Closing the Loop in Adults With Sub-optimally Controlled Type 1 Diabetes Under Free Living Conditions

Type 1 Diabetes Clinical Trial

— AP@home04  

Official title:

An Open-label, Multi-centre, Randomised, Two-period, Crossover Study to Assess the Efficacy, Safety and Utility of 12 Week Day and Night Automated Closed-loop Glucose Control Under Free Living Conditions Compared to Conventional Insulin Pump Therapy Combined With Continuous Glucose Monitoring in Adults With Type 1 Diabetes With Sub-optimal Glucose Control

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01961622
• Other study ID #: AP@home04
• Status: Completed
• Phase: N/A
• First received: August 30, 2013
• Last updated: June 4, 2015
• Start date: April 2014
• Est. completion date: May 2015

Study information

• Verified date: June 2015
• Source: University of Cambridge
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The main objective of this study is to determine whether day and night closed-loop insulin delivery for 12 weeks under free living conditions is superior to addition of real-time continuous glucose monitoring in adults with type 1 diabetes and sub-optimal glucose control on insulin pump therapy.

This is an open-label, multi centre, randomised, crossover design study, involving a 6 to 8 week run-in period, during which glucose control will be optimised by a professional pump educator, followed by two 3 months study periods during which glucose levels will be controlled either by an automated closed-loop system or by subjects usual insulin pump therapy augmented with real-time continuous glucose monitoring in random order. A total of up to 42 adults (aiming for 30 completed subjects) aged 18 years and older with T1D on insulin pump therapy will be recruited through diabetes clinics and other established methods in participating centres. Subjects who drop out of the study within the first 6 weeks of the first intervention arm will be replaced.

Subjects will receive appropriate training in the safe use of closed-loop insulin delivery system. Subjects will have regular contact with the study team during the home study phase including 24/7 telephone support. Subjects will be discouraged from international travel during the first two weeks of closed-loop use.

The primary outcome is time spent in target range between 3.9 and 10.0 mmol/L as recorded by CGM (adjusted for potential over-estimation) during home stay. Secondary outcomes are the HbA1c, time spent with glucose levels above and below target, as recorded by CGM, and other CGM-based metrics.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. The subject has type 1 diabetes as defined by WHO

2. The subject is 18 years of age or older

3. The subject will have been on an insulin pump for at least 6 months with good knowledge of insulin self-adjustment including carbohydrate counting

4. The subject is treated with one of the rapid acting insulin analogues (Insulin Aspart, Insulin Lispro or Insulin Glulisine)

5. HbA1c =7.5% (58mmol/mmol) and = 10% (86 mmol/mmol) based on analysis from central laboratory or equivalent

6. The subject is willing to perform regular finger-prick blood glucose monitoring, with at least 6 measurements per day

7. The subject is willing to wear closed-loop system at home and at work place

8. The subject is willing to follow study specific instructions

9. The subject is willing to upload pump and CGM data at regular intervals

10. Female subjects of child bearing age should be on effective contraception and must have a negative urine-HCG pregnancy test at screening. In addition in Germany, women of childbearing potential must use a highly effective method of birth control, which is defined as those which result in a low failure rate (i.e. less than 1% per year) and must use two independent methods of contraception, e.g. diaphragm and spermicide-coated condom.

Exclusion Criteria:

1. Non-type 1 diabetes mellitus

2. Any other physical or psychological disease or condition likely to interfere with the normal conduct of the study and interpretation of the study results

3. Current treatment with drugs known to have significant interference with glucose metabolism, such as systemic corticosteroids, as judged by the investigator

4. Known or suspected allergy against insulin

5. Subjects with clinically significant nephropathy, neuropathy or proliferative retinopathy as judged by the investigator

6. Significantly reduced hypoglycaemia awareness as judged by the investigator

7. More than one episode of severe hypoglycaemia as defined by American Diabetes Association (31) in preceding 6 months (Severe hypoglycaemia is defined as an event requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions).

8. Random C-peptide > 100pmol/l with concomitant plasma glucose >4 mM(72 mg/dl)

9. Total daily insulin dose > 2 IU/kg/day

10. Subject is pregnant or breast feeding or planning pregnancy in near future (within next 3 months)

11. Severe visual impairment

12. Severe hearing impairment

13. Subjects using implanted internal pacemaker

14. Lack of reliable telephone facility for contact

15. Subject not proficient in English (UK) or German (Germany and Austria)

16. Subjects who are living alone

Additional exclusion criteria specific for Austria and Germany

1. Positive results on urine drug screen (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates).

2. Positive alcohol breath test.

Additional exclusion criteria specific for Germany only

1. Positive reaction to any of the following tests: hepatitis B surface (HBs) antigen, anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus (HIV) 1 antibodies, anti-HIV2 antibodies.

2. Significantly reduced hypoglycaemia awareness withGold score = 4 according to Geddes J et al, Diabetes Care 2007

3. Serious macro- and microangiopathy

4. Serious anomalies of the skin

5. Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located at places of the body, which potentially are possible to be used for localisation of the glucose sensor)

6. Renal insufficiency

7. Epilepsy

8. Eating disorders (like bulimia or anorexia nervosa)

9. Disorders of the lipid metabolism

10. Blood transfusion requiring patients

11. Psychiatric diseases and related conditions

12. Patients with frequent catheter abscesses having occurred in connection with the pump therapy

13. Patients with medically documented allergy towards the adhesive (glue) of plasters

14. Abnormal blood values for:

• the creatinine clearance,

• erythropoietin,

• TSH.

