Closed-loop in Adults With Type 2 Diabetes (COYOTE)

An Open-label, Multinational, Multicentre, Randomised, Single-period Parallel Study to Assess the Efficacy, Safety and Utility of Fully Closed-loop Insulin Delivery Compared to Standard Insulin Therapy With CGM in Adults With Type 2 Diabetes

The main objective of this study is to determine the efficacy, safety and utility of fully closed-loop glucose control in the home setting in adults with type 2 diabetes (T2D). This study builds on previous and on-going studies of closed-loop systems that have been performed in Cambridge in adults with type 2 diabetes in the inpatient and in the home setting and in children and adults with type 1 diabetes.

This is an open-label, multi-national, multi-centre, randomised, single-period parallel study, involving a run-in period followed by a 26-week intervention period during which glucose levels will be controlled either by a fully closed-loop system or by participants usual insulin therapy with continuous glucose monitoring. A total of up to 224 adults with type 2 diabetes using insulin will be recruited through outpatient diabetes clinics, primary care centres, social media advertising and other established methods at participating centres. Participants will receive appropriate training in the safe use of the study devices.

The primary outcome is the between group difference in HbA1c at 26 weeks. Other key outcomes include the time spent with glucose levels within, above and below the target glucose range (3.9-10.0mmol/L) and mean sensor glucose as recorded by CGM over the 26 weeks. Insulin requirements, body weight, renal and liver function will also be compared. Safety evaluation comprises severe hypoglycaemic episodes, and other adverse and serious adverse events. Human factors outcomes include CGM & closed-loop usage, questionnaires and semi-structured interviews.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Treated With Insulin
• Intervention / Treatment: Device: CamAPS HX; Other: Standard insulin therapy with glucose sensor

Detailed Description

Purpose of clinical trial:

To determine the efficacy, safety and utility of fully closed-loop insulin delivery over 26 weeks in the home setting in adults with type 2 diabetes.

Study objectives:

To determine the efficacy, safety and utility of fully closed-loop insulin delivery over 26 weeks in the home setting in adults with type 2 diabetes.

1. EFFICACY: The objective is to assess the ability of fully closed-loop insulin delivery to improve glucose control as measured by HbA1c (primary endpoint) and sensor glucose metrics.
2. SAFETY: The objective is to evaluate the safety of fully closed-loop insulin delivery in terms of episodes and severity of hypoglycaemia, and nature and severity of other adverse events.
3. UTILITY: The objective is to determine the acceptability and duration of use of the CGM and closed-loop system.

4. HUMAN FACTORS: The objective is to assess cognitive, emotional, and behavioural characteristics of participants and their response to the closed-loop system using validated questionnaires and semi-structured interviews.

   Participating clinical centres:

   UK - Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust. - Imperial College Healthcare NHS Trust, London

   - Manchester Royal Infirmary, Manchester University NHS Foundation Trust

   - King's College Hospital, King's College Hospital NHS Foundation Trust, London

   - Guy's and St Thomas' NHS Foundation Trust

   - Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust

   - University Hospitals of Leicester NHS Trust

   Switzerland

   - Inselspital, Bern University Hospital, Bern

   France

   - Centre Hospitalier Universitaire (CHU) de Toulouse

   Germany

   - Medical Center - University of Freiburg

   Austria

   - Medical University of Graz, Graz

   Czech Republic

   - Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague

   Sample Size:

224 participants (112 per group) will be randomised. Recruitment will target a minimum quota of 25% of participants using basal insulin and a minimum quota of 60% of participants using multiple daily insulin injections.

Maximum duration of study for a subject: 30 weeks

Recruitment:

Participants will be recruited through outpatient diabetes clinics, primary care centres, social media advertising or other established methods at participating centres

Consent:

Participants will be asked to provide written informed consent.

Baseline Assessment:

Eligible participants will undergo baseline evaluation involving talking a medical history including demographics, height/weight, waist hip ratio and blood pressure measurement and blood samples for HbA1c, fasted lipid profile, renal and liver function. A urine albumin-creatinine ratio (ACR) will be performed, along with a urine pregnancy test in females of child-bearing age. Human factors questionnaires will be completed and a masked glucose sensor will be applied.

Run-in Period:

During a 2-3 week run-in period, participants will use their usual insulin therapy and wear a masked CGM system. At the end of the run-in period, for compliance, at least 10 days of CGM data needs to be recorded. CGM data during the run-in period will be used to assess baseline glucose control before the start of the intervention phase.

Randomisation:

Eligible participants will be randomised in a 1:1 ratio using central randomisation software to fully closed-loop or standard insulin therapy with CGM for 26 weeks. Randomisation will be stratified by site and baseline HbA1c.

Fully closed loop insulin delivery (intervention arm):

Following randomisation, participants in the closed-loop group will receive training on the study CGM, study insulin pump and closed-loop App during a 1-2 hour outpatient session. Competency on the use of the closed-loop system will be evaluated. Further training may be delivered as required. Participants will be advised to use the closed-loop system for the next 26 weeks.

Standard insulin therapy with CGM (control arm):

Following randomisation, participants in the control group will use their usual insulin therapy and the study CGM. Training on the use of the CGM will be provided. Participants will use standard insulin therapy and CGM for the next 26 weeks.

3 month study visit: Weight, waist hip ratio and blood pressure will be measured and a blood sample will be taken for measurement of HbA1c, fasted lipid profile, renal and liver function. Data from the closed-loop system and CGM system will be reviewed. Human factors questionnaires will be completed.

End of study assessments:

Weight, waist hip ratio and blood pressure will be measured and a blood sample will be taken for measurement of HbA1c, fasted lipid profile, renal and liver function. Urinary ACR will be measured. Human factors questionnaires will be completed and a subset of participants will participate in interviews. Study devices will be returned and participants will resume their usual insulin therapy and standard glucose monitoring.

Procedures for safety monitoring during trial:

Standard operating procedures for monitoring and reporting of all adverse events and adverse device events will be in place, including serious adverse events (SAE), serious adverse device effects (SADE) and specific adverse events (AE) such as severe hypoglycaemia.

A data safety and monitoring board (DSMB) will be informed of all serious adverse events and any unanticipated serious adverse device effects that occur during the study and will review compiled adverse event data at periodic intervals.

Criteria for withdrawal of subjects on safety grounds:

A participant may terminate participation in the study at any time without necessarily giving a reason and without any personal disadvantage. An investigator can stop the participation of a subject after consideration of the benefit/risk ratio. Possible reasons are:

• Participant is unable to demonstrate safe use of study devices as judged by the investigator
• Serious adverse events
• Significant protocol violation or non-compliance
• Decision by the investigator, or the Sponsor, that termination is in the participant's best medical interest
• Pregnancy, planned pregnancy, or breast feeding
• Allergic reaction to insulin or severe allergic reaction to adhesive surface of infusion set or glucose sensor
• Technical grounds (e.g. participant relocates)

• Study Type: Interventional
• Enrollment (Estimated): 224
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charlotte K Boughton, PhD; Phone Number: +44 (0)1223 769066; Email: cb2000@medschl.cam.ac.uk
• Study Contact Backup: Name: Angel Tseung; Email: ftt20@cam.ac.uk

Study Locations

• Australia
  • Melbourne, Australia
    • Not yet recruiting
    • University of Melbourne
    • Contact: David O'Neal
• Austria
  • Graz, Austria
    • Not yet recruiting
    • Medical University of Graz
    • Contact: Julia Mader
• Czechia
  • Prague, Czechia
    • Not yet recruiting
    • Diabetes Centre, Institute of Clinical and Experimental Medicine
    • Contact: Martin Haluzík
• France
  • Toulouse, France
    • Not yet recruiting
    • CHU de Toulouse
    • Contact: Hélène Hanaire
• Switzerland
  • Bern, Switzerland
    • Not yet recruiting
    • Bern University Hospital
    • Contact: Lia Bally
• United Kingdom
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust
    • Contact: Charlotte Boughton
  • Derby, United Kingdom
    • Not yet recruiting
    • Royal Derby Hospital
    • Contact: Emma Wilmot
  • Leicester, United Kingdom
    • Recruiting
    • Leicester Diabetes Centre
    • Contact: Pratik Choudhary
  • London, United Kingdom
    • Recruiting
    • Guy's and St Thomas' NHS Foundation Trust
    • Contact: Sufyan Hussain
  • London, United Kingdom
    • Recruiting
    • King's College Hospital, King's College NHS Foundation Trust
    • Contact: Yee Cheah
  • Manchester, United Kingdom
    • Not yet recruiting
    • Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust
    • Contact: Hood Thabit
  • Norwich, United Kingdom
    • Recruiting
    • Norfolk and Norwich University Hospital
    • Contact: Sankalpa Neupane

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 18 years and older
• Type 2 diabetes diagnosed for at least 12 months
• Established on an SGLT2 inhibitor and/or GLP-1 receptor agonist for at least 3 months, or have been offered these therapies previously.
• Treatment with insulin therapy for at least 6 months
• HbA1c ≤ 15% (140 mmol/mol) analysis from local laboratory or equivalent
• Willing to wear study devices and follow study instructions
• Capacity to consent to participate in the study

Exclusion Criteria:

• Type 1 diabetes
• Current use of insulin pump
• Current use of any closed-loop system
• Any physical/psychological disease or medication(s) likely to interfere with the conduct of the study and interpretation of the study results, as judged by study clinician
• Known or suspected allergy against insulin
• Medically documented allergy towards the adhesive
• Pregnancy, planned pregnancy, or breast feeding
• Severe visual impairment
• Severe hearing impairment
• Medically documented allergy towards the adhesive (glue) of plasters
• Serious skin diseases located at places of the body, which potentially are possible to be used for localisation of the glucose sensor
• Illicit drugs abuse
• Prescription drugs abuse
• Alcohol abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fully closed-loop insulin delivery (CamAPS HX); The automated closed loop system (CamAPS FX) will consist of: YpsoPump insulin pump (Ypsomed, Burgdorf, Switzerland); FreeStyle Libre 3 glucose sensor (Abbott Diabetes Care, CA, USA); Smartphone hosting CamAPS HX app with the Cambridge model predictive control algorithm; Cloud upload system to review CGM/insulin data. Participants will use the fully closed-loop system for 26 weeks at home	Device: CamAPS HX; The automated closed loop system (CamAPS HX) will consist of: YpsoPump insulin pump Freestyle Libre 3 glucose sensor Smartphone hosting CamAPS HX app with the Cambridge model predictive control algorithm
Active Comparator: Standard insulin therapy with glucose sensor; Usual insulin therapy and FreeStyle Libre 3 glucose sensor (Abbott Diabetes Care, CA, USA) for 26 weeks at home.	Other: Standard insulin therapy with glucose sensor; Participants usual insulin therapy with Freestyle Libre 3 glucose sensor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycated haemoglobin (HbA1c) at 26 weeks	Centralised measurement of HbA1c	at 26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of time spent in target glucose range (3.9 to 10.0mmol/L)	Sensor glucose metric measured as a %	over 26 weeks
Mean glucose (mmol/L)	Sensor glucose metric measured in mmol/L	over 26 weeks
Proportion of time spent above target glucose (>10.0mmol/l)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent below target glucose (<3.9mmol/L)	Sensor glucose metric measured as a %	over 26 weeks
Standard deviation of sensor glucose	Sensor glucose metric measured in mmol/L	over 26 weeks
Coefficient of variation of sensor glucose	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent below target glucose (<3.5mmol/L)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent below target glucose (<3.0mmol/L)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent above target glucose (>13.9mmol/l)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent above target glucose (>16.7mmol/l)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of time spent above target glucose (>20.0mmol/l)	Sensor glucose metric measured as a %	over 26 weeks
Proportion of participants with HbA1c <7.0% [53mmol/mol] (%)	Binary metric of HbA1c	at 26 weeks
Proportion of participants with HbA1c <7.5% [58mmol/mol] (%)	Binary metric of HbA1c	at 26 weeks
Total daily insulin dose	Measured in units/day	over 26 weeks
Body weight	Measured in kilograms	at 26 weeks
Waist hip ratio	Ratio	26 weeks
Body Mass Index (BMI)	Measured in kg/m2	26 weeks
Fasted lipid profile	Measured in mmol/L	26 weeks
Renal function	Renal function as measured by serum creatinine	26 weeks
Renal function	Renal function as measured by estimated Glomerular Filtration Rate	26 weeks
Renal function	Renal function as measured by urinary albumin creatinine ratio	26 weeks
Liver function	Liver function as measured by FIB4 index	26 weeks
Liver function	Liver function as measured by alanine transaminase (ALT)	26 weeks
Liver function	Liver function as measured by aspartate transaminase (AST)	26 weeks
Liver function	Liver function as measured by alkaline phosphatase (ALP)	26 weeks
Liver function	Liver function as measured by gamma-glutamyl transferase (yGT)	26 weeks
Liver function	Liver function as measured by serum bilirubin	26 weeks
Blood Pressure (mmHg)		26 weeks
Liver function	Liver function as measured by albumin	26 weeks
Number of severe hypoglycaemia events		26 weeks
Number of participants with any severe hypoglycaemia event		26 weeks
Number of diabetic ketoacidosis events		26 weeks
Number of participants with any diabetic ketoacidosis event		26 weeks
Number of adverse events per participant		26 weeks
Number of serious adverse events per participant		26 weeks
Proportion of CGM use (%)		26 weeks
Proportion of closed-loop use (%)		26 weeks

Collaborators and Investigators

• Sponsor: University of Cambridge
• Collaborators: University of Edinburgh; Swansea University; Jaeb Center for Health Research
• Investigators: Principal Investigator: Roman Hovorka, University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: August 16, 2024
• First Submitted That Met QC Criteria: August 27, 2024
• First Posted (Actual): August 30, 2024

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Closed-loop insulin delivery
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Hypoglycemic Agents; Insulin
• Other Study ID Numbers: COYOTE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication. To gain access, data requestors will need to sign a data access agreement.

Fully anonymised data may be shared with third parties (EU or non-EU based) for the purposes of advancing management and treatment of diabetes.

• IPD Sharing Time Frame: Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication.
• IPD Sharing Access Criteria: Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• 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