Clinical trial NCT03682640: Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes
Official title: Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Diabetes Mellitus
Metabolic Disease
Glucose Metabolism Disorders
Endocrine System Diseases
Juvenile Diabetes
Insulin Dependent Diabetes
Type 1 Diabetes Mellitus
Inflammation
Diet Modification
Lead sponsor: Uppsala University
Sponsor class: OTHER
Collaborators: name: Göteborg University
First posted: 2018-09-24
Enrollment: 60
Sex: ALL
Minimum age (years): 72
Maximum age (years): 192
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a 2-arm, randomized, open, clinical trial comparing the AIDIT protocol with treatment as usual.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Stimulated C-peptide during an MMTT
timeFrame: 12 months after inclusion
Secondary outcomes:
measure: >60% of time in target blood glucose levels
timeFrame: two weeks in the 12th month after initiation of the study treatment
measure: Time in target blood glucose levels
timeFrame: 30 days in the 12th month after initiation of the study treatment
measure: Time in range blood glucose levels
timeFrame: 30 days in the 12th month after initiation of the study treatment
measure: Insulin dose
timeFrame: 30 days in the 12th month after initiation of the study treatment
measure: HbA1c levels
timeFrame: 12 months
measure: Hypoglycaemic events
timeFrame: From study start to 12 months
measure: Time in hypoglycemic range
timeFrame: 30 days in the 12th month
measure: IDAA1c
timeFrame: 12 months
measure: Pro-insulin/c-peptide
timeFrame: 12 months
measure: Pancreas inflammation
timeFrame: 12 months
measure: QoL
timeFrame: 12 months
measure: Gastrointestinal symptoms
timeFrame: 12 months
measure: Time spent eating
timeFrame: 12 months
measure: Intake of saturated fat
timeFrame: four days in the 12th month
measure: Intake of fruit
timeFrame: four days in the 12th month
measure: Intake of macronutrients
timeFrame: four days in the 12th month
measure: Intake of fibre
timeFrame: four days in the 12th month
measure: Physical activity measured with accelerometer
timeFrame: 6 months
measure: Physical activity measured with accelerometer
timeFrame: 12 months
measure: Oral microbiome
timeFrame: 12 months
measure: Change in stimulated C-peptide
timeFrame: change from 6 weeks to 12 months after initiation of study treatment
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: The Queen Silvia Children's Hospital / Sahlgrenska University Hospital
Study officials:
affiliation: The Queen Silvia Children's Hospital /Sahlgrenska University Hospital (SU), Sahlgrenska Academy, Dept of Pediatrics, University of Gothenburg
name: Gun Forsander, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: