Closing the Loop in Adults With Sub-optimally Controlled Type 1 Diabetes Under Free Living Conditions (AP@home04)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of Cambridge
Sponsor:
Collaborators:
Profil Institut für Stoffwechselforschung GmbH
Medical University of Graz
Information provided by (Responsible Party):
Dr Roman Hovorka, University of Cambridge
ClinicalTrials.gov Identifier:
NCT01961622
First received: August 30, 2013
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention
Type 1 Diabetes
Device: Florence D2A or similar closed loop glucose control system
Device: CSII with real-time CGM

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

Resource links provided by NLM:


Further study details as provided by University of Cambridge:

Primary Outcome Measures:
  • Time spent in the target glucose range from 3.9 to 10.0 mmol/l based on subcutaneous glucose monitoring [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • HbA1c [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Measure of average glycaemic control during study period

  • Insulin dose [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Total, basal and bolus insulin dose during 90 days of home periods

  • Adverse Events [ Time Frame: 10 months ] [ Designated as safety issue: Yes ]
    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

  • Utility Evaluation [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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.

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Time spent above and below the target glucose 3.9 to 10.0 mmol/l, during the 90 days of home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Average,standard deviation and coefficient of variation of glucose levels during 90 days of home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
    The time with glucose levels < 3.5 mmol/l and <2.8 mmol/l during 90 days of home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    The time with glucose levels in the significant hyperglycaemia,(glucose levels > 16.7 mmol/l during 90 days of home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Low Blood Glucose Index during 90 days of home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
    Duration of periods when sensor glucose values was below 3.5mmol/l for at least 20 minutes

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    The "Area Under the Curve" below 3.5 mmol/l during 90 days home periods

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Between 24 hour period variability: Coefficient of variation of CGM glucose between 24 hour periods (midnight to midnight)

  • Continuous subcutaneous glucose monitoring (CGM) based outcome [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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

  • Continuous subcutaneous glucose monitoring (CGM) based outcome during overnight period between 23:00 and 08:00 [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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

  • Continuous subcutaneous glucose monitoring (CGM) based outcome during day period between 08:00 to 23:00 [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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


Other Outcome Measures:
  • Accuracy of CGM [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    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

  • Per Protocol Analysis [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Per protocol analysis will be conducted to explore the relationship between usage of study treatments and study outcomes.

  • Effect of study intervention based on pre-study glycaemic control [ Time Frame: 90 days ] [ Designated as safety issue: No ]

    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



Estimated Enrollment: 30
Study Start Date: April 2014
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Florence D2A Closed Loop Glucose control
Subjects glucose levels are controlled by Florence D2A or similar closed loop insulin delivery system
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
Active Comparator: CSII with real-time CGM
Subject glucose level controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (FreeStyle Navigator CGM)
Device: CSII with real-time CGM
Subject glucose level controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01961622

Contacts
Contact: Josephine Hays 00 44 769084 jfh31@medschl.cam.ac.uk

Locations
Austria
Medical University of Graz Not yet recruiting
Graz, Austria, A8036
Contact: Thomas Pieber, MD    +43 3163 8512 383    thomas.pieber@medunigraz.at   
Principal Investigator: Thomas Pieber, MD         
Germany
Profil Institut für Stoffwechselforschung GmbH Not yet recruiting
Neuss, Germany, D41460
Contact: Sabine Arnolds, MD    + 49 2131 4018 401    sabine.arnolds@profil.com   
Principal Investigator: Sabine Arnolds, MD         
United Kingdom
University of Cambridge Recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Josephine Hays    00 44 1223 769084    jfh31@medschl.cam.ac.uk   
Principal Investigator: Mark Evans, MD         
Sub-Investigator: Lalantha Leelarathna, MRCP(UK)         
Sponsors and Collaborators
University of Cambridge
Profil Institut für Stoffwechselforschung GmbH
Medical University of Graz
Investigators
Principal Investigator: Roman Hovorka, PhD University of Cambridge
  More Information

Publications:
Responsible Party: Dr Roman Hovorka, Director of Research, University of Cambridge
ClinicalTrials.gov Identifier: NCT01961622     History of Changes
Other Study ID Numbers: AP@home04
Study First Received: August 30, 2013
Last Updated: April 23, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Cambridge:
Type 1 diabetes
Closed loop insulin delivery
Continuous subcutaneous glucose monitoring
Continuous subcutaneous insulin infusion

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014