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Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes (AIDIT)

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ClinicalTrials.gov Identifier: NCT03682640
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : September 24, 2018
Sponsor:
Collaborator:
Göteborg University
Information provided by (Responsible Party):
Uppsala University

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.


Condition or disease Intervention/treatment Phase
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 Drug: Azithromycin Monohydrate Drug: Insulin Lispro Behavioral: Dietician support Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study is a 2-arm, randomized, open, clinical trial comparing the AIDIT protocol with treatment as usual.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: AIDIT protocol

Treatment as usual with the addition of:

i) Azithromycin Monohydrate, three times a week (≥ 48 h between doses) during 52 weeks. 500 mg if body weight ≥ 30 kg, 250 mg if body weight < 30 kg.

ii) Extra intensive insulin treatment periods for maximum beta-cell rest with Insulin lispro (Sanofi). This treatment will be given i.v. for one episode of 72 hours in the first week after inclusion and s.c. on seven 6-8 h occasions during the study year. The dose will be individually titrated to reach target blood glucose 4.0±0.5 mmol/L.

ii) Dietician support; Extra advice and support from the study dietician within the first week after randomization and after 1.5 and 4 months.

Drug: Azithromycin Monohydrate
Azithromycin Monohydrate tablet (Azithromycin Sandoz) or oral suspension (Azithromax).
Other Names:
  • Azithromycin Sandoz
  • Azithromax

Drug: Insulin Lispro
Solution for intravenous or subcutaneous use
Other Name: Insulin lispro Sanofi

Behavioral: Dietician support
Dietary advice

No Intervention: Control
Patients will receive treatment as usual (TAU). All patients will receive standard therapeutic treatment consisting of insulin replacement with insulin analogues aiming for normoglycemia from diagnosis. Rapid acting insulin analogue will be administered via insulin pump (continuous subcutaneous infusion) with access to insulin injections in case of malfunction in the pump system.



Primary Outcome Measures :
  1. Stimulated C-peptide during an MMTT [ Time Frame: 12 months after inclusion ]
    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.


Secondary Outcome Measures :
  1. >60% of time in target blood glucose levels [ Time Frame: two weeks in the 12th month after initiation of the study treatment ]
    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.

  2. Time in target blood glucose levels [ Time Frame: 30 days in the 12th month after initiation of the study treatment ]
    Time in target (3.9-7.8 mmol/L) during 30 days in the 12th month after initiation of the study treatment.

  3. Time in range blood glucose levels [ Time Frame: 30 days in the 12th month after initiation of the study treatment ]
    Time in range (3.9-10 mmol/L) during 30 days in the 12th month after initiation of the study treatment.

  4. Insulin dose [ Time Frame: 30 days in the 12th month after initiation of the study treatment ]
    Mean daily insulin dosage per kilo bodyweight during 30 days in the 12th month after initiation of the study treatment.

  5. HbA1c levels [ Time Frame: 12 months ]
    HbA1c at 12 months after study initiation

  6. Hypoglycaemic events [ Time Frame: From study start to 12 months ]
    Number of severe hypoglycaemic events (hypoglycaemia level 3) during the study year.

  7. Time in hypoglycemic range [ Time Frame: 30 days in the 12th month ]
    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.

  8. IDAA1c [ Time Frame: 12 months ]
    Insulin-dose-adjusted HbA1c (IDAA1c) 12 months after study initiation

  9. Pro-insulin/c-peptide [ Time Frame: 12 months ]
    Pro-insulin/c-peptide ratio in serum 12 months after study initiation

  10. Pancreas inflammation [ Time Frame: 12 months ]
    Inflammation in the pancreas measured by contrast enhanced MRI at 12 months after initiation of the study

  11. QoL [ Time Frame: 12 months ]
    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. Gastrointestinal symptoms [ Time Frame: 12 months ]
    Questionnaire on gastrointestinal symptoms: "The gastrointestinal symptom rating scale" (GSRS) at study start and 12 months after study initiation .

  13. Time spent eating [ Time Frame: 12 months ]
    Average time spent eating at meals during four days in the 12th month after initiation of the study treatment.

  14. Intake of saturated fat [ Time Frame: four days in the 12th month ]
    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.

  15. Intake of fruit [ Time Frame: four days in the 12th month ]
    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.

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

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

  18. Physical activity measured with accelerometer [ Time Frame: 6 months ]
    Physical activity registered with accelerometer during one week in the 6th month after initiation of the study treatment.

  19. Physical activity measured with accelerometer [ Time Frame: 12 months ]
    Physical activity registered with accelerometer during one week in the 12th month after initiation of the study treatment.

  20. Oral microbiome [ Time Frame: 12 months ]
    The oral microbiome at 12 months after study initiation.

  21. Change in stimulated C-peptide [ Time Frame: change from 6 weeks to 12 months after initiation of study treatment ]
    Change in stimulated c-peptide two-hour under the curve profile from 6 weeks to 12 months after initiation of study treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   72 Months to 192 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03682640


Contacts
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Contact: Olle Korsgren, MD, PhD +46176114187 olle.korsgren@igp.uu.se

Locations
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Sweden
The Queen Silvia Children's Hospital / Sahlgrenska University Hospital Recruiting
Gothenburg, Sweden
Contact: Gun Forsander         
Sponsors and Collaborators
Uppsala University
Göteborg University
Investigators
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Principal Investigator: Gun Forsander, MD, PhD The Queen Silvia Children's Hospital /Sahlgrenska University Hospital (SU), Sahlgrenska Academy, Dept of Pediatrics, University of Gothenburg

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Responsible Party: Uppsala University
ClinicalTrials.gov Identifier: NCT03682640     History of Changes
Other Study ID Numbers: AIDIT
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Metabolic Diseases
Glucose Metabolism Disorders
Inflammation
Endocrine System Diseases
Pathologic Processes
Autoimmune Diseases
Immune System Diseases
Insulin
Insulin, Globin Zinc
Insulin Lispro
Azithromycin
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents