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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

Tracking Information
First Submitted Date  ICMJE September 18, 2018
First Posted Date  ICMJE September 24, 2018
Last Update Posted Date September 24, 2018
Estimated Study Start Date  ICMJE September 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • >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.
  • 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.
  • 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.
  • 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.
  • HbA1c levels [ Time Frame: 12 months ]
    HbA1c at 12 months after study initiation
  • Hypoglycaemic events [ Time Frame: From study start to 12 months ]
    Number of severe hypoglycaemic events (hypoglycaemia level 3) during the study year.
  • 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.
  • IDAA1c [ Time Frame: 12 months ]
    Insulin-dose-adjusted HbA1c (IDAA1c) 12 months after study initiation
  • Pro-insulin/c-peptide [ Time Frame: 12 months ]
    Pro-insulin/c-peptide ratio in serum 12 months after study initiation
  • Pancreas inflammation [ Time Frame: 12 months ]
    Inflammation in the pancreas measured by contrast enhanced MRI at 12 months after initiation of the study
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Oral microbiome [ Time Frame: 12 months ]
    The oral microbiome at 12 months after study initiation.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes
Official Title  ICMJE Azithromycin Insulin Diet Intervention Trial in Type 1 Diabetes
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.

    Interventions:
    • Drug: Azithromycin Monohydrate
    • Drug: Insulin Lispro
    • Behavioral: Dietician support
  • 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.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2018)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 72 Months to 192 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Olle Korsgren, MD, PhD +46176114187 olle.korsgren@igp.uu.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03682640
Other Study ID Numbers  ICMJE AIDIT
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Uppsala University
Study Sponsor  ICMJE Uppsala University
Collaborators  ICMJE Göteborg University
Investigators  ICMJE
Principal Investigator: Gun Forsander, MD, PhD The Queen Silvia Children's Hospital /Sahlgrenska University Hospital (SU), Sahlgrenska Academy, Dept of Pediatrics, University of Gothenburg
PRS Account Uppsala University
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP