Diabetes Mellitus, Type 1SAFE-AP3NCT03577158
SAFE-AP: Automatic Control of Blood Glucose Under Announced and Unannounced Exercise
A study testing Open-loop insulin infusion system in people with Diabetes Mellitus, Type 1, run by Hospital Clinic of Barcelona at 1 site in Spain.
Trial summary
Achieving near-normoglycemia has been established as the main objective for most patients with diabetes. Despite growing evidence about the health benefits of regular exercise in diabetes, exercise-associated glycemic imbalance remains a challenge in subjects with type 1 diabetes (T1D) due to a higher risk of… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Diabetes Mellitus, Type 1
- What is being tested?
- Open-loop insulin infusion system
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteSpain
- Study dates
- 1 Jun 2018to 31 Jul 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age between 18-65 years.
- Under CSII treatment for at least six months before visit 1.
- Body mass index between 18 and 30 kg/m2.
- HbA1c 6.0-8.5% at visit 1.
- Physical examination, laboratory data and EKG without alterations. Abnormalities considered clinically irrelevant by the investigator will not be exclusion criteria.
- Postmenopausal women or women of childbearing age using contraceptives of proven effectiveness and with negative urine pregnancy test at screening visit.
Who cannot join
- Pregnancy and breastfeeding.
- Hypoglycemia unawareness (Clarke Test >3).
- Progressive fatal disease.
- History of drug or alcohol abuse.
- History HIV positive, active hepatitis B or hepatitis C.
- Impaired liver function, as shown in, but not limited to, SGPT (serum gutamate pyruvate transaminase) or SGOT (serum glutamate oxaloacetate transaminase) more than twice the upper limit of normal at Visit 1.
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- Clinically relevant microvascular complications (macroalbuminuria, pre-proliferative and proliferative retinopathy), cardiovascular, hepatic, neurological, endocrine or other systematic, apart from T1D, which may hamper the implementation of the clinical study protocol or interpretation of results study.
- Scheduled surgery during the study period.
- Mental conditions that prevent the subject to understand the nature, purpose and possible consequences of the study.
- Subjects those are unlikely to meet the clinical study protocol, eg uncooperative attitude, inability to return for follow-up visits, or poor probability of completing the study.
- Using an experimental drug or device during the past 30 days.
Trial locations and contacts
1 site in 1 country.
About this study
Achieving near-normoglycemia has been established as the main objective for most patients with diabetes. Despite growing evidence about the health benefits of regular exercise in diabetes, exercise-associated glycemic imbalance remains a challenge in subjects with type 1 diabetes (T1D) due to a higher risk of hypoglycemia.
Automatic glucose control, the so-called artificial pancreas (AP) or closed-loop system, may represent the ideal solution for reaching the therapeutic goals in diabetic patients. Intuitively, closed-loop insulin delivery may be superior to open-loop insulin delivery due to a better compensation of the variability of subcutaneous insulin absorption and the intra-subject insulin sensitivity. However, several challenges exist to effectively realize an optimal closed-loop control of blood glucose during exercise. Indeed, the physical exercise induces one of the major glucose perturbations that need to be controlled by an artificial pancreas and is currently one of the main challenges found in clinical validations of the few existing prototypes of an artificial pancreas. In particular, experiments carried out with the currently used algorithms for glucose control (the so called PID (proportional-integrative-derivative) and MPC) showed that closed-loop insulin delivery is deteriorated by exercise, increasing the risk of hypoglycemia even with pre-exercise carbohydrate ingestion when non-announcement strategies are used.
Read more
In this project, a rigorous clinical testing of a novel closed-loop controller ('artificial pancreas') will be carried out in T1D patients treated with continuous subcutaneous insulin infusion (CSII). The innovative element of the controller is a safety auxiliary feedback based on sliding mode reference conditioning (SMRC), which has been demonstrated to limit over-insulinization and the resulting hypoglycemia, reducing glycaemic variability.
Announced and unannounced exercise will be performed in T1D subjects treated with CSII, comparing the number of hypoglycemic episodes with a controller-driven insulin delivery (closed-loop study) based on continuous subcutaneous glucose monitoring (CGM).
If any glucose value <70 mg/dL 15 gr of glucose will be provided. Moreover 15gr of glucose will be provided in AP studies when AP system recommends it.
The hypothesis is that closed loop control will provide better glycemic control, with less hypoglycemia episodes.
- Conditions
- Diabetes Mellitus, Type 1
- Being tested
- Closed-loop controller with exercise mitigation module, Closed-loop controller without exercise mitigation module, Open-loop insulin infusion system
- Keywords
- Diabetes Mellitus, Type 1, Insulin, Exercise, Closed-loop, Artificial Pancreas
- Medical subject headings
- Diabetes Mellitus, Type 1, Insulin Resistance, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Closed-loop controller with exercise mitigation moduleDevice
Each subject will undergo three exercise tests, each one at 1-2 week intervals, thus completing the 3 experiments in about 6 weeks. The day of the experiment, the participant will do 3 sets of 15 minutes of cycloergometer at 70% of VO2max with 5 minutes of rest between them. On the first arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with a mitigation mode, based on subcutaneous continuous glucose monitoring (First arm, Closed-loop study with mitigation module).
Commercial insulin infusion systems and continuous glucose monitoring devices will be used.
Closed-loop controller without exercise mitigation moduleDevice
On the second arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration without a mitigation mode, based on subcutaneous continuous glucose monitoring (Second arm, Closed-loop study without mitigation module).
Commercial insulin infusion systems and continuous glucose monitoring devices will be used.
Open-loop insulin infusion systemDevice
Standard subcutaneous insulin infusion based on the individual insulin sensibility. Commercial insulin infusion systems and continuous subcutaneous glucose monitoring devices will be used.
| Study group | Role | What they receive |
|---|---|---|
| Closed-loop controller with exercise mitigation module | Experimental | Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with mitigation module.
Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP with mitigation module) based on blood glucose estimations from CGM. Receives: Device: Closed-loop controller with exercise mitigation module; Device: Closed-loop controller without exercise mitigation module; Device: Open-loop insulin infusion system |
| Closed-loop controller without exercise mitigation module | Experimental | Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP without mitigation module) based on blood glucose estimations from CGM. Receives: Device: Closed-loop controller with exercise mitigation module; Device: Closed-loop controller without exercise mitigation module; Device: Open-loop insulin infusion system |
| Open-loop insulin infusion system | Active comparator | Standard Open-loop intensive insulin treatment with continuous subcutaneous insulin infusion (CSII). Commercially available insulin infusion systems will be used. Receives: Device: Closed-loop controller with exercise mitigation module; Device: Closed-loop controller without exercise mitigation module; Device: Open-loop insulin infusion system |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of hypoglycaemias
Number of hypoglycemic episodes (defined as plasma glucose (PG) <70mg/dL) during exercise and recovery.
Measured: 180 minutes psot-exercise period
Secondary outcomes (3)
AUC (area under curve) of PG during exercise and recovery
AUC0_180min, AUC0_60min and AUC60_180min of PG and time spent in different glycemic ranges (< 70; 70-180; > 180 mg/dL) during exercise and recovery.
Measured: 180 minutes post-exercise period
AUC of SG during exercise and recovery
AUC0-180min, AUC0-60min and AUC60-180min of sensor glucose (SG) and time spent in different glycemic ranges (< 70; 70-180; > 180 mg/dL) during exercise and recovery.
Measured: 180 minutes post-exercise period
Rate-of-change of glucose during exercise (ROCe) and recovery (ROCr)
Measured: 180 minutes post-exercise period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jul 2018
- Study start1 Jun 2018
- Primary completion30 Apr 2019
- Study completion31 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- More trials run by Hospital Clinic of BarcelonaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Longitudinal, prospective, interventional study.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Collaborators
- Universitat Politècnica de València, Universitat de Girona
- Responsible party
- Principal investigator, Ignacio Conget, Hospital Clinic of Barcelona
- Investigators
- Jorge Bondia, PhD, Study director, Universitat Politècnica de ValènciaJosep Vehi, PhD, Study director, Universitat de GironaIgnacio Conget Donlo, MD, Study director, Hospital Clinic of BarcelonaMarga Gimenez Alvarez, MD, Study chair, Hospital Clinic of Barcelona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03577158
- Sponsor's protocol ID
- SAFE-AP3
- Acronym
- SAFE-AP3
- Status last verified
- Aug 2019
- First submitted
- 22 Jun 2018
- Last updated
- 7 Aug 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Quiros C, Bertachi A, Gimenez M, Biagi L, Viaplana J, Vinals C, Vehi J, Conget I, Bondia J. Blood glucose monitoring during aerobic and anaerobic physical exercise using a new artificial pancreas system. Endocrinol Diabetes Nutr (Engl Ed). 2018 Jun-Jul;65(6):342-347. doi: 10.1016/j.endinu.2017.12.012. Epub 2018 Feb 23. English, Spanish.
PubMed 29483036Rossetti P, Quiros C, Moscardo V, Comas A, Gimenez M, Ampudia-Blasco FJ, Leon F, Montaser E, Conget I, Bondia J, Vehi J. Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target. Diabetes Technol Ther. 2017 Jun;19(6):355-362. doi: 10.1089/dia.2016.0443. Epub 2017 May 1.
PubMed 28459603Vinals C, Beneyto A, Martin-SanJose JF, Furio-Novejarque C, Bertachi A, Bondia J, Vehi J, Conget I, Gimenez M. Artificial Pancreas With Carbohydrate Suggestion Performance for Unannounced and Announced Exercise in Type 1 Diabetes. J Clin Endocrinol Metab. 2021 Jan 1;106(1):55-63. doi: 10.1210/clinem/dgaa562.
PubMed 32852548
Study at a glance
From the registry record, last updated by the sponsor on 7 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SAFE-AP: Automatic Control of Blood Glucose Under Announced and Unannounced Exercise
- ClinicalTrials.gov ID
- NCT03577158
- Acronym / sponsor ID
- SAFE-AP3 / SAFE-AP3
- Conditions
- Diabetes Mellitus, Type 1
- Keywords
- Diabetes Mellitus, Type 1, Insulin, Exercise, Closed-loop, Artificial Pancreas
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Collaborators
- Universitat Politècnica de València, Universitat de Girona
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 30 Apr 2019 (actual)
- Study completion
- 31 Jul 2019 (actual)
- First posted
- 5 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Achieving near-normoglycemia has been established as the main objective for most patients with diabetes. Despite growing evidence about the health benefits of regular exercise in diabetes, exercise-associated glycemic imbalance remains a challenge in subjects with type 1 diabetes (T1D) due to a higher risk of hypoglycemia.
Automatic glucose control, the so-called artificial pancreas (AP) or closed-loop system, may represent the ideal solution for reaching the therapeutic goals in diabetic patients. Intuitively, closed-loop insulin delivery may be superior to open-loop insulin delivery due to a better compensation of the variability of subcutaneous insulin absorption and the intra-subject insulin sensitivity. However, several challenges exist to effectively realize an optimal closed-loop control of blood glucose during exercise. Indeed, the physical exercise induces one of the major glucose perturbations that need to be controlled by an artificial pancreas and is currently one of the main challenges found in clinical validations of the few existing prototypes of an artificial pancreas. In particular, experiments carried out with the currently used algorithms for glucose control (the so called PID (proportional-integrative-derivative) and MPC) showed that closed-loop insulin delivery is deteriorated by exercise, increasing the risk of hypoglycemia even with pre-exercise carbohydrate ingestion when non-announcement strategies are used.
In this project, a rigorous clinical testing of a novel closed-loop controller ('artificial pancreas') will be carried out in T1D patients treated with continuous subcutaneous insulin infusion (CSII). The innovative element of the controller is a safety auxiliary feedback based on sliding mode reference conditioning (SMRC), which has been demonstrated to limit over-insulinization and the resulting hypoglycemia, reducing glycaemic variability.
Announced and unannounced exercise will be performed in T1D subjects treated with CSII, comparing the number of hypoglycemic episodes with a controller-driven insulin delivery (closed-loop study) based on continuous subcutaneous glucose monitoring (CGM).
If any glucose value <70 mg/dL 15 gr of glucose will be provided. Moreover 15gr of glucose will be provided in AP studies when AP system recommends it.
The hypothesis is that closed loop control will provide better glycemic control, with less hypoglycemia episodes.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 3
- Model description
- Longitudinal, prospective, interventional study.
| Arm | Type | Receives |
|---|---|---|
| Closed-loop controller with exercise mitigation module | Experimental | Device: Closed-loop controller with exercise mitigation module, Device: Closed-loop controller without exercise mitigation module, Device: Open-loop insulin infusion systemSliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with mitigation module. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP with mitigation module) based on blood glucose estimations from CGM. |
| Closed-loop controller without exercise mitigation module | Experimental | Device: Closed-loop controller with exercise mitigation module, Device: Closed-loop controller without exercise mitigation module, Device: Open-loop insulin infusion systemSliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP without mitigation module) based on blood glucose estimations from CGM. |
| Open-loop insulin infusion system | Active comparator | Device: Closed-loop controller with exercise mitigation module, Device: Closed-loop controller without exercise mitigation module, Device: Open-loop insulin infusion systemStandard Open-loop intensive insulin treatment with continuous subcutaneous insulin infusion (CSII). Commercially available insulin infusion systems will be used. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age between 18-65 years.
- Under CSII treatment for at least six months before visit 1.
- Body mass index between 18 and 30 kg/m2.
- HbA1c 6.0-8.5% at visit 1.
- Physical examination, laboratory data and EKG without alterations. Abnormalities considered clinically irrelevant by the investigator will not be exclusion criteria.
Key exclusion criteria (11 listed)
- Pregnancy and breastfeeding.
- Hypoglycemia unawareness (Clarke Test >3).
- Progressive fatal disease.
- History of drug or alcohol abuse.
- History HIV positive, active hepatitis B or hepatitis C.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Closed-loop controller with exercise mitigation moduleEach subject will undergo three exercise tests, each one at 1-2 week intervals, thus completing the 3 experiments in about 6 weeks. The day of the experiment, the participant will do 3 sets of 15 minutes of cycloergometer at 70% of VO2max with 5 minutes of rest between them. On the first arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with a mitigation mode, based on subcutaneous continuous glucose monitoring (First arm, Closed-loop study with mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used. | Device | Closed-loop controller with exercise mitigation module, Closed-loop controller without exercise mitigation module, Open-loop insulin infusion system |
| Closed-loop controller without exercise mitigation moduleOn the second arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration without a mitigation mode, based on subcutaneous continuous glucose monitoring (Second arm, Closed-loop study without mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used. | Device | Closed-loop controller with exercise mitigation module, Closed-loop controller without exercise mitigation module, Open-loop insulin infusion system |
| Open-loop insulin infusion systemStandard subcutaneous insulin infusion based on the individual insulin sensibility. Commercial insulin infusion systems and continuous subcutaneous glucose monitoring devices will be used. | Device | Closed-loop controller with exercise mitigation module, Closed-loop controller without exercise mitigation module, Open-loop insulin infusion system |
Primary outcome
Number of hypoglycaemias
Time frame: 180 minutes psot-exercise period
Number of hypoglycemic episodes (defined as plasma glucose (PG) <70mg/dL) during exercise and recovery.
3 secondary outcomes
AUC (area under curve) of PG during exercise and recovery
Time frame: 180 minutes post-exercise period
AUC of SG during exercise and recovery
Time frame: 180 minutes post-exercise period
Rate-of-change of glucose during exercise (ROCe) and recovery (ROCr)
Time frame: 180 minutes post-exercise period
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Aug 2019.
- Background: PubMed 29483036Quiros C, Bertachi A, Gimenez M, Biagi L, Viaplana J, Vinals C, Vehi J, Conget I, Bondia J. Blood glucose monitoring during aerobic and anaerobic physical exercise using a new artificial pancreas system. Endocrinol Diabetes Nutr (Engl Ed). 2018 Jun-Jul;65(6):342-347. doi: 10.1016/j.endinu.2017.12.012. Epub 2018 Feb 23. English, Spanish.
- Background: PubMed 28459603Rossetti P, Quiros C, Moscardo V, Comas A, Gimenez M, Ampudia-Blasco FJ, Leon F, Montaser E, Conget I, Bondia J, Vehi J. Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target. Diabetes Technol Ther. 2017 Jun;19(6):355-362. doi: 10.1089/dia.2016.0443. Epub 2017 May 1.
- Derived from this study: PubMed 32852548Vinals C, Beneyto A, Martin-SanJose JF, Furio-Novejarque C, Bertachi A, Bondia J, Vehi J, Conget I, Gimenez M. Artificial Pancreas With Carbohydrate Suggestion Performance for Unannounced and Announced Exercise in Type 1 Diabetes. J Clin Endocrinol Metab. 2021 Jan 1;106(1):55-63. doi: 10.1210/clinem/dgaa562.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jorge Bondia, PhD study director
Universitat Politècnica de València
Josep Vehi, PhD study director
Universitat de Girona
Ignacio Conget Donlo, MD study director
Hospital Clinic of Barcelona
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Open-loop insulin infusion system in people with Diabetes Mellitus, Type 1, run by Hospital Clinic of Barcelona at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of hypoglycaemias (time frame: 180 minutes psot-exercise period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03577158, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2019.