15. Patients with the following concomitant medications or misuse of substances:

• steroids,

• anticoagulant therapies.

16. Patients with a planned intervention under general anaesthesia.

17. Patients who do shift work

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Device:
• Florence D2A or similar closed loop glucose control system
Subject's glucose level will be controlled by the Florence D2A or similar automated closed loop glucose control system. The system comprises of FreeStyle Navigator 2 ® Continuous Glucose Monitoring (CGM) System (Abbott Diabetes Care, Alameda, CA, USA), Dana R Diabecare subcutaneous insulin infusion pump (Sooil Corp. Seoul, South Korea)or similar insulin pump, and MPC-based glucose control algorithm running on a smartphone
• CSII with real-time CGM
Subject glucose level controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM)

Locations

Country	Name	City	State
Austria	Medical University of Graz	Graz
Germany	Profil Institut für Stoffwechselforschung GmbH	Neuss
United Kingdom	University of Cambridge	Cambridge

Sponsors (3)

Lead Sponsor	Collaborator
University of Cambridge	Medical University of Graz, Profil Institut für Stoffwechselforschung GmbH

Countries where clinical trial is conducted

Austria,  Germany,  United Kingdom, 

References & Publications (3)

Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, Kollman C, Hovorka T, Larsen AM, Nodale M, De Palma A, Wilinska ME, Acerini CL, Dunger DB. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet. 2010 Feb 27;375(9716):743-51. doi: 10.1016/S0140-6736(09)61998-X. Epub 2010 Feb 4. — View Citation

Hovorka R, Kumareswaran K, Harris J, Allen JM, Elleri D, Xing D, Kollman C, Nodale M, Murphy HR, Dunger DB, Amiel SA, Heller SR, Wilinska ME, Evans ML. Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies. BMJ. 2011 Apr 13;342:d1855. doi: 10.1136/bmj.d1855. — View Citation

Hovorka R. Closed-loop insulin delivery: from bench to clinical practice. Nat Rev Endocrinol. 2011 Feb 22;7(7):385-95. doi: 10.1038/nrendo.2011.32. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Accuracy of CGM	CGM accuracy during 3 months home period; Capillary glucose vs. CGM will be evaluated using standard measures of numerical and clinical accuracy including absolute relative deviation and error grid analysis	90 days	No
Other	Per Protocol Analysis	Per protocol analysis will be conducted to explore the relationship between usage of study treatments and study outcomes.	90 days	No
Other	Effect of study intervention based on pre-study glycaemic control	Following outcomes will be calculated separately for participants with baseline HbA1c <8.5% vs. = 8.5%; Time spent with CGM glucose concentration in the target range (3.9-10.0mmol/L), Time spent with CGM glucose levels in hypoglycaemic range (< 3.9 mmol/L), Time spent with CGM glucose levels in hyperglycaemic range (> 10.0 mmol/L), Mean CGM glucose levels and the AUC below 3.5mmol/l based on continuous subcutaneous glucose monitoring	90 days	No
Primary	Time spent in the target glucose range from 3.9 to 10.0 mmol/l based on subcutaneous glucose monitoring	Time spent in the target glucose range from 3.9 to 10.0 mmol/l based on subcutaneous glucose monitoring (CGM) during the 90 days of home stay. Intention to treat basis.	90 days	No
Secondary	HbA1c	Measure of average glycaemic control during study period	90 days	No
Secondary	Insulin dose	Total, basal and bolus insulin dose during 90 days of home periods	90 days	No
Secondary	Adverse Events	Safety evaluation will comprise the number of episodes of hypoglycaemia, significant ketonemia (> 3.0mmol/l)as well as nature and severity of any other adverse events	10 months	Yes
Secondary	Utility Evaluation	Utility evaluation is the frequency and duration of use of the closed-loop system at home and time between failures of closed-loop system components.	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Time spent above and below the target glucose 3.9 to 10.0 mmol/l, during the 90 days of home periods	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Average,standard deviation and coefficient of variation of glucose levels during 90 days of home periods	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	The time with glucose levels < 3.5 mmol/l and <2.8 mmol/l during 90 days of home periods	90 days	Yes
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	The time with glucose levels in the significant hyperglycaemia,(glucose levels > 16.7 mmol/l during 90 days of home periods	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Low Blood Glucose Index during 90 days of home periods	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Duration of periods when sensor glucose values was below 3.5mmol/l for at least 20 minutes	90 days	Yes
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	The "Area Under the Curve" below 3.5 mmol/l during 90 days home periods	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Between 24 hour period variability: Coefficient of variation of CGM glucose between 24 hour periods (midnight to midnight)	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome	Glucose concentration in the target range (3.9-10.0mmol/L), and above and below target range based on adjusted CGM. Adjustment described in Hovorka R et. al.; Diabetes Technol Ther 14:1-9, 2012	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome during overnight period between 23:00 and 08:00	Time spent with CGM glucose concentration in the target range (3.9-8.0mmol/L), Mean CGM glucose levels, The AUC below 3.5mmol/l, CV of CGM glucose levels, Coefficient of variation of CGM glucose between nights and Total insulin dose during overnight period between 23:00 and 08:00	90 days	No
Secondary	Continuous subcutaneous glucose monitoring (CGM) based outcome during day period between 08:00 to 23:00	Time spent with CGM glucose concentration in the target range (3.9-10.0mmol/L), Mean CGM glucose levels, The AUC below 3.5mmol/l, CV of CGM glucose levels, Coefficient of variation of CGM glucose between days and Total insulin dose during day period between 08:00 to 23:00	90 days	No