin faster-acting aspart insulin will facilitate the functional insulin therapy. More particularly for CF patients, optimization of metabolic control should contribute to maintain a good nutritional status and to slowing the decline of respiratory function and improve the quality of life. Patients with cystic fibrosis related diabetes and treated by multiple insulin injection (minimal three insulin injection per day or basal bolus insulin regimen) or insulin pump with CGM from over 3 months were included in an open, randomized, two-treatments - 4 periods of 3 months - 2 groups cross-over superiority study. Each group of patients will test both insulin treatments (A = pre prandial Aspart insulin, F = post prandial Faster-acting aspart insulin) in alternating periods with the following sequences: Group 1: A-F-A-F, Group 2: F-A-F-A The patients will be randomized to either one or the other sequence, which defines the groups, and take A or F in each of the 4 periods of the study. Each treatment period will last 3 months. CGM (free style libre, Abott) will be performed for 2 weeks at baseline and after each 4 months period.

Official Title
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Effect of Postprandial Insulin Administration of Faster-acting Insulin Analogue Versus Pre-prandial Administration of Acting-insulin Analogue in Cystic Fibrosis Related Diabetes : MIRE Trial

Conditions
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Cystic Fibrosis-related Diabetes

Intervention / Treatment
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* Drug: A-F-A-F (NovoRapid-FIASP-NovoRapid-FIASP)
* Drug: F-A-F-A (FIASP-NovoRapid-FIASP-NovoRapid)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with cystic fibrosis related diabetes aged over 10 years (no upper age limite) Patient treated by multiple insulin injections (minimal three insulin injections per day or basal bolus insulin regimen) or insulin pump Patient with CGM from over 3 months (at the signature of the study's informed consent) or patient not wearing a CGM device, but agreeing a CGM at the inclusion and at the end of each treatment period of 3 months Naive patient of Fiasp or patient under Fiasp, having carried out a run-in period of one month with rapid acting insulin treatment Affiliated to a social security scheme Subject able to understand the objectives and the risks related to the research and to give a dated and signed informed consent Subject having been informed of the results of the prior medical examination Written informed consent, dated and signed before initiating any trial-related procedure (if the subject is a minor, the consent must be signed by the 2 legal representative and the patient if he/she is able to give consent) Exclusion Criteria: Patient with type 1 or type 2 diabetes Patient with cystic fibrosis related diabetes treated with 2 injections / day Patient with an HbA1C greater than 12% who demonstrate therapeutic non-compliance Patient pregnant (positive urinary pregnancy test) or wishing to pregnancy Contraindication to Aspart insulin Patient on lung transplant waiting list or transplanted within one year prior to the inclusion visit Patient who started treatment with Trikafta® within 3 months prior to the inclusion visit Patient who cannot be followed during 12 months Subject in exclusion period (determined by previous or current clinical study) Impossibility of giving the subject enlightened information (subject in emergency situation, difficulties of understanding, cognitive impairment...) Subject under the protection of justice Subject under guardianship or curatorship

Ages Eligible for Study
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Minimum Age: 10 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: A-F-A-F<br>The study is an open, randomized, two-treatment - 4 periods of 3 months - 2 group cross-over superiority study. All patients will test both insulin treatments (A and F) in alternating periods. The patients of group 1 will start with pre-prandial aspart insulin (NovoRapid). Each treatment period will last 3 months. | Drug: A-F-A-F (NovoRapid-FIASP-NovoRapid-FIASP)<br>* A = pre-prandial aspart insulin (NovoRapid) F = post prandial Faster-acting aspart insulin (FIASP)<br>* Other names: All patients will have both treatments: NovoRapid + FIASP;|
| Active Comparator: Groupe 2: F-A-F-A<br>The study is an open, randomized, two-treatment - 4 periods of 3 months - 2 group cross-over superiority study. All patients will test both insulin treatments (A and F) in alternating periods. The patients of group 2 will start with post prandial Faster-acting aspart insulin (FIASP). | Drug: F-A-F-A (FIASP-NovoRapid-FIASP-NovoRapid)<br>* A = pre-prandial aspart insulin (NovoRapid) F = post prandial Faster-acting aspart insulin (FIASP)<br>* Other names: All patients will have both treatments: NovoRapid + FIASP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of time in range of blood glucose variation (70-180 mg/dl) versus baseline at the end of each treatment period of 3 months (the last 2 weeks of the period of 3 months) is assessed. |  | This measurement is assessed at the end of each treatment period of 3 months (the last 2 weeks of the period of 3 months). Month 3, month 6, month 9 and month 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other CGM parameters: mean glucose value per day (mg/dl) |  | screening(Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3(3 months after inclusion)-Month 6-Month 9-Month 12 | 
| Other CGM parameters: glucose area under the curve for glucose value>180mg/dl - number of glucose values<70 mg/dl-number of glucose values<53mg/dl |  | screening(Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3(3 months after inclusion)-Month 6-Month 9-Month 12 | 
| Other CGM parameters: time in range of blood glucose >180, >140 <70mg/dl |  | screening(Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3(3 months after inclusion)-Month 6-Month 9-Month 12 | 
| Hypoglycaemic events experienced by the patient - number of symptomatic hypoglycaemic events under 70 mg/dl par mois - number of major hypoglycaemic events per year - number of nocturnal hypoglycaemic events per month |  | Inclusion visit (Day0)-visit Month 3(3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Markers of nutritional status: Body Mass Index (BMI) |  | visit (Day 0 to 3 months to Day 0-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Markers of nutritional status : bioelectrical impedance - Albumin and Pre albumin |  | visit (Day 0 to 3 months to Day 0-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Markers of nutritional status : Albumin and Pre albumin (g/l) |  | visit (Day 0 to 3 months to Day 0-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Markers of metabolic status: HbA1c (mmol/l and %) |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Markers of metabolic status: daily exogenous need of insulin (UI/day) |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Assessment of respiratory function parameters : FEV1, CV (L and %) |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Assessment of respiratory function parameters : O2 saturation (%) |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Assessment of respiratory function parameters : Number of cures of IV antibiotics per year (collect this information at each visit) |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Number patients with severe hypoglycaemia and serious adverse events |  | Inclusion visit (Day 0)-visit Month 3(3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 | 
| Other CGM parameters: Time in range of blood glucose 70-140 mg/dl |  | screening visit (Day 0 to 3 months to Day 0)-Inclusion visit (Day 0)-visit Month 3 (3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 |