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

• ClinicalTrials.gov Identifier: NCT04381429
• Recruitment Status: Recruiting
• First Posted: May 8, 2020
• Last Update Posted: January 6, 2023
• Sponsor: University Hospital, Strasbourg, France
• Information provided by (Responsible Party): University Hospital, Strasbourg, France

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis-related Diabetes	Drug: A-F-A-F (NovoRapid-FIASP-NovoRapid-FIASP); Drug: F-A-F-A (FIASP-NovoRapid-FIASP-NovoRapid)	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 17, 2020
• Estimated Primary Completion Date: August 2025
• Estimated Study Completion Date: August 2025

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Group 1: A-F-A-F; 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); A = pre-prandial aspart insulin (NovoRapid) F = post prandial Faster-acting aspart insulin (FIASP); Other Name: All patients will have both treatments: NovoRapid + FIASP
Active Comparator: Groupe 2: F-A-F-A; 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); A = pre-prandial aspart insulin (NovoRapid) F = post prandial Faster-acting aspart insulin (FIASP); Other Name: All patients will have both treatments: NovoRapid + FIASP

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: 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 :

1. Other CGM parameters: mean glucose value per day (mg/dl) [ Time Frame: 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 ]
2. 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 [ Time Frame: 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 ]
3. Other CGM parameters: time in range of blood glucose >180, >140 <70mg/dl [ Time Frame: 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 ]
4. 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 [ Time Frame: Inclusion visit (Day0)-visit Month 3(3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 ]
5. Markers of nutritional status: Body Mass Index (BMI) [ Time Frame: 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 ]
6. Markers of nutritional status : bioelectrical impedance - Albumin and Pre albumin [ Time Frame: 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 ]
7. Markers of nutritional status : Albumin and Pre albumin (g/l) [ Time Frame: 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 ]
8. Markers of metabolic status: HbA1c (mmol/l and %) [ Time Frame: 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 ]
9. Markers of metabolic status: daily exogenous need of insulin (UI/day) [ Time Frame: 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 ]
10. Assessment of respiratory function parameters : FEV1, CV (L and %) [ Time Frame: 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 ]
11. Assessment of respiratory function parameters : O2 saturation (%) [ Time Frame: 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 ]
12. Assessment of respiratory function parameters : Number of cures of IV antibiotics per year (collect this information at each visit) [ Time Frame: 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 ]
13. Number patients with severe hypoglycaemia and serious adverse events [ Time Frame: Inclusion visit (Day 0)-visit Month 3(3 months after inclusion visit)-Visit Month 6-Month 9-Month 12 ]
14. Other CGM parameters: Time in range of blood glucose 70-140 mg/dl [ Time Frame: 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 ]

Eligibility Criteria

• Ages Eligible for Study: 10 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

France

Hôpitaux Universitaires de Strasbourg; Recruiting

Strasbourg, France, 67091

Contact: Laurence KESSLER, MD PhD 0388116267 ext +33 laurence.kessler@chru-strasbourg.fr

Sponsors and Collaborators

University Hospital, Strasbourg, France

More Information

• Responsible Party: University Hospital, Strasbourg, France
• ClinicalTrials.gov Identifier: NCT04381429
• Other Study ID Numbers: 7546
• First Posted: May 8, 2020
• Last Update Posted: January 6, 2023
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Hypoglycemic Agents; Physiological Effects of Drugs