Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes

Diabetes Mellitus Clinical Trial

— AIDIT  

Official title:

Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03682640
• Other study ID #: AIDIT
• Status: Recruiting
• Phase: Phase 2
• Start date: September 2018
• Est. completion date: December 31, 2021

Study information

• Verified date: September 2018
• Source: Uppsala University
• Contact: Olle Korsgren, MD, PhD
• Phone: +46176114187
• Email: olle.korsgren[@]igp.uu.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 72 Months to 192 Months

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Diet Modification
• Endocrine System Diseases
• Glucose Metabolism Disorders
• Inflammation
• Insulin Dependent Diabetes
• Juvenile Diabetes
• Metabolic Disease
• Metabolic Diseases
• Type 1 Diabetes Mellitus

Intervention

Drug:
• Azithromycin Monohydrate
Azithromycin Monohydrate tablet (Azithromycin Sandoz) or oral suspension (Azithromax).
• Insulin Lispro
Solution for intravenous or subcutaneous use

Behavioral:
• Dietician support
Dietary advice

Locations

Country	Name	City	State
Sweden	The Queen Silvia Children's Hospital / Sahlgrenska University Hospital	Gothenburg

Sponsors (2)

Lead Sponsor	Collaborator
Uppsala University	Göteborg University

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	12 months after inclusion
Secondary	>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.	two weeks in the 12th month after initiation of the study treatment
Secondary	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.	30 days in the 12th month after initiation of the study treatment
Secondary	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.	30 days in the 12th month after initiation of the study treatment
Secondary	Insulin dose	Mean daily insulin dosage per kilo bodyweight during 30 days in the 12th month after initiation of the study treatment.	30 days in the 12th month after initiation of the study treatment
Secondary	HbA1c levels	HbA1c at 12 months after study initiation	12 months
Secondary	Hypoglycaemic events	Number of severe hypoglycaemic events (hypoglycaemia level 3) during the study year.	From study start to 12 months
Secondary	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.	30 days in the 12th month
Secondary	IDAA1c	Insulin-dose-adjusted HbA1c (IDAA1c) 12 months after study initiation	12 months
Secondary	Pro-insulin/c-peptide	Pro-insulin/c-peptide ratio in serum 12 months after study initiation	12 months
Secondary	Pancreas inflammation	Inflammation in the pancreas measured by contrast enhanced MRI at 12 months after initiation of the study	12 months
Secondary	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.	12 months
Secondary	Gastrointestinal symptoms	Questionnaire on gastrointestinal symptoms: "The gastrointestinal symptom rating scale" (GSRS) at study start and 12 months after study initiation .	12 months
Secondary	Time spent eating	Average time spent eating at meals during four days in the 12th month after initiation of the study treatment.	12 months
Secondary	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.	four days in the 12th month
Secondary	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.	four days in the 12th month
Secondary	Intake of macronutrients	Intake of macronutrients (E% and g/day) during four days in the 12th month after initiation of the study treatment.	four days in the 12th month
Secondary	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.	four days in the 12th month
Secondary	Physical activity measured with accelerometer	Physical activity registered with accelerometer during one week in the 6th month after initiation of the study treatment.	6 months
Secondary	Physical activity measured with accelerometer	Physical activity registered with accelerometer during one week in the 12th month after initiation of the study treatment.	12 months
Secondary	Oral microbiome	The oral microbiome at 12 months after study initiation.	12 months
Secondary	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.	change from 6 weeks to 12 months after initiation of study treatment