Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes

Uppsala University60 enrolled

Overview

Increasing evidences suggest that infections are important etiological factors for the development of Type 1 Diabetes (T1D). The overall hypothesis of the study is that the treatment of children, during the first year after diagnosis of T1D with Azithromycin, combined with repeated episodes of intensified insulin treatment to induce maximal beta-cell rest, and dietician support to promote dietary habits that minimize the likelihood of bacterial reflux from the duodenum to the pancreatic duct, will lead to preservation of beta cell function. This trial will examine whether the AIDIT protocol initiated within one week from diagnosis could preserve insulin production in children with Type 1 Diabetes.

The study is a 2-arm, randomized, open, single center, clinical trial. Eligible patients with type 1 diabetes will be randomized to the AIDIT protocol or treatment as usual (TAU). All patients diagnosed with T1D and included in the study will receive standard of care. In addition, the AIDIT protocol will include 1) treatment with Azithromycin for 52 weeks using a protocol for children with cystic fibrosis, 2) repeated treatments with intensified supervised high dose insulin infusion, and 3) extra advice and support from the study dietician. 1. Azithromycin Azithromycin will be administered orally. Azithromycin will be given three times per week for 52 weeks. The dose will be 500 mg for children with body weight ≥ 30 kg and 250 mg if body weight \< 30 kg. 2. Intensified supervised high dose insulin infusions Participants will, in addition to Azithromycin, also be subjected to intensified anti-diabetic treatment to achieve increased beta-cell rest. This will be achieved by insulin lispro given as a supervised iv infusion for 72 hours within one week of diagnosis and by subcutaneous infusion 6-8 hours during one day in study week 5, 9, 13, 17 (±1 week) and 25, 34, 43 (±2 weeks) after inclusion. The intensified treatments will aim to target a blood glucose level of 4.0 ± 0.5 mmol/l. The efficacy of the intended maximal beta cell rest will be evaluated by measurement of plasma glucose and endogenous C-peptide. If C-peptide remains positive during the supervised infusion of insulin lispro this will be interpreted as that the insulin dose needs to be increased at the next treatment occasion to achieve beta-cell rest. 3. Dietician support Participants will receive extra advice and support from the study dietician within the first week after randomization, and after 7 and 17 weeks. Personalized nutritional advice on intake of carbohydrates, fat and protein based on four-day food records will be given to in order to reduce insulin resistance and insulin need in accordance with ISPAD guidelines. By giving nutritional advices on less volume of the meals, especially of the fluid (maximum 300 ml per meal), and by trying to extend the meal time to at least 20 minutes, the reflux into ductus pancreaticus might be reduced. All patients will be offered an examination of their pancreas with MRI at 0 and 12 months after inclusion. In addition, plasma samples taken at inclusion and after 1.5 and 12 months will be analysed for the presence of cell-free DNA indicating ongoing cell destruction. Cell-specific methylation patterns of this cell-free DNA will be analysed to determine cell-type specific cell death. The effect of the addition of treatment according to the AIDIT protocol will be evaluated with a Mixed Meal Tolerance Test (MMTT) to explore the effect on preservation of beta-cell function.

Eligibility

Sex: ALLMin age: 72 MonthsMax age: 192 Months

Medical Language ↔ Plain English

Inclusion Criteria: 1. Clinically diagnosed Type 1 Diabetes. First injection of insulin maximum ten days prior to inclusion. 2. Must be willing and capable of taking the study drugs, perform tests and follow up as described as judged by the investigator. 3. Signed informed consent and expected cooperation of the patients for the treatment and follow up. 4. Aged 6.00 -15.99 years at inclusion. 5. Females of childbearing potential must agree to avoid pregnancy during the study period (by abstinence from heterosexual intercourse, or by hormonal or barrier contraception) and have a negative urine pregnancy test. Exclusion Criteria: 1. Other diabetes diagnosis than Type 1 diabetes as judged by the investigator 2. Severe ketoacidosis (DKA) with lowest pH \<7.1 within 36 hours from diagnosis. 3. Treatment with any oral or injected anti-diabetic medications other than insulin 4. Significantly abnormal haematology results at screening. 5. Participation in other clinical trials with a new chemical entity within the previous 3 months. 6. Obesity at diagnosis (Iso-BMI ≥ 30 kg/m2 according to http://www.rikshandboken-bhv.se). 7. Other autoimmune disease present at inclusion that in the opinion of the investigator would interfere with the study protocol. 8. Celiac disease present at diagnosis. 9. Treatment with medication known to affect glucohomeostasis, i.e. glucocorticoids (inhaled, nasal or skin topic will be accepted), statins, ACE inhibitors. 10. Pregnancy or lactation 11. Known gastro-intestinal malabsorption disorders 12. Abnormalities in ECG or known cardiac disease 13. Known hearing defects 14. Known hypersensitivity to penicillin 15. Inability or unwillingness to comply with the provisions of this protocol 16. Presence of serious disease or condition in patient or family, which in the opinion of the investigator makes the patient non-eligible for the study. 17. Known renal or hepatic impairment

Outcomes

Primary Outcomes

Stimulated C-peptide during an MMTT

Residual insulin secretion measured by mixed meal tolerance test (MMTT) stimulated C-peptide two-hour under the curve profile measured one year after study inclusion.

Time frame: 12 months after inclusion

Secondary Outcomes

>60% of time in target blood glucose levels

Proportion of subjects with time in target 3.9-7.8 mmol/L ≥ 60% and with a glycaemic variability expressed as standard deviation \< 2 mmol/L according to continuous glucose monitoring during two weeks in the 12th month after initiation of the study treatment.

Time frame: two weeks in the 12th month after initiation of the study treatment

Time in target blood glucose levels

Time in target (3.9-7.8 mmol/L) during 30 days in the 12th month after initiation of the study treatment.

Time frame: 30 days in the 12th month after initiation of the study treatment

Time in range blood glucose levels

Time in range (3.9-10 mmol/L) during 30 days in the 12th month after initiation of the study treatment.

Time frame: 30 days in the 12th month after initiation of the study treatment

Insulin dose

Mean daily insulin dosage per kilo bodyweight during 30 days in the 12th month after initiation of the study treatment.

Time frame: 30 days in the 12th month after initiation of the study treatment

HbA1c levels

HbA1c at 12 months after study initiation

Time frame: 12 months

Hypoglycaemic events

Number of severe hypoglycaemic events (hypoglycaemia level 3) during the study year.

Time frame: From study start to 12 months

Time in hypoglycemic range

Time in hypoglycaemic range level 1 and 2 (\<3.9 mmol/l and \<3.0 mmol/l) respectively in CGM registrations during 30 days in the 12th month after initiation of the study treatment.

Time frame: 30 days in the 12th month

IDAA1c

Insulin-dose-adjusted HbA1c (IDAA1c) 12 months after study initiation

Time frame: 12 months

Pro-insulin/c-peptide

Pro-insulin/c-peptide ratio in serum 12 months after study initiation

Time frame: 12 months

Pancreas inflammation

Inflammation in the pancreas measured by contrast enhanced MRI at 12 months after initiation of the study

Time frame: 12 months

QoL

Health related Quality of Life; Varni PedsQL, Generic and Diabetes specific questionnaire, by child and proxy (parents or other caregivers) at study start and 12 months after study initiation.

Time frame: 12 months

Gastrointestinal symptoms

Questionnaire on gastrointestinal symptoms: "The gastrointestinal symptom rating scale" (GSRS) at study start and 12 months after study initiation .

Time frame: 12 months

Time spent eating

Average time spent eating at meals during four days in the 12th month after initiation of the study treatment.

Time frame: 12 months

Intake of saturated fat

Intake of saturated fat (E% and if the child reaches Nordic Nutritional Recommendations, NNR) during four days in the 12th month after initiation of the study treatment.

Time frame: four days in the 12th month

Intake of fruit

Intake of fruit and vegetables (g/day and if the child reaches NNR) during four days in the 12th month after initiation of the study treatment.

Time frame: four days in the 12th month

Intake of macronutrients

Intake of macronutrients (E% and g/day) during four days in the 12th month after initiation of the study treatment.

Time frame: four days in the 12th month

Intake of fibre

Intake of fibre (g/day and if the child reaches NNR) during four days in the 12th month after initiation of the study treatment.

Time frame: four days in the 12th month

Physical activity measured with accelerometer

Physical activity registered with accelerometer during one week in the 6th month after initiation of the study treatment.

Time frame: 6 months

Physical activity measured with accelerometer

Physical activity registered with accelerometer during one week in the 12th month after initiation of the study treatment.

Time frame: 12 months

Oral microbiome

The oral microbiome at 12 months after study initiation.

Time frame: 12 months

Change in stimulated C-peptide

Change in stimulated c-peptide two-hour under the curve profile from 6 weeks to 12 months after initiation of study treatment.

Time frame: change from 6 weeks to 12 months after initiation of study treatment

Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts