Evaluation of a Closed-loop Insulin Delivery System at Home With Tailored Home Care Services in Poorly Controlled Type 2 Diabetes: a Randomized Controlled Trial vs Usual Care
Phase: NA
Conditions: Diabetes Type 2
Sponsor: Air Liquide Santé International

  
  
 
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CLINICAL INVESTIGATION PLAN  
PROTOCOL  
Clinical Investigation Plan number: ALMED-19-003  
Acronym: CLOSE AP+  
Title: Evaluation of a closed-loop insulin delivery system at home with tailored home care services 
in poorly controlled Type 2 diabetes: a randomized controlled trial vs usual care  
ID-RCB Number: 2019-A02317-50  
Revised Version 2.0 dated on 06/12/2019   
Revised Version 3.0 dated on 28/04/2020 (Substantial Amendment #1)  
Revised Version 4.0 dated on 20/01/2021 (Substantial Amendment #2)  
Revised Version 5.0 dated on 17/05/2021 (Substantial Amendment #3)  
Revised Version 6.0 dated on 12/07/2021 (Substantial Amendment #4)  
Revised Version 7.0 dated on 04/03/2025 (blackened version for CT-gov)  
  
Coordinating Investigator  
Professor Yves REZNIK   
Centre Hospitalier Universitaire Avenue de la Côte de Nacre CS 30001 F - 14033 Caen Cedex 9  
Tel: 02 31 06 45 87  
Fax: 02 31 06 48 54  
  Sponsor  
AIR LIQUIDE SANTE INTERNATIONAL  
    
Air Liquide Santé International 75, Quai d’Orsay 75007 Paris  
Tel: 01 49 07 69 62 58  
    
 
Confidential Business information  
The information contained in this protocol is confidential and is intended for the use of clinical investigators.  
It is the property of Air Liquide group or its subsidiaries and should not be copied by or distributed to persons not involved in this clinical 
investigation, unless such persons are bound by a confidential agreement with Air Liquide group or its subsidiaries.  
  
  
  

  
  
 
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SPONSOR  
SIGNATURE PAGE  
  
  
Study title: Evaluation of a closed-loop insulin delivery system at home with tailored home care services in 
poorly controlled type 2 diabetes: a randomized controlled trial vs usual care.  
  
  
  
 
Name & Position  
                         Contact details  
    
 
Contacts: Marie-Danielle Milcent  
                         Air Liquide Santé International  
 
CLOSE Project Manager  
                         28 rue d'Arcueil - Bat A  
Tel: +33 (0) 1 39 07 69 39   
                         94250 Gentilly Tel: +33 (0) 6 70 06 99 15                           
France  
 
 
                         Tel: +33 (0) 1 49 07 60 00  
  
Contacts: Véronique Crone  
International Marketing Manager for Diabetes activities  
Tel: +33 (0) 1 49 69 82 80 Tel: 
+33 (0) 6 13 93 09 64  
Medical supervisor: Dr Juan-Fernando Ramirez,  
  
Medical Vice-President  
Date  
Signature 
___/___/______  
  
    
 
 
 
 

  
  
 
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COORDINATING INVESTIGATOR  
SIGNATURE PAGE  
  
  
Study title: Evaluation of a closed-loop insulin delivery system at home with tailored home care services in 
poorly controlled type 2 diabetes: a randomized controlled trial vs usual care.  
  
  
  
 
Name & Title  
Address & Tel.  
 
Professor Yves REZNIK  
Centre Hospitalier Universitaire  
Avenue de la Côte de Nacre  
CS 30001  
F - 14033 Caen Cedex 9  
Tel: 02 31 06 45 87  
Fax: 02 31 06 48 54  
 
Date  
Signature  
 
___/___/______  
  
    
 
 
 
 
 
 
 
 
 

  
  
 
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INVESTIGATOR STATEMENT  
SIGNATURE PAGE  
  
  
Study title: Evaluation of a closed-loop insulin delivery system at home with tailored home care services in 
poorly controlled type 2 diabetes: a randomized controlled trial vs usual care.  
  
By my signature below, I hereby confirm that I agree:  
- To conduct the trial described in the protocol, in compliance with the ICH Harmonized Tripartite 
Guidelines for Good Clinical Practice (ICH E6), the provisions of the Declaration of Helsinki (Appendix 3) 
and the European Directive 2001/20/EC as well as with applicable local regulatory requirements and with 
the study procedures  
- To conduct the study in compliance with this protocol, any mutually agreed future protocol amendments, 
and with any other study procedures provided by the Sponsor  
- To document the delegation of significant study-related duties and to notify the Sponsor of changes in 
site personnel involved in the study  
- To dispense, track and retain the study medical device in accordance with Good Clinical Practice (GCP) 
and protocol  
- To comply with procedures and all applicable regulations for data recording and reporting including 
Serious Adverse Event (SAE)  
- To authorize direct access to source data for monitoring, auditing and inspection  
- To retain the trial-related essential documents until the Sponsor informs these documents are no longer 
needed as detailed in section XIII.4  
- To refrain from publishing all or part of the information concerning this study as defined in section XIII.8.  
Furthermore, I hereby confirm that I will have and will use the availability of adequate resources, personnel 
and facilities for the conduct of this trial and to fulfill my obligation as principal investigator.  
  
 
Name & Title  
Address & Tel.  
    
 
Date  
Signature  
 
___/___/______  
  
 
 
 
 

  
  
 
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CONTACTS  
COORDINATING INVESTIGATOR:  
▪ Prof. Yves Reznik  
  
SCIENTIFIC BOARD MEMBERS:  
▪ Mr Nicolas Naïditch  
Fédération Française des Diabétiques-Paris  
  
▪ Dr. Martin Carvalho  
Hôpital Vert Coteau- Marseille  
  
▪ Prof. Hélène Hanaire  
Centre Hospitalier Universitaire- Toulouse  
  
▪ Prof. Yves Reznik  
Centre Hospitalier Universitaire- Caen  
  
▪ Prof. Eric Renard  
Centre Hospitalier Universitaire- 
Montpellier  
  
  
  
  
  
  
SPONSOR:  
 AIR LIQUIDE Santé INTERNATIONAL  
 28 rue d'Arcueil - Bat A  
 F - 94250 Gentilly - France  
RESEARCH AND DEVELOPMENT CENTRE:  
Paris Innovation Campus   
Medical R&D, Healthcare World Business Line   
1, Chemin de la Porte des Loges  
BP 126  
F - 78354 Jouy-en-Josas Cedex - France  
▪  MEDICAL VICE-PRESIDENT:  
 Dr. Juan-Fernando Ramirez Tel: 
+ 33 (0) 6 35 51 11 25  
▪ PHYSICIAN:  
Dr. Guila Lancman  
Tel: + 33 (0) 6 47 19 95 78  
▪ PROJECT MANAGER: Marie-
Danielle Milcent Tel: + 33 
(0) 6 70 06 99 15  
▪ Study Manager:  
Stéphanie Frey-Koba (outsourced)  
Tel: +33 (0)7 70 21 31 02  
▪ STATISTICIAN:  
Hélène Pasche  
Tel: + 33 (0) 7 72 11 53 92  
▪ DATA MANAGERS:  
Sabine Low-Hong  
Tel: + 33 (0)6 20 04 16 90  
  
Sylvie Blais (outsourced)  
Tel:  +33 (0)6 29 32 04 86  
MONITORING DATA MANAGEMENT AND STATISTICAL  
ANALYSIS:  
ICTA PM  
1 Rue du Bocage  
F - 21121 Fontaine-lès-Dijon  
Tel: + 33 (0) 3 80 53 40 00  
  
    
 
 

  
  
 
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SYNOPSIS  
Title 
Evaluation of a closed-loop insulin delivery system at home with 
tailored home care services in poorly controlled Type 2 diabetes: a 
randomized controlled trial vs usual care  
Acronym 
CLOSE AP+  
Sponsor’s protocol code 
number  
ALMED-19-003
Sponsor  AIR LIQUIDE SANTE INTERNATIONAL  
Clinical Phase 
Interventional study  
Coordinating Investigator  Professor Yves REZNIK  
Medical/Scientific Experts  
 
Prof. Eric Renard, Prof. Hélène Hanaire, Dr. Martin Carvalho, Mr Nicolas 
Naïditch  
Study centres  Approximately 10 investigational centres located in France specialized in 
Type 2 Diabetes care  
Number of patients 
A total of 56 randomised patients, i.e., 28 patients in each of the 2 study 
arms, in order to have 42 evaluable patients.   

  
  
 
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Context and rationale of the 
study 
In Type 2 Diabetes (T2D), the pathophysiological process results in an 
inadequate production of insulin and an inability of the body to respond 
fully to insulin, defined as Insulin Resistance (IR). The number of T2D 
cases is expected to increase in all countries as a result of population 
aging, changes in dietary habits and a sedentary lifestyle that have led to 
an increasing prevalence of obesity.  
The burden of the diabetes disease represented 7.9 Bn€ in France in  
2014. Diabetes was thus the fourth item of expenditure of the Health 
Insurance. 
In 
addition, 
the 
management 
of 
diabetes-related 
complications represented 7.7 Bn€.   
The treatment of T2D usually starts with oral antidiabetic drugs (OAD). If 
patients are not able to reach their glucose target, they are prescribed 
the first line of T2D therapy – Metformin. Poor glycaemic control on 
metformin can lead to dual and even triple therapy including injectable 
GLP1 analog.   
For patients who are refractory to basal therapy in addition to previously 
prescribed antidiabetic agents, treatment intensification requires the 
addition of prandial insulin therapy to target the control of postprandial 
hyperglycaemia. The resulting regimen of multiple injections of 
rapidacting insulin with basal insulin achieves target glycaemia in > 70% 
of patients but carries an increased risk of hypoglycaemia and body 
weight gain.   
 

  
  
 
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Full compliance with insulin therapy regimens remains challenging, and 
injection anxiety, quality of life disruption, and discomfort are well 
documented obstacles.  
  
A subgroup of T2D patients on an intensified multiple daily injection 
insulin regimen failed to reach glycemic targets, and pump therapy was 
proven to safely improve glucose control. Unfortunately, about half of 
the patients treated with insulin pumps in the OpT2mise trial still did not 
reach the objective of achieving a HbA1c level < 8%. This observation 
together with the inability of disabling patients to manage their insulin 
treatment and their glucose control system i.e. SMBG/CGM,   argues for 
the development of new optimization strategies for insulin therapeutic 
administration. Using an Artificial pancreas (AP) for closing the loop may 
constitute a reliable solution to further improve T2D insulin treatment 
outcomes and diabetes complications in a subgroup of T2D patients with 
poor glucose control, risk of hypoglycemia, and inability for selfmanaging 
their diabetes treatment so that home nurse intervention becomes a 
prerequisite for implementation of an intensified insulin regimen.  
   
The automated insulin delivery system has the potential to improve the 
condition of many poorly controlled insulin-treated T2D patients, in 
particular those needing home nursing care for their daily insulin 
treatment.  
   
The aim of this interventional study, therefore, is to investigate whether 
a therapeutic solution combining an automated insulin delivery system 
(Closed-loop) with tailored Home Healthcare Provider (HHP) services can 
improve blood glucose control, reduce the rate of acute metabolic 
complications (hypoglycaemia and hyperglycaemia), improve both the 
patients quality of life and experience, and reduce the global healthcare 
related costs in patients with uncontrolled Type 2 Diabetes needing home 
nursing care for their daily insulin treatment versus usual care.  

  
  
 
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Objectives  Primary objective  
The primary objective is to determine whether the therapeutic strategy, 
composed of an automated insulin delivery system and home healthcare 
provider services, will improve the glycaemic control, measured by the 
Time In Range (TIR) at the end of the study, in patients with uncontrolled 
Type 2 Diabetes needing home nursing care for their daily insulin 
treatment, compared to usual care (including multiple daily injection 
regimen).   
Secondary objectives  
- 
To assess glycaemic control,  
- 
To assess safety,  
- 
To assess patient’s satisfaction including health-related quality 
of life and experience,  
- 
To evaluate medico-economic impact,  
- 
To assess patient’s usability and compliance,  
- 
To assess family nurses and investigator’s satisfaction,  
- 
To assess home healthcare provider services  
 

  
  
 
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Endpoints 
Primary endpoint  
Time In Range, defined as the percentage of time spent with glucose 
measurements at 70-180 mg/dL (3.9–10.0 mmol/L) recorded by 
continuous glucose monitoring (CGM), during the last 14 days completed 
CGM recording from days 70 to 90.  
The TIR will be computed considering the full 24-h day.   
In a complementary way, the TIR will also be computed considering the 
diurnal period (from 06.00 H to 23.59 H) and the nocturnal period (from 
00.00 H to 05.59 H) separately. Secondary endpoints  
- 
Efficacy endpoints  
● HbA1c absolute change from baseline,  
● Absolute change of glucose variability from baseline (i.e., 
%CV Coefficient of Variation) considering (1) the full 24-h 
day, (2) the diurnal period (from 06.00 H to 23.59 H) and (3) 
the nocturnal period (from 00.00 H to 05.59 H),  
● Absolute change of Time In Range from the 14 days 
completed CGM recording at baseline to the 14 days 
completed CGM recording between D70 and D90. The 
change from baseline in TIR will be analyzed considering the 
full 24-h day.   
● Time below target range, defined as the percentage of time 
spent with CGM glucose (1) <70 mg/dL (3.9 mmol/L), and (2) 
<54 mg/dL (3.0 mmol/L), during the last 14 days CGM 
completed recording from days 70 to 90. The time below 
target range will be analyzed considering the full 24-h day 
and in a complementary way, by splitting the diurnal period 
(from 06.00 H to 23.59 H) and the nocturnal period (from 
00.00 H to 05.59 H),  
● Time above target range defined as the percentage of time 
spent with CGM glucose (1) >180 mg/dL (10.0 mmol/L) and 
(2) ≥250 mg/dL (13.9 mmol/L), during the last 14 days CGM 
completed recording from days 70 to 90. The time above 
target range will be analyzed considering the full 24-h day 
and in a complementary way, the diurnal period (from 06.00 
H to 23.59 H) and the nocturnal period (from 00.00 H to 
05.59 H),  
● Total daily insulin dose change from baseline to D90,  
● Body weight absolute change from baseline to D90,  
● The number of discontinuations and their causes.  
  
  

  
  
 
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- 
Endpoints related to Quality of Life, satisfaction and usability  

  
  
 
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● ent’s satisfaction (including health-related quality of life 
evaluated with EQ-5D-5L and hypoglycemia fear evaluated 
with HFS-II) and experience,  
● Family nurse and investigator satisfaction,  
● Number of study devices and their consumables (by type of 
device) used versus planned to be used,  
● Usability for patient,  
● Time on auto-mode defined as the percentage of time 
spent with activated closed-loop of the automated insulin 
administration system over 24-h day.  
● HHP services: Time to HHP intervention following 
patient/family nurse notice, time to HHP incident 
resolution following patient/family nurse notice, number 
of patients with validated training at Visit 2 (run-in visit),  
 
-  Safety endpoints  
● Number of diabetes-related hospital admissions, and 
duration  
● Number of hypoglycaemic events, number of diurnal 
hypoglycaemic events (i.e., occurring from 06.00 H to 23.59 
H) and number of nocturnal hypoglycaemic events (i.e., 
occurring from 00.00 H to 05.59 H),  
● Number of severe hypoglycaemic events, number of severe 
diurnal hypoglycaemic events (i.e., occurring from 06.00 H to 
23.59 H) and number of severe nocturnal hypoglycaemic 
events (i.e., occurring from 00.00 H to 05.59 H),  
● Number of severe hypoglycaemic events having led to  
hospitalisation,  
● Number of severe hypoglycaemic events having required a 
third party assistance,  
● Number of severe hyperglycaemic events ≥ 300 mg/dL for 
over 1 hour.   
Adverse events and product technical complaints will be collected from 
the signature of the informed consent to study end.  
  
A Data Safety Monitoring Board (DSMB) will review the safety data of the 
five first patients of each group, then 25 patients having completed the 
study, and more frequently if judged necessary by the DSMB.  
 
-  Medico-economic data       
Overall resources, medical devices, their associated consumables and 
drugs consumption used for the patient’s medical management and 
Home Healthcare service (collected in volume, by type and duration if 
applicable) will be recorded.   

  
  
 
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This includes:  
 

  
  
 
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● The scheduled and unscheduled patients contacts (home 
visit, hospital visit, phone call) from family nurses and home 
healthcare providers,  
● The scheduled and unscheduled training sessions of the 
family nurses by home healthcare providers,  
● Each scheduled hospitalisation for Investigational Medical 
Device (IMD) initiation and run-in (for the patients in the 
investigational group),  
● The 
severe 
and 
serious 
(including 
hospitalisation) 
diabetesrelated 
events, 
and 
especially 
severe 
hypoglycaemias, severe hypoglycaemias having led to 
hospitalisation and severe hypoglycaemias having required 
third party assistance,   
● The diabetes-specific medical devices, equipments and 
consumables used,  
● The diabetes-specific drugs especially the insulin  
Methodology 
Randomised, national, multi-centre, open-label, prospective, controlled, 
parallel group clinical trial  
The randomization will be stratified on the HbA1c level at baseline 
(<10.0% or ≥10.0%).   
The randomization will be done centrally, based on a computergenerated 
randomization scheme.  
Study duration  The total study duration from 1st selection to last completion visit is 
expected to last approximately 29 months (From Q4 2019 to Q2 2022).  
Study duration for each patient is approximately 18 weeks +/- 2 weeks.  

  
  
 
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Patient selection  Target population: Patients with uncontrolled Type 2 Diabetes needing 
home nursing care for their daily insulin treatment  
Selection criteria  
1. Male or female patient aged 18 years or older,  
2. Type 2 Diabetes diagnosed for at least 6 months with a stable 
authorized antidiabetic therapeutic regimen for 3 months,  
3. Treated with insulin for at least 6 months,  
4. Patient with 8.0% ≤ HbA1c <12.0% within the last 3 months 
before selection,  
5. Patient with a current minimum of 2 daily insulin injections and 
who would benefit of an optimisation,  
6. Patient requiring long term family nurse's daily assistance at 
home for performing insulin injections and/or glucose 
monitoring,  
7. Total daily insulin dose < 1.5U/kg,  
8. Patient willing and able to complete the requirements of the 
study,  
 

  
  
 
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9. Patient living with a caregiver or a diabetes care partner, or 
patient living alone but with a caregiver living nearby who has 
a telephone and a key to his or her home,  
10. Patient living in an area covered by a GSM (Global System for 
Mobile Communications) network and not considering a trip 
outside of France or out of an area covered by a GSM network 
within the planned dates corresponding to the 30 days of the 
installation of the pump (to cover the open-loop period and 
first 15 days of the closed-loop period), and the last 20 days 
of the study.  
Inclusion criteria  
1. Patient having demonstrated ability to understand the 
benefits and harms of the automated insulin delivery system 
and to continuously and safely wear a CGM, as per 
investigator’s judgement,   
2. Family nurse having demonstrated ability to use the 
automated insulin delivery system, as per HHP judgement,  
3. Patient able to use basic technology such as a cell phone and 
having demonstrated ability to use the automated insulin 
delivery system, as per Home Healthcare Provider (HHP) 
judgment. In case the patient has not demonstrated ability to 
use the automated insulin delivery system, his (her) caregiver 
has to demonstrate ability to use basic technology such as a 
cell phone and the automated insulin delivery system instead 
as per Home Healthcare Provider (HHP) judgment. The 
caregiver has to be an adult person able to speak and read 
French, having demonstrated ability to use the automated 
insulin delivery system, with no known medical condition that 
in the judgment of the investigator might interfere with the 
completion of the protocol. The caregiver must have 
committed to maintain uninterrupted availability via personal 
cell phone and to provide assistance to the patient and must 
be knowledgeable at all times of the participant's location 
during the day when closed loop is in use.    
4. 14 days completed (ie ≥ 70% of the daily data points non 
missing) CGM data from the selection period (the CGM period 
may be repeated only once if uncompleted data),  
5. Patient covered by healthcare insurance (in accordance with 
French regulation),  
6. Patient who has received verbal and written information 
about the study and who signed the informed consent form 
before any study related procedure.  

  
  
 
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7. Patient under curatorship must have received the agreement 
of their legal guardian to participate to the study.  
Exclusion criteria  
1. Pregnant or breastfeeding woman,  
2. Patient who experienced a severe hypoglycaemic event 
having led to a hospitalisation or having required a third party 
assistance within the past 6 months,  
3. Patient who experienced a diabetic ketoacidosis within the 
past 6 months,  
4. Patient who has demonstrated a marked decrease in 
hypoglycaemia perception defined by a Gold score > 4,  
5. Patient who has disabilities which could compromise the 
compliance to the study, in the investigator's opinion,  
6. Patient with severe health impairment resulting in short life 
expectancy (< 1 year) as assessed by the investigator,  
7. Patient 
participating 
in 
another 
interventional 
or 
observational clinical trial or who participated in another 
interventional clinical trial within 30 days before selection,  
8. Patient known allergy to any component of the automated 
insulin delivery system compounds,  
9. Proliferative retinopathy (assessed with a fundus examination 
or retinal photography performed within 6 months before 
selection or before the randomisation at the latest) with visual 
impairment which could compromise the safety of rapid 
glucose control normalisation and  the compliance to the 
study,  
10. Planned initiation of a treatment that would impact the blood 
glucose levels (such as steroids) during the study period,  
11. Patient deprived of liberty by a judicial or administrative 
decision, patient admitted to a social institution, patient 
hospitalized without consent or who is in an emergency 
situation,  
12. Lack of effective contraception in women of childbearing 
potential,  
13. Subject with a history of hearing or vision impairment 
hindering perception of glucose display and alarms (as this 
point is a contra-indication stated in the user's manual of the 
investigational medical device),  
14. Severe impairment of renal function (Creatinine Clearance < 
30 mL/min),  

  
  
 
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15. Patient on dialysis (as the user's manual of Dexcom G6 states 
that G6 readings may be inaccurate in this population),  

  
  
 
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16. Conditions which may increase the risk of induced hypoglycemia 
as per the investigator's judgment,  
17. lnpatient psychiatric treatment in the past 6 months,  
18. Current or recent abuse of alcohol or recreational drugs,  
19. Patients that have frequent exposure to magnetic resonance 
imaging (MRl), computed tomography (CT) scan, or 
highfrequency electrical heat (diathermy) treatment (as this 
point is a contra-indication stated in the user's manual of the 
investigational medical device and Dexcom G6.  

  
  
 
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Investigational Plan 
1/ Selection Period:   
After patient eligibility has been assessed by the investigator and the 
automated insulin delivery system has been presented to the patient,  
and caregiver, the patient gives his/her written consent to participate in 
the study. A 14 days blinded CGM use is initiated for patient baseline 
evaluation of his (her) glycaemic control and acceptance of the CGM 
device sensors. The home healthcare provider provides family nurse 
training on CGM and visits the patient at home, in presence of the family 
nurse, to provide patient and caregiver instructions and training on CGM. 
The family nurse, under HHP supervision will set up the first blinded CGM 
and will change the sensor after 10 days.  
The HHP will set up the connection of the CGM to the cloud-based 
CLARITY® platform, through a dedicated laptop, to ensure remotely data 
access to the Investigator.   
The family nurse continues to visit the patient daily as usual to perform 
glucose monitoring and insulin injections.  
The home healthcare provider visits the patient after 14 days of CGM 
recording to upload the data to the visualisation platform. In case of 
incomplete CGM data after 14 days recording, a new CGM could be set 
up to repeat this period.  
  
At the end of this period and upon validation of the selection / inclusion 
/ exclusion criteria by the investigator based on written information 
provided by the home healthcare provider, the patient is randomly 
assigned to one of the 2 study groups.   
  
2/ Initiation Period:   
For the patients randomized to the investigational group:  
A pump is set up for 2 days use (including 2 nights) in open mode at 
hospital and a new CGM is installed to monitor glucose levels for insulin 
dose adjustments if needed. Those adjustments will be performed at 
hospital according to the investigator’s instructions.   
  
 

  
  
 
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The home healthcare provider will provide family nurse and caregiver 
training on Tandem pump (Tandem-control IQ) and will visit the patient 
at home in presence of the family nurse, to provide patient and caregiver 
instructions.  
The home healthcare provider will set up the connection of the Tandem 
pump, through a dedicated laptop, to the cloud-based t:connect® 
platform to ensure the Investigator has a remote access to data following 
patient hospital discharge.  
The patient will be followed, for 2 weeks, by the family nurse for his/her 
daily glycaemic controls and insulin injections (bolus) through the pump 
and for uploading the data of the CGM and pump to the cloud-based 
t:connect® platform.  
  
For the patients randomized to the control group:  
During the hospital visit, patients randomized to the control group will 
receive instructions from the investigator for optimization of their usual 
insulin therapy (multi injection basal and bolus) to be performed at home 
by their family nurse.  
  
3/ Run-In Period (Patients allocated to investigational group only):  
Patients allocated to investigational group will be hospitalized for 2 
nights. The automated insulin delivery system will be switched from open 
to closed-loop mode. Patients will be monitored during those days by the 
hospital medical team and any insulin dose adjustment will be performed 
according to investigator’s judgement during the hospitalization.   
The HHP will verify the connection of the automated insulin delivery 
system, through a dedicated laptop, to the cloud-based t:connect® 
platform to ensure the Investigator has a remote access to data following 
patient hospital discharge.  
Patients and caregivers will receive instructions and training from Home 
Healthcare Provider on Tandem Control-IQ technical usage at hospital. A 
validation of their learning will be performed at that time.  
  
4/ Follow-Up Period:   
During that period, the patient will receive his/her allocated therapeutic 
strategy.   
For patients in the investigational group:  
- Following the hospital discharge, between 7 to 10 days at the time 
of the next CGM change   
Specific to the study and for safety purpose, the patient will be followed 
by the family nurse twice a day at minimum 6 hours interval to ensure 
the patient uses the automated insulin delivery system properly and to 
upload the data to the visualisation platform. The investigator will 
perform a twice daily follow-up by remote monitoring of patient’s data 
and will call the family nurse as needed.  

  
  
 
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In addition, the home healthcare provider will visit the patient at home 
the day after the hospital discharge (at day 3) and the day of the 1st CGM 
change (day 9) for reminders on the automated insulin delivery system 
training and instructions on how to manage any trouble, and to ensure 
the patient uses the automated insulin delivery system properly.  
  
 
-  For the rest of the Follow-Up Period (after the 1st CGM change) 
The family nurse will visit the patient every 3 days for the insulin cartridge 
refilling, catheter replacement, battery charge and for uploading  data 
from the pump to the cloud-based t:connect® platform and every 9 days 
for CGM replacement. The family nurse will inquire about any event, 
make sure that it is reported in the patient diary and report to the 
investigator and/or HHP as appropriate.   
  
  
The HHP will call the patient 5 days after his/her last visit (day 15) and 
then will visit the patient at home, at day 30 and day 60, for reminders 
on the automated insulin delivery system training and instructions on 
how to manage any trouble.   
  
At each visit, and whenever needed, the HHP will review the data and will 
inform the investigator of any abnormalities. The HHP will make sure the 
patient reports any event and will notify the investigator of any event 
recorded.  
  
For patients in the control group:  
The family nurse will perform the usual care i.e. daily glycaemic controls 
and insulin injections. The family nurse will also make sure the patient is 
reporting any event in his/her diary.   
  
The family nurse and HHP will visit the patient at home at day 70, to set 
up a CGM for 20 days blinded recording. The patient and/or caregiver will 
receive a training with reminders of the proper usage of the CGM.  
  
5/ Ending Period:  
All patients come to the investigator site at day 90 for final data collection 
and evaluation.  
All patients will then return to their pre-study therapy.  

  
  
 
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Investigational Medical Device  The tested therapeutic strategy consists of an automated insulin delivery 
system and a tailored home healthcare provider service to ensure its 
proper use by the patient and family nurse. The automated insulin 
delivery system is made up of 2 medical devices, an insulin pump with a 
closed-loop algorithm, which is the Tandem t:slim X2 Insulin Pump with 
Control-IQ Technology (CE mark for T1D patients), and a CGM which is 
the Dexcom G6 system (CE mark).       
  
 

  
  
 
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Tandem t:slim X2 Insulin Pump with Control-IQ Technology “The Pump”
is made up of:  
- The t:slim X2 Insulin Pump and the t:slim 3mL (300 units) cartridge - 
The catheter (infusion set) which needs to be changed every 3 days.  
In addition, patients, their caregivers and investigating centre staff will 
have access to the t:connect® Diabetes Management Application in both 
home and clinical settings. This t:connect® Application (so-called 
cloudbased t:connect® platform) supports diabetes management 
through the display and analysis of information uploaded from the Pump 
and specified CGM. Thus, the data sharing functionality will keep the 
investigator remotely updated between the visits.   
Data will be uploaded by the healthcare professionals i.e., either the 
family nurse or the home healthcare provider or the investigator 
according to the study period. Data from CGM and Pump will be 
synchronized and displayed on the t:connect® Application during run-in 
and follow-up periods.  
Specific to the study, for safety purpose, following the patient’s discharge 
after the run-in period and during the 7 to 10 days after patient hospital 
discharge (up to the next CGM sensor change) data will be uploaded by 
the family nurse to the visualization platform twice a day at 6 hours 
minimum interval to ensure the patient is using the automated insulin 
delivery system safely.  
Dexcom G6 CGM system includes 3 different components with a sensor 
that is to be changed every 10 days (at maximum):  
A: Simple auto-applicator - a one-touch applicator which easily inserts a 
small sensor just beneath the skin.  
B: Sensor and transmitter - a slim sensor which continuously measures 
glucose levels just beneath the skin and sends data every 5 minutes 
wirelessly through a transmitter to the display device or study pump 
when paired.   
Once installed, no calibration is required.  
C: Display device - a small touch screen receiver which generally displays 
glucose data.  
In addition, Dexcom CLARITY® is the dedicated Dexcom diabetes 
management application available on various platforms (smartphone, 
website) allowing the Healthcare professionals with the data sharing 
functionality the visualization of patients glycaemia data remotely 
keeping them updated between the visits.   
A blinded display device (blinded for control group and investigational 
group during selection and initiation periods) will be provided to the 
study patients to ensure the display of data on CLARITY® platform 
accessible to healthcare professionals only.  
  

  
  
 
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Data will be uploaded by the healthcare professionals i.e., either the 
home healthcare provider or the investigator. Data from CGM will be 
synchronized and displayed on the CLARITY® platform during selection 
period for all patients and during the end of follow-up period for patients 
in the control group.  
During the initiation, run-in and follow-up periods, CGM data will be 
displayed to the t:connect® platform via the insulin pump.  
  
Home Healthcare Provider role consists:  
● In education and training sessions of the patients, caregivers 
and family nurses,  
● In assessment of patients’, caregivers’, and family nurses’ 
knowledge acquired,  
● In supplying the medical devices and consumables,  
● In coordination between patients, caregivers, family nurse 
and investigating center staff,   
● In follow-up by visiting patients, by uploading the Pump 
and/or CGM data and providing written feedback to the 
investigator,  
● In synchronizing the CGM data to the CLARITY® platform for 
patients in the control group,  
● In motivation and encouragement of the patient to the study 
compliance,  
● In providing technical assistance for patients, caregivers and 
family nurses by providing Hotline 24/24h -7 days in case of 
technical complaints,  
● In providing technical intervention at home in case of any 
technical complaint within 12 hours.   
  
The Home Healthcare Provider will apply the Code of Practice for 
Home Healthcare Providers, set out in Appendix 2, for its stipulations 
that would be applicable to the CLOSE AP+ study.  
Accordingly, the home healthcare provider is present at the patient 
home/hospital for CGM and Pump training during selection and initiation 
periods.   
In the investigational group, the home healthcare provider will be 
present at home at D3 (at the time of the 1st bolus), at D9 (at the 1st 
CGM sensor change), at D28 and at D56. In addition, HHP will call the 
patient at D15 and more if judged necessary.  
Specific to the study for safety purpose, CGM and Pump data are 
synchronized to the remote server of the t:connect® application twice 
daily at 6 hours minimum intervals during the first 7 to 10 days after 

  
  
 
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switching to closed-loop mode (up to 1st CGM sensor change) by the 
family nurse.  
  

  
  
 
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In the control group, the home healthcare provider will perform a 
refresh training to the family nurse and patient before set-up of a new 
CGM at D70.   
In addition, the home healthcare provider is present at the hospital for 
the study end visit at D90.  
Concomitant treatments  Non-authorized concomitant treatments  
Glinides, sulfonylurea, glucocorticoids*, any other medication that could 
interfere with glycaemic levels.   
*To note: glucocorticoids are not authorized with the exception of 
patients treated with stable prednisolone < at 10 mg equivalent per day 
since 3 months  
Authorized glycaemic control concomitant treatments Metformin, 
DDP4 inhibitors, GLP1-receptor agonists.   
First aid kit  
In the event of any deficiency of one or more of the components of the 
automated insulin delivery system, the patient should have immediate 
access to a first aid kit including replacement therapy (fast-acting insulin 
and insulin pen).  
Statistical analyses  Analyses will be adjusted on the HbA1c level at baseline (<10.0% or 
≥10.0%) if the study recruitment allows it.  
Thorough description of all parameters recorded will be presented 
separately by study group, using the observed case approach (apart from 
the primary endpoint). Summary tabulated results will be provided by 
group and assessment time/visit, if relevant or they will be replaced by 
the corresponding individual data listings if too few patients are 
concerned.  
Quantitative variables will be summarized in tables displaying number of 
patients, means, standard deviations, medians and percentiles when 
appropriate, and extreme values. When applicable, the Wald two-tailed 
95.0% Confidence Interval (95%CI) of the means will be provided.  
Qualitative variables will be described in terms of frequencies and 
percentages of the total number of non-missing recordings described. 
When applicable, the Agresti-Coull 95%CI of the percentages will be 
provided.  
  
The statistical analysis of the primary endpoint (TIR at D90) will be based 
on modified Intention To Treat (ITT) efficacy and Per Protocol (PP) data 
sets with the PP analysis considered as a sensibility analysis.  
The modified ITT efficacy data set will include all randomised patients 
with at least 3 days with ≥ 70% of non missing CGM data points recording 
at baseline (selection period), as well as at the end of the study (planned 
from D70 to D90).   

  
  
 
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The TIR at D90 will be compared between groups using a parametric 
analysis of covariance model adjusted on the HbA1c stratification factor 
and the TIR value at baseline.  
This analysis will be performed (1) considering the full 24-h day (primary 
efficacy analysis), (2) diurnal period (from 06.00 H to 23.59 H) and (3) 
nocturnal period (from 00.00 H to 05.59 H).  
  
  
 

  
  
 
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Figure 1: STUDY FLOW CHART  
  
  
    
TABLE OF CONTENTS  
I -  Introduction 
41 
I.1 -  Background 
41 
I.1.1 -  Pathophysiology of Type 2 Diabetes 
41 
I.1.2 -  Epidemiology of T2D 
41 
I.1.3 -  Burden of the disease 
41 
I.1.4 -  T2D treatments and care 
42 
I.1.5 -  Initial treatment 
42 
I.1.5.1 -  Intensification 
42 
I.1.5.2 -  Insulin Pump and CGM 
43 

  
  
 
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I.1.5.3 -  Closed-loop systems 
43 
I.1.5.4 -  Outcome measurement 
43 
I.1.5.5 -  Autonomy and global care of patients 
44 
I.2 -  Investigational Medical Device 
44 
I.3 -  Rationale of the study 
45 
I.4 -  Risk and benefits of the investigational design and clinical investigation 
46 
II -  Study objectives 
49 
II.1 -  Primary objective 
49 
II.2 -  Secondary objectives 
49 
III -  Overview Of Study design 
49 
IV -  Study patients 
50 
IV.1 -  Eligibility criteria 
50 
IV.1.1 -  Selection criteria 
50 
IV.1.2 -  Inclusion criteria 
50 
IV.1.3 -  Exclusion criteria 
51 
IV.2 -  Role of caregiver 
52 
IV.3 -  Study duration for the patient 
52 
IV.4 -  Premature study discontinuation 
52 
V -  INVESTIGATIONAL THERAPEUTIC STRATEGY 
53 
V.1 -  Overview of IMD: an automated insulin delivery system 
53 
V.1.1 -  Tandem t:slim X2 Insulin Pump with Control-IQ Technology 
54 
V.1.1.1 -  Control-IQ algorithm system 
54 
V.1.1.2 -  t:connect® Diabetes Management Application 
54 
V.1.2 -  Dexcom G6 CGM system 
55 
V.2 -  Home Healthcare Provider (HHP) services 
56 
V.3 -  Comparator Intervention 
57 
V.4 -  Use of the investigational medical device 
57 
V.4.1 -  Management and dispensing of medical device 
58 
V.4.2 -  Study medical device: automated insulin delivery system packaging and labelling 
58 
V.4.3 -  Study medical device: automated insulin delivery system storage 
59 
V.4.4 -  Dispensation of study medical device: automated insulin delivery system 
59 
V.4.5 -  Management of used and unused IMD 
60 
V.5 -  IMD allocation-Randomization 
60 
V.6 -  Intervention duration 
61 
V.7 -  Observance/Compliance 
61 

  
  
 
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V.8 -  Concomitant medications 
62 
VI -  Schedule of assessments 
62 
VI.1 -  Study flowchart 
62 
VI.2 -  Selection visit (V0) and selection period 
62 
VI.2.1 -  Roles of the investigator 
63 
VI.2.2 -  Roles of the Home Healthcare Provider (HHP) 
64 
VI.2.3 -  Roles of the family nurse 
65 
VI.3 -  Initiation visit (V1) and initiation period 
66 
VI.3.1 -  Roles of the investigator 
67 
VI.3.2 -  Roles of the Home Healthcare Provider (HHP) 
68 
VI.3.3 -  Roles of the family nurse 
69 
VI.4 -  Run-In visit (V2) 
69 
VI.4.1 -  Roles of the investigator 
70 
VI.4.2 -  Roles of the Home Healthcare Provider (HHP) 
71 
VI.4.3 -  Roles of the family nurse 
71 
VI.5 -  Follow-up visits (V3 to V8) 
71 
VI.5.1 -  Roles of the investigator 
71 
VI.5.2 -  Roles of the Home Healthcare Provider (HHP) 
72 
VI.5.3 -  Roles of the family nurse 
73 
VI.6 -  End of study visit (V9) 
74 
VI.6.1 -  Roles of the investigator 
74 
VI.6.2 -  Roles of the Home Healthcare Provider (HHP) 
74 
VI.6.3 -  Roles of the family nurse 
75 
VI.7 -  Assessments and procedures 
76 
VI.7.1 -  Patient’s assessments and procedures 
76 
VI.7.1.1 -  Demographics and child-bearing potential 
77 
VI.7.1.2 -  Medical and surgical history 
77 
VI.7.1.3 -  Physical examination, blood pressure, body weight and height 
77 
VI.7.1.4 -  Treatments 
78 
VI.7.1.5 -  Fundus examination or retinal photography 
78 
VI.7.1.6 -  Pregnancy test 
78 
VI.7.1.7 -  Laboratory data 
78 
VI.7.1.8 -  Glycaemic control and glycaemic variability 
79 
VI.7.1.9 -  Adverse Events/Device Deficiencies/failure 
79 
VI.7.1.10 -  Patient reported outcomes and experiences 
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VI.7.2 -  HHP services utilisation 
81 
VI.7.3 -  Assessment of investigators satisfaction 
82 
VI.7.4 -  Assessment of family nurses satisfaction 
83 
VII -  Endpoints 
84 
VII.1 -  Primary endpoint 
84 
VII.2 -  Secondary endpoints 
84 
VII.2.1 -  Efficacy endpoints 
84 
VII.2.2 -  Patient reported outcomes, experiences and usability 
85 
VII.2.3 -  Health resource utilisation and medical devices consumption 
85 
VII.3 -  Satisfaction 
86 
VII.3.1 -  Safety parameters 
86 
VII.3.2 -  Medico-economic data 
86 
VIII -  Safety and Device Deficiencies 
88 
VIII.1 -  Definitions 
88 
VIII.2 -  Collection, assessment and forwarding/reporting by the investigator 
89 
VIII.2.1 -  Collection and assessment 
89 
VIII.2.2 -  Reporting to the sponsor 
90 
VIII.2.3 -  Assessment by the sponsor 
90 
VIII.2.4 -  Regulatory safety submissions by the sponsor 
90 
VIII.3 -  New safety Events 
91 
IX -  Data handling 
92 
IX.1 -  Electronic Case Report Form (e-CRF) 
92 
IX.2 -  Data Management 
93 
IX.3 -  Study committees 
93 
X -  Statistical methods 
93 
X.1 -  Sample Size 
93 
X.2 -  Data sets analysed 
94 
X.2.1 -  Patients data sets 
94 
X.2.2 -  Investigators data set 
95 
X.2.3 -  Family nurses data set 
95 
X.3 -  Statistical analyses 
96 
X.3.1 -  General considerations 
96 
X.3.2 -  Demographic and other baseline characteristics 
96 
X.3.3 -  Primary efficacy endpoint analysis 
97 
X.3.4 -  Secondary efficacy endpoints analysis 
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X.3.5 -  Safety evaluation 
98 
X.3.5.1 -  Extent of exposure 
98 
X.3.5.2 -  Adverse Events (AEs) 
98 
X.3.5.3 -  Clinical laboratory evaluation 
100 
X.3.5.4 -  Vital signs, physical findings and other observations related to safety 
100 
X.3.5.5 -  Concomitant treatments 
100 
X.3.6 -  Medico-economic evaluations 
100 
X.3.6.1 -  Costs and time estimation 
101 
X.3.6.2 -  Cost-effectiveness 
102 
X.3.6.3 -  Cost-utility 
102 
X.4 -  Handling of dropouts or missing data 
103 
X.5 -  Handling of modifications to the initial statistical methods 
104 
XI -  Quality control/Monitoring 
104 
XI.1 -  Access to source data 
104 
XI.2 -  Audit and inspection 
105 
XII -  Responsibilities 
106 
XII.1 -  Sponsor’s responsibilities 
106 
XII.2 -  Investigator responsibilities 
106 
XIII -  Administrative and regulatory aspects 
106 
XIII.1 -  Good clinical practices/ Declaration of Helsinki 
106 
XIII.2 -  Independent ethics committee and competent authority 
107 
XIII.3 -  Personal data protection and Confidentiality 
107 
XIII.4 -  Commission Nationale de l’Informatique et des Libertés (CNIL) 
108 
XIII.5 -  Patient’s information and consent 
108 
XIII.6 -  Conseil National de l’Ordre des Médecins (CNOM) 
109 
XIII.7 -  Protocol Amendment 
109 
XIII.8 -  Use of Information and Publication of study results 
109 
XIV -  Bibliography 
111 
XV -  APPENDICES 
113 
Appendix 1- Patient validation of knowledges and skills acquired form 
114 
Appendix 2- Code of Practice for Home Healthcare Providers 
116 
Appendix 3- Declaration of Helsinki 
146 
Appendix 4- Hyperglycemia and Hypoglycemia protocol instructions 
155 
 

  
  
 
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LIST OF ABBREVIATIONS AND DEFINITIONS  
Abbreviation  
Definition  
AE 
Adverse Event  
ADA 
American Diabetes Association  
ADE 
Adverse Device Effect  
ADR 
Adverse Drug Reaction  
ALT 
ALanine aminoTransferase  
ANCOVA 
ANalysis of COVAriance  
ANSM 
Agence Nationale de Sécurité du Médicament et des produits de santé  
AP 
Artificial Pancreas  
ASADE 
Anticipated Serious Adverse Device Effect  
AST 
ASpartate aminoTransferase  
ATC 
Anatomical Therapeutic Chemical  
CA 
Competent Authority  
CGM 
Continuous Glucose Monitoring  
CNEDiMTS 
(French) Commission Nationale d’Evaluation des Dispositifs Médicaux et des 
Technologies de Santé  
CNIL 
Commission Nationale de l'Informatique et des Libertés  
CRA 
Clinical Research Associate  
CRF 
Case Report Form  
CRO 
Contract Research Organisation  
CS 
Clinically Significant   
CV 
Coefficient of Variation  

  
  
 
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DRM 
Data Review Meeting  
DSMB 
Data Safety Monitoring Board  
EC 
Ethics Committee  
ENCC 
Echelle Nationale de Coûts à méthodologie Commune  
FDA 
Food Drug Administration  
GCP 
Good Clinical Practice  
GDPR 
General Data Protection Regulation  
HAS 
(French) Haute Autorité de Santé  
HbA1c 
Haemoglobin A1c  
HCP 
HealthCare Provider  
HDL 
High-Density Lipoprotein  
 
HHP 
Home Healthcare Provider  
ICF 
Informed Consent Form  
iCGM 
Integrated Continuous Glucose Monitoring  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IFU 
Instructions For Use  
IMD 
Investigational Medical Device  
IR 
Insulin Resistance  
ISF 
Investigator Site File 
ITT 
Intention To Treat  
IWRS 
Interactive Web Randomization System  

  
  
 
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LDL 
Low-Density Lipoprotein  
MD 
Medical Device  
MDI 
Multi Drug Injections  
MedDRA 
Medical Dictionary for Regulatory Activities  
MMSE 
Mini Mental State Examination   
MoCA 
Montreal Cognitive Assessment  
NGAP 
Nomenclature Générale des Actes Professionnels  
OAD 
Oral Antidiabetic Drug  
PP 
Per Protocol  
PT 
Preferred Term  
QALY 
Quality-Adjusted Life Year  
QoL 
Quality of Life  
RBC 
Red Blood Cell  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation  
SDV 
Source Data Verification  
SEAE 
Study Emergent Adverse Event  
SOC 
System Organ Class  
SOP 
Standard Operating Procedure  
SADE 
Serious Adverse Device Effect  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
 

  
  
 
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T2D 
Type 2 Diabetes  
TIR 
Time In Range  
TMF 
Trial Master File  
UADE 
Unanticipated Adverse Device Effect  
USADE 
Unanticipated Serious Adverse Device Effect   
WBC 
White Blood Cell  
WHO 
World Health Organization  
 
 

  
  
 
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I -  INTRODUCTION  
I.1 -  BACKGROUND   
I.1.1 -  PATHOPHYSIOLOGY OF TYPE 2 DIABETES  
In Type 2 Diabetes (T2D), the pathophysiological process results in an inadequate production of insulin and 
an inability of the body to respond fully to insulin, defined as insulin resistance (IR). Due to insulin resistance 
in muscle and liver tissue, the body’s ability to metabolize glucose becomes compromised. IR is widely 
recognized as one of the earliest steps in the progression of T2D. Although a genetic component to this 
condition exists in many patients, environmental conditions (lifestyle) are thought to be key players in the 
disease’s emergence [8].  
One of the characteristic features of T2D is the progressive nature of the disease. In patients with 
prediabetes and early T2D, the pancreatic beta cells can compensate for insulin resistance by secreting 
greater amounts of insulin to maintain normal glycaemic control. Prediabetic state turns to a diabetic state 
as pancreatic beta cells gradually become exhausted and can no longer meet the demands of 
insulinresistant tissues. Increasing insulin resistance combined with worsening of beta-cell dysfunction, and 
eventual failure, lead to loss of glycaemic control. The consequence of such continued disease progression 
is the increased risk of diabetic complications, with macrovascular complications being the most frequent 
comorbidity associated with T2D. Similarly, microvascular complications, such as neuropathy, nephropathy, 
or retinopathy, are likely to occur. Moreover, multiple pathophysiologic abnormalities including defects in 
functioning in α-cells, adipocytes, gastrointestinal tract, kidney, and brain play important roles in the 
development of glucose intolerance in T2D as well [9].  
I.1.2 -  EPIDEMIOLOGY OF T2D  
Type 2 Diabetes is the most common type of diabetes with a population approximately 10 times larger than 
the T1D population with a fast growth rate [10]. T2D most commonly affects older adults, but rates of T2D 
are increasing in children, adolescents and younger adults [10]. Indeed, the prevalence of T2D is strongly 
associated with aging and obesity. The number of T2D cases is expected to increase in all countries as a 
result of population aging, changes in dietary habits and a sedentary lifestyle that have led to an increasing 
prevalence of obesity [1-4]. The World Health Organization (WHO) has estimated that Type 2 Diabetes will 
affect over 366 million people by 2030 [4]. Given the high mortality associated with the disease, primarily 
due to macrovascular complications, Type 2 Diabetes is a major public health concern worldwide [11]. Like 
many other countries in the world, T2D is a major public health issue in France, facing to an increasing 
number of patients with T2D, and thus an increasing burden of diabetes-related complications [21]. 
Moreover, diabetes is the principal cause of terminal renal insufficiency, adult-onset blindness and 
lowerlimb amputation in Western Europe [2].  
Improvement in T2D care has led to a significant increase in life expectancy of T2D patients during the last 
decades [13]. However, a large number of T2D patients do not achieve an optimal HbA1c level.   
    
I.1.3 -  BURDEN OF THE DISEASE  
In 2014, diabetes was the 4th reason of healthcare expenditure in France with 7.9 Bn € out of a total of 155 
Bn€. Diabetes comes after psychiatric diseases, neuro-cardiovascular diseases and cancers. Healthcare 

  
  
 
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expenses affected 3 Million patients: 83% of expenses were related to primary care, 10% to hospital care 
and 7% to other care. Expenses directly related to diabetes were of 2.3 M€: antidiabetic drugs at 48%, 
medical devices (strips, insulin pens and other medicines such as insulin pumps, CGMs) at 35%, and 
hospitalizations for diabetes as the main reason of admission at 12%. The increase of the prevalence of 
diabetes in France from 2012 to 2014 was of 2.9% [50].  
I.1.4 -  T2D TREATMENTS AND CARE  
The goal of diabetes treatment is the prevention of the onset and progression of micro- and macrovascular 
complications, as well as the achievement of quality of life and longevity equivalent to people without 
diabetes. The UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complications 
Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Kumamoto Study [48] 
have established the importance of glycaemic control [3, 14, 15].  
Poor glycaemic control is a significant challenge in the management of Type 2 Diabetes, with 36% to 69% 
of patients failing to reach glycaemic control targets. These individuals are at an increased risk of developing 
diabetes-related complications, which impact negatively on their quality of life and have cost implications 
for healthcare providers [16].   
Glucose control in Type 2 Diabetes deteriorates progressively over time, and, after failure of diet and 
exercise alone, needs on average a new intervention with glucose-lowering agents every 3-4 years in order 
to obtain/retain good control [17].  
The management of the T2D patient is carried out on the front line by the general practitioner. It often 
requires multidisciplinary cooperation with dieticians, physical activity professionals, nurses, ... 
Diabetologists and other specialists may be needed.  
I.1.5 -  INITIAL TREATMENT  
As long as a residual beta-cell function is retained, the therapy of T2D is designed to support the natural 
regulatory system instead of replacing it completely [13]. The treatment of T2D usually starts with oral 
antidiabetic drugs (OAD). Indeed, if patients are not able to reach their glucose target, they are prescribed 
the first line of T2D therapy – Metformin. Poor glycaemic control on metformin can lead to dual and even 
triple therapy where a patient is given an additional (or two additional) therapeutic(s). This can be a SGLT2 
inhibitor or an incretin-based therapy (DPP4 inhibitor or GLP1 receptor agonist). If the patient also fails to 
achieve tight glycaemic control following this, they may expect to be prescribed insulin [18, 19]. Usually one 
or two daily injections of basal insulin are sufficient for an extended period [20]. The addition of basal insulin 
improves glycaemic control and achieves the target HbA1c level in over 50-60% of patients.   
    
I.1.5.1 -  INTENSIFICATION  
For patients who are refractory to basal therapy in addition to previously prescribed antidiabetic agents, 
treatment intensification requires the addition of prandial insulin therapy to target the control of 
postprandial hyperglycaemia. The resulting regimen of multiple injections of rapid-acting insulin with basal 
insulin achieves target glycaemia in > 70% of patients but carries an increased risk of hypoglycaemia and 
body weight gain. Full compliance with insulin therapy regimens remains challenging, and injection anxiety, 
quality of life disruption, and discomfort are well documented obstacles [5].  

  
  
 
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I.1.5.2 -   INSULIN PUMP AND CGM  
In the OpT2mise trial, it was shown that for insulin-treated T2D patients with unsatisfactory glycaemic 
control on Multi Drug Injections (MDI) therapy a significant improvement (in terms of HbA1c, but also Time 
In Range) could be achieved by using an insulin pump [5-7].  
In the Diamond trial, it was found that CGM use could help to improve glycaemic control on MDI therapy 
(HbA1c and Time In Range) for insulin-treated T2D patients [21].   
It can be estimated that today T2D patients account for 17 to 20% of the total insulin pump users in France 
among an estimated total of 60 000 patients in 2018 (extrapolation from Air Liquide Healthcare data 
through its different affiliates like Orkyn, Vitalaire, LVL, and Dinno Santé). This estimated ratio is unique in 
Europe and may be explained by existing pump funding for T2D patients in France which is not the case in 
some other European countries where pump use is only funded for T1D patients.  
A higher frequency of treatment discontinuation by T2D patients versus T1D can been observed at 6 months 
after treatment initiation, as well as 3 years afterwards. Most of treatment discontinuations before 6 
months are associated with psychological issues regarding the acceptability of the device. Clearly T1D / T2D 
patients differ in many ways, and mainly in the fact that most T2D persons are not insulin dependent for 
several years.  
This type of patients is usually older (an average age of 59 years for T2D patients). Therefore, these patients 
might see the pump as a new constraint associated with a new and invasive step in their disease. Moreover, 
using this device can induce some stress, for it involves comprehension and an active participation from the 
patients to make it effectively work. In this regard, it is key to educate patients and to train healthcare 
professionals, so they can provide the necessary help to ensure the proper and safe use of therapeutic 
tools, and empower the patients so they can manage their glycaemic control.  
I.1.5.3 -  CLOSED-LOOP SYSTEMS  
The development of a closed-loop system that combines CGM with computer-based algorithm to determine 
the amount of insulin to be delivered by the pump may provide further improvements in both glycaemic 
control and reduction in the risk of hypoglycaemia. Hybrid closed-loop systems are characterized by 
automated insulin delivery system, apart from when the user administers insulin boosts at meal time. 
Superior control may delay the onset of macro- and microvascular complications of diabetes [22].  
Several closed-loop (Artificial Pancreas (AP)) systems have been developed and successfully evaluated in 
people with type 1 diabetes leading to improved glucose control and less time in hypoglycaemia [23].   
Opposed to the multitude of clinical trials in T1D, there is far less data with AP solutions in patients with 
T2D [24-28]. In those studies, it was found that AP had the potential to significantly improve Time In Range 
and to reduce time in hyperglycaemia for patients with T2D in hospital settings [13].  
A closed-loop insulin delivery system has also been shown to be safe and feasible in insulin-naïve patients 
with T2D in a controlled research facility setting [28].  
I.1.5.4 -  OUTCOME MEASUREMENT  
The ease and accuracy with which glycated haemoglobin A1c (HbA1c) can be measured has made it an 
invaluable clinical tool for the evaluation of the treatment effect for patients with diabetes. However, 
HbA1c has some inherent drawbacks. While HbA1c reflects average blood glucose over the last 2–3 months, 

  
  
 
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its limitation is the lack of information about acute glycaemic excursions and the acute complications of 
hypo- and hyperglycaemia events. HbA1c also fails to identify the magnitude and frequency of intra- and 
interday blood glucose variation [29]. Moreover, HbA1c is unreliable in patients with anemia, 
haemoglobinopathies or iron deficiency and in female patients who are pregnant [30, 31].  
The introduction of CGM has provided an opportunity to develop metrics of glycaemic control that provide 
valuable information beyond that furnished by glycated haemoglobin A1c (HbA1c). Time In Range refers to 
the time an individual spends within the glucose target range (70 to 180 mg/dL) [31].   
Up to now, HbA1c was considered as the surrogate marker of interest in diabetes.   
Despite its perceived clinical value by clinicians and patients alike, the Food and Drug Administration (FDA) 
has not yet recognized TIR as a valid outcome in order to prove efficacy [32]. In France, the Haute Autorité 
de Santé (HAS) / Commission Nationale d’Evaluation des Dispositifs Médicaux et des Technologies de Santé 
(CNEDiMTS) is willing to consider a surrogate endpoint if validated for the prediction of the expected clinical 
outcome in a scientific paper [33].   
Time In Range (TIR) may be used as an appropriate clinical endpoint in diabetes research and as a measure 
of glycaemic control in patients. Evidence suggests that TIR is inversely correlated to risk of developing 
vascular complications in patients with diabetes [32]. TIR is associated with the prevalence of diabetic 
retinopathy and/or microalbuminuria in T2D [21, 31, 32].    
In 2019, the International Consensus panel at the American Diabetes Association (ADA) [49] identified 
“Time in Range” as a metric of glycaemic control that provides more actionable information than A1c alone. 
The panel agreed that establishing target percentages of time in the various glycaemic ranges with the 
ability to adjust the percentage cut points to address the specific needs of special diabetes populations 
(e.g., pregnancy, high-risk) would facilitate safe and effective therapeutic decision making within the 
parameters of the established glycaemic goals.  
I.1.5.5 -  AUTONOMY AND GLOBAL CARE OF PATIENTS  
Patients play a central role in diabetes care because of their daily responsibility for a large number of 
behavioural choices and activities. More concretely, patients have to take into account their diet, exercise, 
medication administration, blood glucose testing, smoking behaviour and medical examinations, including 
inspections of eyes and feet. Such self-management is a complex activity and includes the ability to monitor 
one’s condition and affects the cognitive, behavioural and emotional responses necessary to maintain a 
satisfactory Quality of Life (QoL).   
Although modern care and education are becoming more patient-centred, many patients find it difficult to 
maintain adequate self-management. High-quality care is therefore needed, to better support patients’ 
self-management abilities [15].  
In France, approximately 25% of home-based T2D patients require assistance to manage their treatment. 
Most of them are elderly patients with several comorbidities requiring private visiting nurses paid by the 
National Social Security for assistance in the management of their T2D.  
For some patients in need of intensification, logistics may be challenging as family nurse is expected to visit 
at meal times.    
I.2 -  INVESTIGATIONAL MEDICAL DEVICE   
The investigated automated insulin delivery system is made up of 2 medical devices.  

  
  
 
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The medical devices components are:  
- 
The Dexcom G6 Continuous Glucose Monitoring (CGM) system (CE marking, class IIb),  
- 
The Tandem t:slim X2 Insulin Pump with Control-IQ Technology. The Control-IQ algorithm is 
implemented into the Tandem t:slim X2 Insulin Pump (CE marked for T1D patients).  
The Tandem t:slim X2 Insulin Pump with Control-IQ Technology system allows automated glycaemia 
recording every 5 minutes and comparison to the pre-set target glucose range. The need for insulin 
subcutaneous infusion or carbohydrates consumption is automatically calculated if the glucose level 
rises above the pre-set glycaemia upper limit or drops below the pre-set glycaemia lower limit, 
respectively. If the upper limit is exceeded, the required amount of insulin is automatically delivered by 
the insulin pump. If the lower limit is dropped below, the required amount of carbohydrates to be 
ingested is indicated to the patient. However, for optimal performance of the system, carbohydrates 
announcements have to be performed before each meal. The performance of the Tandem t:slim X2 
Insulin Pump with Control-IQ Technology system in T1D patients (adults and infants) has been 
demonstrated in several trials [25, 34, 35]. A FDA approval is expected by the end of 2019. However, the 
performance of the Tandem t:slim X2 Insulin Pump with Control-IQ Technology system in T2D has not 
been yet established while closed-loop algorithms have already been evaluated [24, 26, 27, 36]. An in 
silico study was performed to assess the performance of the University of Virginia (UVA) closed loop 
glucose control algorithm (as implemented in the Tandem t:slim X2 Insulin Pump with Control-IQ 
technology) in T2D patients data and using replay simulation methodologies [47]. More specifically, the 
objectives of this in silico study were to determine:  
- 
The most appropriate mode of the Tandem t:slim X2 Insulin Pump with Control-IQ technology i.e., 
exercise or standard, for T2D patients,  
- 
The basal insulin rate,  
- 
If an insulin bolus fixed dosage could be used for every meal announcement.   
This study has showed that all controller modes were safe and superior to open loop therapy. For both 
standard and exercise modes, a basal rate at 100% of the open loop values, associated with fixed meal bolus 
between 10 % to 20% of the total daily dose led to above 75% time between 70 and 180 mg/dL (versus 62% 
in open loop) with similar exposure to low glucose (below 70 mg/dL) at around 2.2% (or 30 min a day). 
Therefore, standard mode of Control-IQ algorithm including a fixed bolus between 10% to 20% of the total 
insulin daily dose (to be modulated based on clinicians observation in real-life use) and a basal insulin 
dosage at 100% of the initial value were identified as the recommended association of values for the setup 
and instructions during the conduct of the CLOSE AP+ study.  
    
I.3 -  RATIONALE OF THE STUDY  
Closed-loop insulin delivery system has the potential to improve the condition of many poorly controlled 
insulin-treated T2D patients.   
A wide acceptance of the AP usage in T2D care will strongly depend on the identification of subpopulations 
and care settings where the AP could significantly improve the risk- and cost-benefit balances of T2D 
management as compared to established practice [36].  
The aim of this interventional study, therefore, is to investigate whether a therapeutic solution combining 
an automated insulin delivery AP system with a tailored HHP service can improve blood glucose control, 
reduce the rate of acute metabolic complications (hypoglycaemia and hyperglycaemia), improve both the 
patients quality of life and experience, and reduce the healthcare related costs in patients with uncontrolled 
Type 2 Diabetes needing home nursing care for their daily insulin treatment versus usual care.  

  
  
 
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I.4 -  RISK AND BENEFITS OF THE INVESTIGATIONAL DESIGN AND CLINICAL INVESTIGATION  
The main benefit for the patient that can be anticipated from the investigational design and clinical 
investigation is an improvement of his/her glycaemic control.   
For the control group, an improvement may be expected from the insulin dosage adjustment based on the 
data collected by CGM. For the investigational group, an improvement is expected from the automated 
insulin delivery AP system with a tailored HHP service.  
All possible risks identified from the investigational design and clinical investigation have been listed 
hereunder with the mitigation actions.  
  
Item  
Explanation  
Mitigation details & actions  
Inappropriate 
insulin dosage 
delivery  
Wrong calculation of 
the insulin dosage by 
the algorithm (not 
performant) Failure 
of the automated 
delivery system  
- 
An in-silico study was performed to assess the 
performance and efficiency of the algorithm on Type 2 
patients’ data (as mentioned in section I.2). The study 
concluded to the superiority of the closed-loop versus the open 
loop with TIR at 75% vs 62% respectively with no severe events. 
- 
A dedicated training of the patient and caregiver in 
case of hyper/hypoglycaemia (detailed in Appendix 4) and 
system failure/deficiency will be set up;   
- 
A hotline 24/24h by the HHC for medical devices 
support and issues will be implemented;  
- 
A hotline 24/24h by the investigator center for medical 
support is available;  
- 
Access to a first-aid kit including replacement insulin 
therapy will be ensured;  
- 
Same algorithm i.e. Control IQ used into 2 recent trials: 
The NIH-funded DCLP3 study (NCT03563313) and the French 
paediatric study Freelife Kid AP study (NCT03739099).  
     
 
 Item  
Explanation  
Mitigation details & actions  
Inappropriate 
and suitable 
technology 
for T2D 
patients  
Bad 
performanc 
e  
No medical 
benefits for  
patients No  
acceptability 
by patients  
- 
Already existing published studies with Closed loops for Type 2 
showing improved glycaemia controls [24, 26, 27, 36].  
- 
An in silico study was performed to assess the performance of 
the University of Virginia (UVA) closed loop glucose control algorithm 
that is implemented in the Tandem t:slim X2 Insulin Pump with 
Control-IQ technology) in T2D patients. This study has showed that all 
controller modes were safe and superior to open loop therapy.   

  
  
 
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Insufficient 
Training and 
patients’ 
monitoring  
Complex 
home return 
Patients 
safety issues 
- 
Training and care will be provided to patients, caregivers and 
healthcare professionals by the HHC with knowledges and skills 
assessment (Appendix 1);   
- 
The data monitoring during the first week following patient 
hospital discharge (pump in closed-loop) will be performed twice a day 
at minimum 6 hours interval by the family nurse at home and remotely 
by the investigator.  
- 
The family nurse will be present at patient home every day 
during the initiation period (pump in open mode).  
- 
The HHC will be present at home with the family nurse for the 
1st medical devices set-up by the family nurse and the day of the patient 
will be back home.  
- 
The use of the devices (CGM, pump and pump with Control IQ 
technology) will be optimised with simplified instructions.   
- 
A dedicated training of the patient and caregiver in case of 
hyper/hypoglycaemia / system failure will be set up;   
- 
A hotline 24/24h by the HHC for medical devices support and 
issues will be implemented;  
- 
A hotline 24/24h by the investigator center for medical support 
is available;  
- 
Access to a first-aid kit including replacement insulin therapy 
(back-up solution).  
Inappropriate 
Interface with 
family nurses  
Lack of 
coordination 
and followup 
around 
patients at 
home  
- 
HHC will ensure good interface and appropriate coordination 
with family nurse and all investigating center staff.   
- 
Family nurse will get all detailed contacts and information 
relating to the role and mission of each participating personnel.   
- 
Family nurse will be present every day during the initiation 
period, every 3 days during follow-up period reinforced by a twice daily 
visit during the first week of the follow-up period i.e. 1st week following 
patient hospital discharge;  
- 
The HHC will be present at home with the family nurse for the 
1st medical devices set-up by the family nurse and the day of the patient 
will be back home;  
- 
The patient will be asked to mention in a specific diary all 
adverse events and device deficiencies/failure. Diary will be controlled 
at each visit of the family nurse and/or HHC.    
  
  
  
 Item  
Explanation  
Mitigation details & actions  
 

  
  
 
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Patient unable 
to use the 
device - lack of 
patients’ 
support  
Patients 
requiring one 
daily visit of 
family nurse  
at home at 
least   
- 
Patients skills assessed for study’s inclusion by the investigator;  
- 
Technical training as well as family nurses support will be 
provided to patients by HHC. The HHC will evaluate the patient’s 
knowledge acquisition and skills after its technical training during each 
visit (Appendix 1);  
- 
Sequential plan (CGM, then Pump in open mode, then closed-
loop system) and periods (selection, initiation, run in)  for the set-up of 
the IMD system to patient including hospital stays (2 nights for open 
mode set-up and 2 nights for closed-loop set-up) and monitoring before 
home returns will be implemented;  
- 
Simplified process to enter a fix value for meal announcement 
with a dedicated and simplified instruction;  
- 
Each meal value entered in the Pump, as well as schedule and 
date will be taken back by the patient in his/her dedicated diary and 
checked by the family nurse during each visit;  
- 
Strong support provided at home including family and HHC 
nurses visits;    
- 
Usual visits provided by the family nurse at home during the first 
week then every 3 days for pump’s consumables replacement and every 
9 days for CGM sensor change;  
- 
A hotline 24/24h 7 days/7 by the HHC for medical devices 
support and issues will be implemented;   
- 
A hotline 24/24h by the investigator center for medical support 
is available  
- 
Regular feedbacks including alerts will be given to investigators 
by the HHC nurse in connection with the family nurse about the patient’s 
knowledge acquisition and the control of his/her treatment.   
- 
Remote monitoring of connected IMD access possible by the 
investigators through dedicated web-based platforms (CLARITYⓇ and 
t:connectⓇ).  
Study 
deviations - 
Lack of process 
to detect 
problems in the 
patient  
Lack of 
reactivity to 
take 
appropriate 
measures  
- 
Alert and recommendation from Sponsor Pharmacovigilance 
Department;   
- 
A DSMB will be put in place during the whole study duration with 
independent members. Definition of stopping rules and review of the 
safety data of the five first patients of each group, then after the 25 
patients having completed the study, and more frequently if judged 
necessary by the DSMB.  
- 
Progressive patients recruitment (recruitment period during 13 
months) with the support of approximately 10 centers.  
Material safety 
issues  
Device failure 
or misuse by 
the patient  
- 
The educational materials are aimed at risk minimisation and 
will support safe and effective use of the product by the patient. The 
HHC will evaluate the patient’s knowledge acquisition after each 
training (Appendix 1).  
- 
The Tandem t:slimX2 insulin pump basal-IQ is CE marked and 
ControlIQ algorithm was investigated into two recent trials, i.e. the NIH-
funded DCLP3 study (NCT03563313) and the French paediatric study 
Freelife Kid AP study (NCT03739099).  

  
  
 
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Of note, where training is required and knowledges and skills assessed as described in Appendix 1, the level 
“en cours” or “acquis” must be obtained for each item by the patient. Otherwise, these levels must have 
been obtained by the caregiver.  
II -  STUDY OBJECTIVES  
II.1 -  PRIMARY OBJECTIVE  
The primary objective is to determine whether the tested therapy strategy, composed of an automated 
insulin delivery system and home healthcare provider services, will improve glycaemic control, measured 
by the Time In Range (TIR) at the end of the study, in patients with uncontrolled Type 2 Diabetes needing 
home nursing care for their daily insulin treatment, compared to usual care (including multiple daily 
injection regimen).                                          
II.2 -  SECONDARY OBJECTIVES  
The secondary objectives are the following:  
- 
To assess glycaemic control,  
- 
To assess safety,  
- 
To assess patient’s satisfaction including health-related quality of life and experience,  
- 
To evaluate medico-economic impact,  
- 
To assess patient’s usability and compliance,  
- 
To assess family nurses and investigator’s satisfaction, - To assess home healthcare provider services.  
  
III -  OVERVIEW OF STUDY DESIGN  
This is a randomised, national, multi-centre, open-label, prospective, controlled study performed in two 
parallel groups.  
Approximately 10 public hospitals located in France and specialized in T2D care management will be 
recruited to enroll a targeted total number of 56 randomized patients with Type 2 Diabetes needing home 
nursing care for their daily insulin treatment (number of patients per group 28 with 1:1 ratio and estimated 
dropout of 25%). The randomization will be stratified according to the level of HbA1c at baseline (<10.0% 
or ≥10.0%). The patient recruitment period will last approximately 24 months and the individual patient 
study duration will be approximately 18 weeks +/- 2 weeks (including a selection, initiation and run-in 
period of 6 weeks +/-2 weeks and a follow-up period of 12 weeks). The total study duration from 1st 
selection to last completion is thus expected to last approximately 29 months.  
    

  
  
 
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IV - STUDY PATIENTS  
IV.1 -  ELIGIBILITY CRITERIA  
Patient selection is based on the selection, inclusion and exclusion criteria listed below. Patients who meet 
each of the selection and inclusion criteria and none of the exclusion criteria are eligible to participate in 
this study.  
All patients will receive oral and written information on the study and will sign a written Informed Consent 
Form (ICF) prior to any study specific assessments and before any data collection is performed.  
IV.1.1 -  SELECTION CRITERIA  
During the selection visit (V0) detailed in section VI.2, the investigator will check that study eligible patients 
meet all the following selection criteria:  
1. Male or female patient aged 18 years or older,  
2. Type 2 Diabetes diagnosed for at least 6 months with a stable authorized antidiabetic therapeutic 
regimen for 3 months,  
3. Treated with insulin for at least 6 months,  
4. Patient with 8.0% ≤ HbA1c <12.0% within the last 3 months before selection,  
5. Patient with a current minimum of 2 daily insulin injections and who would benefit of an 
optimisation,  
6. Patient requiring long term family nurse's daily assistance at home for performing insulin injections 
and/or glucose monitoring,  
7. Total daily insulin dose < 1.5U/kg,  
8. Patient willing and able to complete the requirements of the study,  
9. Patient living with a caregiver or a diabetes care partner, or patient living alone but with a caregiver 
living nearby who has a telephone and a key to his or her home,  
10. Patient living in an area covered by a GSM (Global System for Mobile Communications) network and 
not considering a trip outside of France or out of an area covered by a GSM network within the 
planned dates corresponding to the 30 days of the installation of the pump (to cover the open-loop 
period and first 15 days of the closed-loop period) and the last 20 days of the study.  
    
IV.1.2 -  INCLUSION CRITERIA  
Before randomisation, the investigator will check that study eligible patients meet all the following inclusion 
criteria:  
1. Patient having demonstrated ability to understand the benefits and harms of the automated insulin 
delivery system and to continuously and safely wear a CGM, as per investigator’s judgement,   
2. Family nurse having demonstrated ability to use the automated insulin delivery system, as per Home 
Healthcare Provider (HHP) judgement,  
3. Patient able to use basic technology such as a cell phone and having demonstrated ability to use the 
automated insulin delivery system, as per Home Healthcare Provider (HHP) judgment. In case the 

  
  
 
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patient has not demonstrated ability to use the automated insulin delivery system, his (her) caregiver 
has to demonstrate ability to use basic technology such as a cell phone and the automated insulin 
delivery system instead as per Home Healthcare Provider (HHP) judgment. The caregiver has to be 
an adult person able to speak and read French, having demonstrated ability to use the automated 
insulin delivery system, with no known medical condition that in the judgment of the investigator 
might interfere with the completion of the protocol. The caregiver must have committed to maintain 
uninterrupted availability via personal cell phone and to provide assistance to the patient and must 
be knowledgeable at all times of the participant's location during the day when closed loop is in use.  
4. 14 days completed (i.e.≥ 70% of the daily data points non missing) CGM data from the selection 
period (the CGM period may be repeated only once if uncompleted data),  
5. Patient covered by healthcare insurance (in accordance with French regulation),  
6. Patient who has received verbal and written information about the study and who signed the 
informed consent form before any study related procedure.  
7. Patient under curatorship must have received the agreement of their legal guardian to participate 
to the study.  
IV.1.3 -  EXCLUSION CRITERIA  
During the selection visit (V0) detailed in section VI.2, the investigator will check that study eligible patients 
do not meet any of the following exclusion criteria:  
1. 
Pregnant or breastfeeding woman,  
2. 
Patient who experienced a severe hypoglycaemic event having led to a hospitalisation or having 
required a third party assistance within the past 6 months,  
3. 
Patient who experienced a diabetic ketoacidosis within the past 6 months,  
4. 
Patient who has demonstrated a marked decrease in hypoglycaemia perception defined by a Gold 
score > 4,  
5. 
Patient who has disabilities which could compromise the compliance to the study, in the 
investigator's opinion,  
6. 
Patient with severe health impairment resulting in short life expectancy (< 1 year) as assessed by 
the investigator,  
7. 
Patient participating in another interventional or observational clinical trial or who participated in 
another interventional clinical trial within 30 days before selection,  
8. 
Patient known allergy to any component of the automated insulin delivery system compounds,  
9. 
Proliferative retinopathy (assessed with a fundus examination or retinal photography performed 
within 6 months before selection or before the randomisation at the latest) with visual impairment 
which could compromise the safety of rapid glucose control normalisation and the compliance to 
the study,  
10. Planned initiation of a treatment that would impact the blood glucose levels (such as 
glucocorticoids, sulfonylurea, glinide) during the study period,  
11. Patient deprived of liberty by a judicial or administrative decision, patient admitted to a social 
institution, patient hospitalized without consent or who is in an emergency situation,  
12. Lack of effective contraception in women of childbearing potential,  

  
  
 
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13. Subject with a history of hearing or vision impairment hindering perception of glucose display and 
alarms (as this point is a contra-indication stated in the user's manual of the investigational medical 
device),  
14. Severe impairment of renal function (Creatinine Clearance < 30 mL/min),  
15. Patient on dialysis (as the user's manual of Dexcom G6 states that G6 readings may be inaccurate in 
this population),  
16. Conditions which may increase the risk of induced hypoglycemia as per the investigator's judgment,  
17. lnpatient psychiatric treatment in the past 6 months,  
18. Current or recent abuse of alcohol or recreational drugs,  
19. Patients that have frequent exposure to magnetic resonance imaging (MRl), computed tomography 
(CT) scan, or high-frequency electrical heat (diathermy) treatment (as this point is a contra-
indication stated in the user's manual of the investigational medical device and Dexcom G6.  
IV.2 -  ROLE OF CAREGIVER   
Patients who are not capable to follow all protocol instructions on their own as per investigator’s judgment 
or who have not acquire all knowledge and skills required by the protocol as per Home Healthcare Provider 
(HHP) judgment (as described in Appendix 1), must have a caregiver who should be able to follow protocol 
instructions instead of the Patient.   
The caregiver will assist the patient in the observance of the protocol instructions and in the management of 
his diabetes treatment.   
The caregiver has to be an adult person, with no known medical condition that in the judgment of the 
investigator might interfere with the completion of the protocol and who committed to maintaining 
uninterrupted availability via personal cell phone and to provide assistance to patient. The caregiver must 
have demonstrated the ability to use basic technology such as a cell phone and to use the automated insulin 
delivery system as per Home Healthcare Provider (HHP) judgment.   
  
  
IV.3 -  STUDY DURATION FOR THE PATIENT  
Trial termination is defined by the date of the last completed visit (actual or planned to be performed at 
the time of premature withdrawal if applicable) by the last participating patient. The maximum patient’s 
individual study duration will be of 20 weeks.  
IV.4 -  PREMATURE STUDY DISCONTINUATION  
The study could be interrupted temporarily or definitively by the Sponsor and/or the Ethics Committee 
(EC) and/or the Competent Authority (CA). If such a situation occurs, the investigator should promptly 
inform the patients and complete the study electronic Case Report Form (e-CRF) with all available data 
at that time. Study temporary or definitive discontinuation must be declared to Competent Authority 
(and EC if applicable) in accordance with French local requirements, including its reason such as:  

  
  
 
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- 
The investigational intervention is considered as too noxious (as per Ethics Committee (EC) and/or 
Competent Authority (CA) and/or DSMB (detailed in section IX.3) and/or Sponsor 
Pharmacovigilance Department recommendation);  
- 
A new fact occurs that modifies Sponsor/Competent Authority approval on the trial, such as 
benefit/risk ratio for instance;  
- 
Any unethical reason;  
- 
Sponsor decision to discontinue the IMD development.  
  
Also, patients have the right to withdraw from the study at any time for any reason, without prejudice to 
further treatment. All the data collected until then will be kept in the study, but not the data collected 
afterwards.  
In addition, the Sponsor or the Investigator may decide to stop the trial or part of the trial at any time for a 
given patient.   
Reasons for individual premature withdrawal recorded by the investigator in the e-CRF will include:  
  
- 
At least 1 selection or inclusion criterion not met,   
- 
Any lack of compliance to the study procedures which can compromise the safety of the patient 
and/or study progress and, in particular, for the investigational group only, the lack of safe and 
competent use of the automated insulin delivery system in both open and closed-loop features.  
- 
Discontinuation of one of the investigational medical devices during the initiation and/or run-in 
periods.  
- 
Less than 70% of CGM data recorded during selection period after having retried for an additional 
14 days period of CGM recordings.  
- 
Patient’s inability to attend study visits, - Patient’s consent withdrawal, - Death.  
In these above mentioned cases, the patient will be withdrawn and replaced by another patient who will 
undergo the study protocol in the same study group if the withdrawal occurs before D3. The “end of study” 
module of the e-CRF (detailed in section VI.6) will be completed accordingly by the investigator and the 
date and reason of premature withdrawal will be reported in both the e-CRF and the patient's medical file. 
These withdrawn patients will return to their usual care therapy i.e., multiple daily injection insulin therapy 
and nursing care.  
  
V -  INVESTIGATIONAL THERAPEUTIC STRATEGY  
The study investigational therapy is composed of an automated insulin delivery system made up 2 medical 
devices and of a tailored home healthcare provider service.  
V.1 -  OVERVIEW OF IMD: AN AUTOMATED INSULIN DELIVERY SYSTEM   
An automated insulin delivery system uses an automated insulin delivery pump with an automated insulin 
delivery algorithm and an integrated CGM (iCGM) data to adjust basal insulin delivery and deliver automatic 
insulin correction boluses. The study automated insulin delivery pump is the Tandem t:slim X2 insulin pump 
in which the automated insulin delivery algorithm is directly implemented into the pump to form one 
medical device: the Tandem t:slim X2 insulin pump with the Control-IQ technology. The iCGM data will be 
transmitted from the Dexcom G6 Continuous Glucose Monitoring (CGM) system. Thus, the study 
automated insulin delivery system made up of 2 medical devices are:  
- 
The Tandem t:slim X2 Insulin Pump with Control-IQ technology, hereafter entitled the “Pump”.  

  
  
 
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- 
The Dexcom G6 Continuous Glucose Monitoring (CGM) system (CE marking, class IIb), hereafter 
entitled the “CGM”.  
The automated insulin delivery system allows automated glycaemia recording every 5 minutes and 
comparison to the pre-set target glucose range. The need for insulin subcutaneous infusion or 
carbohydrates consumption is automatically calculated if the glucose level rises above the pre-set 
glycaemia upper limit or drops below the pre-set glycaemia lower limit, respectively. If the upper limit is 
exceeded, the required amount of insulin is automatically delivered by the Pump. If the lower limit is 
dropped below, the required amount of carbohydrates to be ingested is indicated to the patient.   
Insulin is not part of the automated insulin delivery system. The automated insulin delivery system is 
intended to be used with U100 Humalog® or NovoRapid® rapid-acting insulin analogues only. Use of insulin 
with lesser or greater concentration can result in under delivery or over delivery of insulin. This can cause 
a very high or a very low blood glucose.  
V.1.1 -  TANDEM T:SLIM X2 INSULIN PUMP WITH CONTROL-IQ TECHNOLOGY  
This medical device consists of the Tandem t:slim X2 insulin pump with the Control-IQ algorithm system 
implemented to the pump.  
The Tandem t:slim X2 Insulin Pump with Control-IQ technology package includes the following items:  
- 
t:slim X2 Insulin Pump with Control-IQ Technology. The t:slim X2 Insulin Pump is made up of the 
t:slim X2 Insulin Pump (English product with units of insulin designated in mg) and the t:slim 3mL 
(300 units) cartridge.  
- 
Pump Case.   
- 
t:slim X2 Insulin Pump with Control-IQ Technology current user guide in English and the previous one 
in French with a summary of differences.  
- 
USB Cable.   
- 
Wall Power USB Adapter and plug adapter suitable for French electrical outlets.   
- 
Cartridge Removal Tool.  
- 
Assortment of infusion sets.   
The infusion set will be changed by the family nurse every 3 days at the same time the cartridge is refilled.   
V.1.1.1 -  
CONTROL-IQ ALGORITHM SYSTEM  
The Control-IQ algorithm system is implemented in the pump. It includes automated insulin correction 
boluses for high blood glucose in addition to basal rate modulation and it has a dedicated hypoglycaemia 
safety system. The algorithm is initialized based on the patient’s body weight and estimated total daily 
insulin dose. It calculates the required insulin infusion rate or suspends insulin delivery when low blood 
glucose is predicted, aiming at a predefined target glucose level by continuously adapting model 
parameters.  
V.1.1.2 -  
T:CONNECT® DIABETES MANAGEMENT APPLICATION   
The cloud-based t:connect® Diabetes Management Application is intended for patients with diabetes 
mellitus who use Tandem Diabetes Care® insulin pumps, their caregivers and healthcare providers in both 

  
  
 
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home and clinical settings. This t:connect® Application supports diabetes management through the display 
and analysis of information uploaded from Tandem Diabetes Care® insulin pumps and specified blood 
glucometers and/or CGM’s.  
The t:connect® Diabetes Management Application includes the following components:   
The t:connect® HCP Portal which is used by HealthCare Providers (HCP) having collected patient’s consent 
to view patient data that have already been uploaded by either the provider or the patient. Once an account 
is created, users can sign in to the HCP Portal without installing any additional software.  
The t:connect® HCP Software which is an additional application for healthcare providers that must be 
installed on each computer that will be utilized to upload device data in HCP office. This software provides 
the computer a means to upload data successfully to the t:connect® Application through the HCP Portal, 
and does not need to be opened or started separately from the HCP Portal once installed. During the trial, 
the t:connect® HCP Software will not be used.  
The t:connect® Patient Application which is used by patients to upload device data outside of HCP office, 
and to generate and view reports. Once patients upload their data, authenticated and authorized 
healthcare providers can view the patient's reports in the t:connect® HCP Portal. During the trial, the 
t:connect® Patient Application will be used by the family nurse and the HHP to upload device data at home.   
During the CLOSE AP+ trial, patient glycaemic and insulin data will be uploaded at home from the Pump, 
through a dedicated laptop, to the web-based t:connect® platform by either the family nurse, or HHP or 
the investigator according to the study periods (further detailed in section VI).  
  
V.1.2 -  DEXCOM G6 CGM SYSTEM   
The Dexcom G6 CGM medical device allows the continuous measuring of the glucose levels in the interstitial 
fluid.  
The Dexcom G6 CGM is composed by:   
- 
An auto-applicator: a one-touch applicator which easily inserts a small sensor just beneath the skin.  
- 
A glucose sensor inserted under the skin which continuously measures glucose levels in interstitial 
fluid. The sensor is recommended to be fixed to a smooth surface in the abdomen, at least 8 cm far 
from insulin pump. The glucose sensor is calibrated according to the manufacturer’s instruction. 
Once installed, no further calibration is required. The sensor is to be changed every 10 days (at 
maximum). In case of sensor wire rupture or detachment, the patient should contact the healthcare 
provider to avoid any infection or inflammation at the insertion site.  
- 
A transmitter that is attached to the sensor after sensor’s insertion. The Dexcom G6 CGM transmitter 
can only be paired with one medical device at the same time.  
- 
A dedicated receiver: glucose measurements are generally displayed on the receiver (it will set in 
blind mode for all patients during the selection period) and updated every 5 minutes. Data are sent 
wirelessly (Bluetooth Low Energy) to the receiver (during the selection period for all patients and 
during the end of follow-up period for patients in the control group) or to the Pump (during the 
open-mode and closed-loop periods for patients in the Intervention group) through the transmitter. 
Pairing of the receiver to the transmitter can only be achieved if the distance between them does 
not exceed 6 meters.   
Of note, any contact of sunscreens, insect repellents and/or skin care products should be avoided.  

  
  
 
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The following items are provided with the Dexcom G6 CGM medical device:  
- 
USB Cable,  
- 
Wall Power USB Adapter.  
Accessory to Dexcom G6 CGM medical device, the cloud-based Dexcom CLARITY® has data interface 
capabilities. It is intended for use by both home users and healthcare professionals to assist people with 
diabetes and their healthcare professionals in the review, analysis, and evaluation of historical CGM data 
to support effective diabetes management.   
During the CLOSE AP+ trial, the web-based Dexcom CLARITY® will be used by the healthcare professionals 
only during periods where patient is equipped with a blinded CGM. Patient glycaemic data will be uploaded 
at home, from the receiver through a dedicated laptop by the HHP to the Dexcom CLARITY® platform  
 
(further detailed in section VI).  
  
  
V.2 -  HOME HEALTHCARE PROVIDER (HHP) SERVICES  
All referring HHP involved in the CLOSE AP+ trial will be trained to the protocol, study procedures and 
automated insulin delivery system use and management before starting their study participation.   
HHP role consists in:  
- 
delivering the investigational medical devices and associated consumables,  
- 
training session of family nurses to study protocol including procedures, roles and responsibilities, 
and knowledge assessment,  
- 
education and training sessions of family nurses on medical devices (Dexcom G6 CGM and t:slim X2 
Insulin Pump with Control-IQ Technology) functioning, alert management, rescue medication, and 
knowledge assessment,  
- 
performing education and training sessions of patients and caregivers on how to carry / wear the 
CGM and/or t:slim X2 Insulin Pump with Control-IQ Technology and how to manage alerts  
and alarms; giving instructions for 24/24 hours and 7/7 days support; performing knowledge 
assessments of the patients and their caregivers,  
- 
motivating and encouraging the patient to respect the study procedures,  
- 
creating the patient Dexcom CLARITY® account, pairing and blinding the CGM device components 
and uploading the data to the Dexcom CLARITY® platform,  
- 
uploading the glycaemic and insulin data from t:slim X2 Insulin Pump with Control-IQ Technology, 
through the dedicated laptop, to t:connect® platform,  
- 
visualizing and downloading (if needed) insulin and glycaemic data (from Dexcom G6 CGM or t:slim 
X2 Insulin Pump with Control-IQ Technology) and providing report to the investigational site,  
- 
ensuring coordination between patients, caregivers, family nurse and investigating center staff,  

  
  
 
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- 
providing technical assistance for patients, caregivers and family nurses by providing Hotline 24/24h 
-7 days in case of technical complaints or device failure,  
- 
providing technical intervention at home in case of any technical complaint and/or device 
replacement within 12 hours.   
The Home Healthcare Provider will apply the Code of Practice for Home Healthcare Providers, set out in 
Appendix 2, for its stipulations that would be applicable to the CLOSE AP+ study.  
Accordingly, the HHP is present:  
In the investigational group:       
- 
at patient home for Dexcom G6 CGM training and set-up procedure supervision (selection period)  
- 
at hospital for t:slim X2 Insulin Pump with Control-IQ Technology set-up/take off (initiation, run in 
and ending periods)       
- 
at patient home for t:slim X2 Insulin Pump with Control-IQ Technology and/or Dexcom G6 CGM 
refreshing trainings (initiation and follow-up periods), at D3 (ideally at the time of the 1st bolus 
following the hospital discharge of the run-in period), at D9, D30, D60 and any time the patient 
requires it.   
In the investigational group, and specific to the study for safety purpose, the Tandem Pump with ControlIQ 
Technology system data are uploaded to the t:connect® platform twice daily at 6 hours minimum interval 
during the first week (Day 3 to Day 9) by the family nurse (if the patient/caregiver is not able to do it) to 
allow the investigator to closely monitor the patient.   
In the control group:   
- 
at patient home for CGM trainings, at selection and follow-up (at D70) periods.  
In addition, for both study groups, the HHP is present at the hospital for the study end planned at D90 as 
detailed in section VI.6.  
  
  
  
V.3 -  COMPARATOR INTERVENTION   
In the control group, patients continue to receive their usual care which will be composed, according to the 
investigator’s prescription, of basal-bolus multiple daily injection insulin treatment and glycaemic controls 
performed by family nurse during usual daily home visit(s).    
In addition, glucose will be monitored through a Dexcom G6 CGM for 14 days at the selection period and 
for 20 days (to ensure exhaustive data capture for at least 14 days) at the follow-up period ending. The 
initial 14-day monitoring period can be extended by an additional 14-day selection period in case of missing 
CGM data points (corresponding to less than 70% of the data points available over the 1st CGM recording 
as per inclusion criterion detailed in section IV.1.2).  
V.4 -  USE OF THE INVESTIGATIONAL MEDICAL DEVICE  
The automated insulin delivery system is to be used according to instructions given during the investigators, 
family nurses and patients training sessions. Knowledge assessment will be performed at the end of each 
training session.  

  
  
 
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All referring study sponsor and representative personnel, as well as the home healthcare providers nurses 
involved in the CLOSE AP+ trial will be trained to the automated insulin delivery system use and 
management before the study start.  
Investigators have to refer to user guide of medical devices used in the clinical trial regarding 
contraindications, warnings and precautions.  
V.4.1 -  MANAGEMENT AND DISPENSING OF MEDICAL DEVICE  
The two medical devices components of the study automated insulin delivery i.e. Dexcom G6 CGM and the 
Tandem t:slim X2 Insulin Pump with Control-IQ technology will be provided by their manufacturers.  
The Sponsor will order the medical devices to each manufacturer separately. The manufacturers will send 
the medical devices already labelled for clinical trial to the HHP central office.  
The medical devices will be distributed by the HHP nurses to patients and collected at the end of the study 
to return the used and unused medical devices back to the manufacturers.   
Insulin is not provided by the manufacturer and will be purchased directly by the patients at their pharmacy.  
V.4.2 
-  STUDY MEDICAL DEVICE: AUTOMATED INSULIN DELIVERY SYSTEM PACKAGING AND 
LABELLING   
The Dexcom G6 CGM system will be provided in its commercial form (initial kit, consumables and 
replacement equipment) and labelled according to the needs of the clinical study by the manufacturer.  
  
The Tandem t:slim X2 Insulin Pump with Control-IQ technology will be packaged in the form of an initial kit 
as described below and each box will be identified by a serial and/or batch number.  
Initial kit components:  
- 
t:slim X2 Insulin Pump with Control-IQ Technology. The t:slim X2 Insulin Pump is made up of the 
t:slim X2 Insulin Pump (English product with units of insulin designated in mg) and the t:slim 3mL 
(300 units) cartridge.  
- 
Pump Case.   
- 
t:slim X2 Insulin Pump with Control-IQ Technology current user guide in English and the previous one 
in French with a summary of differences.  
- 
USB Cable.   
- 
Wall Power USB Adapter and plug adapter suitable for French electrical outlets.   
- 
Cartridge Removal Tool.  
- 
Assortment of infusion sets.   
Each of the components of the Pump may be provided independently of each other as replacement and/or 
consumable material.  
Thus, throughout the study and according to the needs of the patients and following orders from the HHP, 
the manufacturer will send to the HHP central office the consumables and/or the replacement equipment.  

  
  
 
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V.4.3 -  STUDY MEDICAL DEVICE: AUTOMATED INSULIN DELIVERY SYSTEM STORAGE   
Upon receipt, the HHP central office will electronically record the received kits and will identify them by a 
unique number. The date of receipt will be also recorded. An acknowledgment of receipt will be sent to the 
Sponsor or its representative and kept in the sponsor's Trial Master File (TMF).  
In case of anomaly or damage to the boxes provided, including packaging, the HHP central office will inform 
the manufacturer(s) within 24 business hours.  
In case of batch recall, the manufacturer will warn the Sponsor and HHP central office. The HHP central office 
will follow its recall procedures and will inform the investigators.  
The medical devices will then be stored in a ventilated room, in a dedicated location for the study and in 
accordance with their particular storage conditions (see storage conditions in the MD's operating manual).  
The HHP central office will document any temperature excursions or non-compliance with the storage 
conditions required for the medical devices provided in their file, as well as corrective and preventive 
actions as appropriate.  
V.4.4 -  DISPENSATION OF STUDY MEDICAL DEVICE: AUTOMATED INSULIN DELIVERY SYSTEM  
The investigator, the family nurse and the HHP nurse should use the study medical devices (MDs) only for 
patients who have consented to participate in the study. They will not use or authorize the use of the study 
MDs in circumstances other than those described in this protocol.  
During the selection and inclusion visits, the investigator entrusts the management and initiation of the 
MDs to HHP. If the patient is deemed to be motivated and able to use the automated insulin delivery system 
as per investigator’s judgement, then the HHP will assign a Pump and CGM to the patient as per his/her 
randomisation group allocated.  
The Dexcom G6 CGM system previously labelled for use in a clinical study is provided by the HHP nurse and 
delivered to patients at home for its set-up during the selection period. Additional consumables will be 
provided to allow sensor replacement up to the initiation visit at the hospital.  
The Pump initial kit previously labelled for use in a clinical study is provided by the HHP nurse and delivered 
to the randomised patients in the investigational group on the first day of hospital at the initiation visit.  
Those patients will also be provided with Dexcom G6 CGM consumables to cover the need up to the run-in 
visit at the hospital.  
The MDs replacement can be performed either at the hospital by the investigator (run-in period) or at the 
patient's home by the family nurse or the patient’s caregiver trained by the HHP nurse. The HHP nurse 
will bring the assigned sensor box(es) to the patient's home.  
The HHP nurse will maintain a record of the Pump and CGM kits provided to patients included in the study, 
including the following information:  
- 
Identification of the study,  
- 
Identification of the patient (including patient number in the study) to whom automated insulin 
delivery system under study is distributed,  

  
  
 
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- 
Date(s) of delivery to the patient, quantity(ies), batch/serial number(s) and number of kit(s) 
delivered to the patient (initial shipment, replenishment or replacement),  
- 
Date(s) of return, quantity(ies), batch/serial number(s) and number of kit(s) used, partially used or 
not used by the patient (see section V.4.5). This information will also be recorded in the e-CRF.  
V.4.5 -  MANAGEMENT OF USED AND UNUSED IMD  
Used kits (boxes and empty packaging) or partially used kits are retrieved and stored by the HHP until their 
inventory and reconciliation with the registration of kits administered to patients included in the study.  
During the study, the Home Healthcare Provider will be responsible for the recycling of Dexcom receiver.   
At the end of the study, the HHP will also recover all unused kits (MDs and consumables). He/she will then 
perform an accurate inventory and reconciliation of kits administered to patients with used or partially used 
kits and unused kits.  
Once the reconciliation is done and after explicit agreement of the Sponsor, the HHP will be responsible for 
the return of the MDs to the manufacturer. The manufacturers will be responsible for the destruction 
and/or recycling. The Sponsor will capture a certificate of destruction / recycling, including the following 
information:  
- 
Identification of destroyed / recycled study kits (batch number or patient number)  
- 
Quantity of destroyed / recycled study kits  
- 
Date and method of destruction / recycling  
- 
Name and signature of the person (or company) responsible for the destruction / recycling of the 
MDs and consumables of the study.  
The reconciliation forms and certificates of destruction/recycling will be kept in the HHP, Investigator Site 
File (ISF) and sponsor’s Trial Master File (TMF).  
Any laptop given during the clinical study to patient may be cleaned (hardware) and given to another patient. 
This recycling process guarantees the laptop does not contain any patient data.   
  
  
  
  
  
V.5 -  IMD ALLOCATION-RANDOMIZATION  
At the end of the selection period, as detailed in section VI.2.1, study patients will be randomly assigned in 
a 1:1 ratio to either investigational group or control group according to a central computer-generated 
randomization scheme upon confirmation of their randomisation by their investigator.   
The study randomisation numbers will be allocated sequentially according to a central allocation system,  
i.e., an Interactive Web Response System (IWRS), to limit the possible study group allocation bias. Before 
confirming the patient randomization, the investigator should record the patient’s birth date (month and 
year), the informed consent signature date, the gender, the HbA1c level and the confirmation of the 
inclusion/exclusion criteria met.  
The randomization will be performed by block and stratified on the HbA1c level (either <10.0% or ≥10.0%).  

  
  
 
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The patient will be equipped by the IMD attributed by the IWRS according to his/her randomization number. 
The randomization number will be automatically registered in the e-CRF at the end of the selection period. 
The patient will be informed by phone by the Investigator of the allocated group (control/investigational). 
IMD serial number allocated to each patient will be recorded in the e-CRF at the initiation visit (V1) as per 
the planned IMD dispensation procedure (see section V.4.4).  
The randomization list will be generated via SAS® software by an independent statistician (i.e. out of the 
study team) of the Clinical Research Organization (CRO) delegated by the Sponsor. One signed paper copy 
and one electronic copy of the randomization list will be stored at the Quality Assurance Unit of the CRO. 
The randomization list and individual codes will be kept in the strictest confidentiality until the database 
lock. They will not be accessible to any study team member before the randomisation of a given patient by 
his (her) investigator. Especially, the randomisation blocks size(s) will not be revealed to any study team 
member until the database lock, keeping in mind that this block size may be unique for the whole 
randomisation list or that a combination of 2 or more variable block sizes may have been introduced in the 
randomization list prior to its computer-generation.   
In case of screening failure prior to patient’s randomization, the investigator will specify in the patient’s eCRF 
the date and reason for his (her) non-randomization.   
If a patient withdraws prematurely for any reason after D3, the attributed randomization code and attributed 
IMD will not be reused nor will the patient be allowed to re-enter in the study afterwards.   
V.6 -  INTERVENTION DURATION  
Total duration of the intervention will be of approximately 15 weeks from initiation visit (V1) detailed in 
section VI.3 to end of study visit (V9) detailed in section VI.6 for patients randomised in the study 
investigational group.  
For patients randomised in the control group, the total duration will be approximately 12 weeks from 
initiation visit (V1) detailed in section VI.3 to end of study visit (V9) detailed in section VI.6.   
V.7 -  OBSERVANCE/COMPLIANCE  
All patients will receive appropriate training in the safe use of the automated insulin delivery system in both 
open and closed-loop features for investigational group, and training of CGM only for control group.  
Patient ability to follow instructions for use of the automated insulin delivery system required by the 
protocol will be assessed by the investigator during the selection, initiation and run-in periods. The 
investigator reserves the right to withdraw patients who would not be able to follow the instructions.  
Patients will then come back to their initial treatment. These patients will be replaced if the withdrawal 
occurs before D3.  
Observance of patients during the follow-up period will be assessed by patient’s family nurse, HHP and 
investigator, based on the quality of the glycaemic data and information provided by the patient in the 
patient’s diary. Observance data will be collected in the e-CRF.  
All patients will have regular contacts with the operational study team during the home study periods 
including 24/24 hours 7/7 days telephone support by home healthcare providers. In addition, a hotline 
24/24h by the investigator center for medical support will be available.   

  
  
 
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V.8 -  CONCOMITANT MEDICATIONS  
Any initiation of medication that could interfere with the automated insulin delivery system or with insulin 
therapy will not be authorized during the course of the study. These medications include:  
- 
Glinides,  
- 
Sulfonylurea,  
- 
Glucocorticoids* (*with the exception of patients treated with stable prednisone < at 10 mg 
equivalent per day since 3 months)  
- 
Or any other medication that could interfere with glycaemic levels.  
Authorized glycaemic control concomitant treatments are:  
-Metformin, DDP4 inhibitors, GLP1-receptor agonists.   
-First aid kit    
In the event of any deficiency of one or more of the components of the automated insulin delivery system, 
the patient should have immediate access to a first aid kit including replacement therapy (fast-acting insulin 
and insulin pen).  
  
Of note, acetaminophen is compatible (up to 1 g every 6 hours) with the study automated insulin delivery 
system.  
    
VI - SCHEDULE OF ASSESSMENTS  
VI.1 -  STUDY FLOWCHART  
Ten visits are planned in the study:  
- 
A Selection visit (Visit 0)   
- 
An Initiation visit (Visit 1)  
- 
A Run-In visit (Visit 2)  
- 
Six follow-up visits over a 3-month period (Visits 3 to 8) -  
An end of study visit (Visit 9).  
The study flowchart is available and presented in Figure 1 and Figure 2 with detailed contents per study group 
allocated.  
VI.2 -  SELECTION VISIT (V0) AND SELECTION PERIOD  
The selection will include two different steps: the patient will first be invited to participate in the trial during 
a consultation visit to his (her) diabetes specialist, performed at hospital. The second step consists of a 14- 
to 28-day blinded continuous glucose monitoring period at patient’s home, including regular home visits 
performed by the HHP and the family nurse. Each step of this selection period is detailed below according 
to the healthcare professional in charge of its performance.  

  
  
 
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VI.2.1 -  ROLES OF THE INVESTIGATOR  
Before any inclusion, the Investigator will be trained to the use of the automated insulin delivery system by 
the HHP.  
- 
At patient’s selection visit (Visit 0), the Investigator will:  
● Perform a first verification of selection, inclusion and exclusion criteria to check the potential 
eligibility of the patient to the study, including resource person details for isolated patients.  
● Give an overview of the protocol to the patient. If the patient is interested in participating in the 
trial, the automated insulin delivery system will be presented and the different periods of the 
trial explained in detail to the patient and caregiver (if applicable).  
● Give the information letter to the patient and the patient will sign the informed consent form if 
he/she agrees to participate.  
    
● Perform the following evaluations:  
o 
Blood pregnancy test for women of child-bearing potential.  
o 
Review of the current treatment(s) including T2D treatments and nonauthorized 
concomitant medication (as mentioned in section V.8).   
o 
Physical examination including cognitive assessment (MoCA and/or MMSE), blood 
pressure, body weight and height.  
o 
Visual examination (fundus examination or retinal photography) except for patients 
with fundus examination or retinal photography examination performed within the 
6 months before selection.  
o 
Laboratory data performed within the last 3 months: HbA1c, blood glucose, total 
cholesterol, triglycerides, HDL-Cholesterol, LDL-Cholesterol, serum albumin, AST, 
ALT, gamma GT and serum Creatinine, blood counts (Red Blood Cells (RBC), White 
Blood Cells (WBC), platelets, haemoglobin, hematocrit) with their sampling date, 
fasting status, unit and normal range in use in the local laboratory.  
● Give the schedule of home and hospital visits, the patient’s satisfaction questionnaires and the 
patient diary to the patient. The diary will be used by the patient to collect any adverse events 
and device failure/deficiencies occurring during the trial.  
● Collect the contact details of the family nurse and caregiver of the patient and forward contact 
details information of the patient (and caregiver if applicable) and family nurse to the HHP.  
● Plan the date of the initiation visit (Visit 1).  
● Complete the e-CRF.  
- 
After CGM set-up and 14 days of blinded CGM monitoring at the patient’s home, the Investigator will:  
● Receive the HHP report including information related to study conduct and CGM data collected 
over the 14-day continuous recording period.   

  
  
 
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● Control CGM data and determine if a second 14-day monitoring period is required in case of 
insufficient data collection.  
● If collected data are suitable with study continuation, randomize the patient via IWRS.  
● Inform the patient by phone of the allocated randomization group.  
● Inform the HHP of the patient allocated randomization group.   
- 
Provide required medico-economic information (detailed in section VII.2.6).  
    
VI.2.2 -  ROLES OF THE HOME HEALTHCARE PROVIDER (HHP)  
- 
Before the first visit at the home of the patient, the HHP will:  
● Acknowledge receipt of contact information of the patient (caregiver if applicable) and family 
nurse sent by the investigator.  
● Contact the family nurse by phone to explain the protocol and get his/her oral agreement for 
participation in the study. In case of refusal, all efforts will be made to identify another nurse 
who would be interested in participating in the study. The investigator may have previously 
contacted  the family nurse to introduce the protocol.  
● Upon oral agreement, send the written contract to the family nurse and plan an appointment 
for training of the family nurse to the Dexcom G6 CGM. Of note, the family nurse will designate 
a substitute family nurse who will take over from him/her in case of absence. The same trainings 
will be performed for the family nurse and his/her substitute.  
● Collect the contract signed by the family nurse.  
● Train the family nurse to the use of the Dexcom G6 CGM system according to user guide, hotline 
number in case of product deficiencies or any questions regarding the product.  
● Plan subsequent training sessions with the family nurse.  
● Plan patient’s home visit with the family nurse for installation of the Dexcom G6 CGM system.  
- 
The HHP will visit the patient at home a first time to:  
● Deliver the Dexcom G6 CGM devices for 14 days data collection.   
● Provide a dedicated laptop for data uploading. All laptops will be collected by the HHP after the 
clinical study needs.  
● Train the patient and caregiver to the use of the Dexcom G6 sensor.  
● Supervise the insertion of the Dexcom G6 sensor, pairing of transmitter and receiver, 
configuration of the CLARITY® account on the dedicated laptop, and training of the family nurse 
to data upload. Of note, display device will be set up as blinded device by the HHP.  

  
  
 
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● Instruct the patient, the caregiver and the family nurse to precaution for use, e.g., maximal 
distance between sensor and receiver to be observed, handling of technical and emergency 
problems and adherence issues.  
● Remind the patient of the next hospital visit date and of the schedule of the next visit (potential 
2-nights hospitalization requirement, study design, etc.).   
● Answer patient’s and caregiver’s questions.  
● Remind the patient to answer the patient’s satisfaction questionnaires and to report adverse 
events and technical complaints in the patient diary.  
- 
At the end of the 14-day recording period, the HHP will visit the patient at home for:  
● Uploading the Dexcom G6 CGM data to the CLARITY® platform.   
● Control of uploaded data. If quality requirements of recorded data are fulfilled (≥ 70% non 
missing data points), the Dexcom G6 CGM system will be kept in place and removed at hospital 
during the initiation visit. Otherwise, an additional 14-day recording period will be required and 
the Dexcom G6 CGM system will be changed.  
● Reporting of safety issues and technical complaints from the patient to the study investigator.  
● Immediately after the visit, a written report on validity of Dexcom G6 CGM recorded data and 
on patient ability to follow instructions for study continuation will be sent by the HHP to the 
investigator to proceed to randomisation. The report will also include information on all serious 
adverse events, non-serious adverse events and device deficiencies.  
- 
After randomisation, the HHP will acknowledge receipt of information on randomization group (from 
e-CRF notification) and next visit schedule.  
- 
If the patient is randomized to the investigational group, the HHP will organize an appointment for 
training of the family nurse to the automated insulin delivery system. The HHP will train the family 
nurse on the installation and use of the Pump in open mode. The family nurse will also be reminded 
of the procedure to change the Dexcom G6 sensor.  
- 
After each visit, the HHP will complete the e-CRF and provide the required medico-economic 
information (detailed in section VII.2.6).  
VI.2.3 -  ROLES OF THE FAMILY NURSE  
- 
Before the first study visit at the home of the patient and after information on patient’s participation 
to the trial, introduction to the study protocol by the investigator or HHP, and agreement for 
participation to the study (contract signature), the family nurse will:  
● Be trained to the use of the Dexcom G6 CGM by the HHP, problems management (emergency 
procedures, Dexcom G6 CGM replacement and hotline numbers to be called for either technical 
or medical issues) and upload of Dexcom recordings on the CLARITY® platform.  
● Plan the upcoming training sessions with the HHP.  
● Plan the visit for Dexcom G6 CGM installation at the patient’s home with the HHP.  

  
  
 
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- 
Visits at the patient’s home:  
● The frequency of family nurse visit(s) at the patient’s home for standard diabetes care will 
remain the same as before initiation of the selection period.  
  
  
● The family nurse will visit the patient with the HHP nurse for installation of the Dexcom G6 
sensor. During this visit, the family nurse will be reminded by the HHP on precautions of use 
of the Dexcom G6 CGM system, on emergency procedures, Dexcom G6 CGM replacement, and 
hotline numbers to be called (both technical and medical ones).  
● At each visit, the family nurse will remind the patient of the date of the scheduled visit at 
hospital of the study (potential 2-nights hospitalization requirement, study design, etc.), 
answer the questions of the patient (and caregiver if applicable) and control the information 
in the patient diary.  
● 10 days after Dexcom G6 CGM installation, the family nurse will change and replace the 
Dexcom G6 sensor.  
● If an additional 14-day recording period is required (> 30% missing data points), tasks listed 
above will be repeated during this additional CGM period.  
● The family nurse will be informed on randomization group by the HHP. If the patient is 
randomized to the investigational group, the family nurse will be trained to the automated 
insulin delivery system by the HHP.  
- 
The family nurse will inform the HHP of any serious adverse events, any non-serious adverse events, 
and the device deficiencies/failure.  
- 
After each visit, the family nurse will provide required medico-economic information (detailed in 
section VII.2.6).  
VI.3 -  INITIATION VISIT (V1) AND INITIATION PERIOD   
The purpose of Visit 1 is to initiate the studied diabetes therapies in both randomized groups. The initiation 
period will start with a visit of the patient at hospital for data analysis of the Dexcom G6 CGM system. The 
proceedings of the initiation period will differ depending on the assigned group. Patients randomized to 
the control group will return to their usual T2D care with possible insulin dosage adjustment prescribed by 
the investigator further to CGM data review. Patients randomized to the investigational group will be 
provided with a new Dexcom G6 CGM sensor and a Tandem t:slim X2 insulin pump with control-IQ 
technology that will be installed at the hospital in open-mode for 14 days after a 48h observation period at 
the hospital.  
  

  
  
 
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VI.3.1 -  ROLES OF THE INVESTIGATOR  
- 
Based on CGM data collected during the last 14 days of CGM monitoring, the Investigator will define 
the basal and bolus settings of the pump for the investigational group patients and adjust insulin 
treatment prescription for the control group patients.  
  
  
  
- 
During the visit of the patient at hospital:  
● For all patients:  o The Investigator will collect the questionnaires completed by the patient 
during the selection period. These questionnaires will be sent to the CRO (ICTA PM). o The 
investigator will fill in the e-CRF. In addition, the Investigator will check the patient diary, 
report in the e-CRF any adverse event or device deficiency reported by the patient in his/her 
diary or during the interview and report SAE and device deficiency according to section 
VIII.2.2.  
  
o 
The following evaluations will be performed:  
 
▪  Adverse events and device failure/deficiencies  
 
▪  Physical examination, blood pressure and body weight  
 
▪  Concomitant medications  
▪ Laboratory data: HbA1c, blood glucose, total cholesterol, triglycerides, 
HDL-Cholesterol, LDL-Cholesterol, serum albumin, AST, ALT, gamma GT 
and serum Creatinine, blood counts (Red Blood Cells (RBC), White Blood 
Cells (WBC), platelets, haemoglobin, hematocrit) with their sampling 
date, fasting status, unit and normal range in use.  
  
● For patients randomized to the control group: o The Dexcom G6 sensor will be removed 
and other parts i.e., receiver and transmitter, collected.  
o 
The patient will be reminded of the installation of a CGM for 20 days at Day 70. 
o The patient will be provided with the schedule of visits at home and at the 
hospital, with the patient diary and schedule of patient’s questionnaires to 
complete.  
● For patients randomized in the investigational group: o  
Pump will be installed.  
o 
Patient visit will include 2 nights at hospital for patient observation following the 
set-up of the Dexcom G6 CGM system with the Pump in open mode.  
o 
The patient (and the caregiver if applicable) will be trained to the use of the 
Pump and CGM in open mode, specifically on the management of alarms or 
alerts on the pump and on meal information entry into the pump for bolus insulin 
delivery (always the same value to facilitate the entry and avoid carbohydrate 
calculation). Patients will be provided with a short notice describing the 
management of meals announcement before leaving hospital.  
o 
After 48h of observation, the Investigator will ensure that the patient (or the 
caregiver) is able to go back home and follow the instructions for study 
continuation, and plan the date of the next visit at the hospital to initiate the 

  
  
 
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Run-in period. Otherwise, the patient will be withdrawn from the study and 
replaced.   
o 
The patient will be reminded of the next steps of the protocol and will be 
provided with the schedule of visits at home and at the hospital, with the patient 
diary and schedule of patient’s questionnaires to complete.  
o 
The investigator will fill in the e-CRF.  
o 
During the next weeks, the investigator will have access to patient’s glycaemic 
data through the cloud-based t:connect® platform and will be trained by the HHP 
to the display and exploitation of data on the t:connect® platform. The 
investigator will receive the report from the HHP following his/her visit at patient 
home.   
o 
After Visit 1, the investigator will complete the e-CRF and provide required 
medico-economic information (detailed in section VII.2.6) as needed.  
VI.3.2 -  ROLES OF THE HOME HEALTHCARE PROVIDER (HHP)  
- 
Patients randomized in the control group:  
● The HHP will attend the visit at the hospital to collect the Dexcom G6 CGM devices, the 
dedicated laptop and fill the related certificate.  
● The HHP will contact the family nurse to plan the date for the installation of the Dexcom G6 
CGM system at Day 70 at the patient’s home.  
● The HHP will remind the patient to report adverse events and/or device deficiencies/failure in 
the patient diary.  
  
- 
Patients randomized in the investigational group:  
● The HHP will attend the visit at the hospital for: o Installation of a Dexcom G6 CGM system with 
the Tandem t:slim X2 insulin pump in open mode.  
o Training of the patient (and the caregiver if applicable) to the use of the Tandem 
t:slim X2 insulin pump, to the management of alarms, alerts, hotline numbers, 
contact details in case an HHP intervention would be required.  
● A dedicated training session for the family nurse(s) will be organized before his (her) visit to the 
patient. The family nurse will be trained to the use of the Tandem t:slim X2 insulin pump 
especially in open mode, to the management of alarms, alerts and instructions in case of issues 
and/or required materials replacements. At the end of the training session, a validation of 
knowledge acquired will be performed.  
● The HHP nurse will attend the visit during which the family nurse will change the catheter and 
refill the cartridge of the Pump for the first time for:  
o 
Delivery of all required supplies for the following 2 weeks.  
o 
Reminders on the instructions for the use of the Tandem t:slim X2 insulin pump in 
open mode if required.  
o 
Reminders to the patient (and the caregiver if applicable) and the family nurse on 
the management of alarms, alerts, hotline numbers (both technical and medical 
ones), contact details in case an HHP intervention would be required.  
o 
Upload of Dexcom G6 CGM and pump data on the cloud-based t:connect® platform.  

  
  
 
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o 
Reminders to the patient of the date and duration of the next visit at hospital.  
o 
Reminders to the patient to report adverse events and device deficiencies in the 
patient diary and to answer the patient questionnaires.  
● After each visit, the HHP will send a report to the investigator including the 
glycaemic/insulin data observed, a notification of any adverse events and device 
failure/deficiencies observed or reported by the patient, as well as any additional 
relevant information.  
- 
The HHP nurse will complete the e-CRF and provide required medico-economic information.  
  
VI.3.3 -  ROLES OF THE FAMILY NURSE  
- 
For patients of the control group:  
● The frequency of family nurse visits at patient home will remain unchanged: the family nurse 
will visit the patient at home for standard diabetes care, as prescribed by the Investigator.  
● The family nurse will remind the patient to report adverse events and device failure/ 
deficiencies in the patient diary and the date of the Dexcom G6 CGM system future set-up 
(D70).   
● The family nurse will immediately inform the HHP nurse of any adverse events or device 
failure/deficiencies occurring during the trial period.  
- 
For patients of the investigational group:  
● The family nurse(s) will be trained to the use of the Tandem t:slim X2 with control IQ 
technology system and to the upload of data and to data visualisation on the t:connect® 
platform.  
● The family nurse will administer the insulin bolus during his (her) visit at the patient's home 
using the Tandem t:slim X2 insulin pump as instructed during his (her) training. The frequency 
of the daily home nurse visit(s) will remain the same as for standard diabetes care during the 
initiation period.   
● The family nurse will replace the catheter and refill the insulin cartridge of the Pump every 3 
days at home.   
The family nurse will change and replace the Dexcom G6 sensor every 9 days and upload the 
Dexcom G6 CGM and pump data on the cloud-based t:connect® platform.  
● The family nurse will be reminded of the date of the next visit at the hospital and of the 
procedures to be performed until then.  
● During each visit at the patient’s home, the family nurse will ensure that any adverse events 
and device failure/deficiencies will be reported by the patient in his/her diary. The family 
nurse will immediately inform the HHP nurse of any adverse events or device 
deficiencies/failure occurring during the trial.  
- 
After each visit, the family nurse will provide required medico-economic information (detailed in 
section VII.2.6).  
VI.4 -  RUN-IN VISIT (V2)   
The run-in visit purpose will be to finalize the installation of the automated insulin delivery system studied 
in the investigational group. Thus, this visit will be the starting point of the evaluation of the tested strategy 

  
  
 
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therapy. The run-in visit is performed at the hospital for patients of the investigational group only. It will 
consist in a 2-night hospitalization for the automated insulin delivery system to be initiated (closed-loop 
mode), the settings adjusted and the patient trained to the management of the automated insulin delivery 
system in closed-loop mode.  
VI.4.1 -  ROLES OF THE INVESTIGATOR  
- 
The Investigator will be trained to the automated insulin delivery system in closed-loop mode and to 
the display and exploitation of data on the t:connect® platform.  
- 
The Investigator will set up the automated insulin delivery system and define the settings based on 
insulin pump and CGM data collected during the initiation period, using the standard mode of the 
algorithm. The patient will be closely monitored to ensure the settings and mode chosen are safe.  
- 
Depending on the date of the last change of the Dexcom G6 sensor, the sensor should be changed 
during the run-in visit.  
- 
The patient (and the caregiver if applicable) will be re-trained to enter meal information in the pump 
for bolus insulin delivery (always the same value to facilitate the entry and avoid carbohydrate 
calculation). The Investigator must ensure and confirm that the patient (or the caregiver) will be 
capable to handle the automated insulin delivery system and follow instructions on tasks to be 
performed at home for continuation of the study. Otherwise, the patient will be withdrawn from the 
study and replaced if the withdrawal occurs before D3.  
- 
The investigator will perform a confirmatory fingerstick blood glucose measurements during the first 
12 hours after closed-loop mode activation.  
- 
The investigator will instruct the participant or their caregiver to perform a confirmatory fingerstick 
blood glucose measurements in the following situations:  
● ln case of symptoms of hypoglycemia although CGM glucose 
is > 80 mg/dL  ● lf 20 minutes after fast-acting oral glucose 
intake, CGM glucose is still < 80 mg/dL ● lf 2 hours after bolus 
insulin, CGM glucose is still > 250 mg/dL.  
- 
The following assessments will be performed:  
● Adverse events and device deficiencies/failure collection ● 
Physical examination, blood pressure and body weight ● 
Concomitant medications.  
- 
Before leaving the hospital:   
● The patient and/or his (her) caregiver will be provided with: o 
 
Patient questionnaires,   
o 
Guide on the management of alarms, alerts, hotline numbers,   
o 
Contact details in case of technical intervention required with emergency and 
replacement procedures,  
o 
Contact details in case of a medical emergency, o  
Roles of the investigator, 
the HHP and the family nurse, o  The patient diary including a specific section for 
bolus reporting, o  
The date of the end of study visit planned.  
  
- 
The Investigator will complete the e-CRF and provide required medico-economic information  

  
  
 
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(detailed in section VII.2.6).  
VI.4.2 -  ROLES OF THE HOME HEALTHCARE PROVIDER (HHP)  
The HHP will attend the run-in visit at hospital for the switch to the automated insulin delivery system from 
open to closed-loop mode.  
During this visit, the HHP will:  
- 
Train the patient (and the caregiver if applicable) to the use of the automated insulin delivery system 
in closed-loop mode.  
- 
Identify, with the Investigator, the strengths and weaknesses in the patient (and caregiver if 
applicable) understanding of the management of the closed-loop system and re-explain the tasks that 
are not fully understood.  
- 
Verify the connection of the Pump to the t:connect® platform to ensure the Investigator has access 
to data.  
After the visit, the HHP will complete the e-CRF and provide required medico-economic information (detailed 
in section VII.2.6).  
VI.4.3 -  ROLES OF THE FAMILY NURSE  
The family nurse will not be directly involved in the run-in visit. The HHP will contact the family nurse to 
schedule an appointment at patient home the day after hospital discharge.  
VI.5 -  FOLLOW-UP VISITS (V3 TO V8)  
The Investigator will not attend the follow-up visits at patient’s home, but he/she will receive the reports 
of each of them and he/she will be alerted if needed by the HHP. These visits will be performed at the 
patient’s home by the HHP to ensure that the patient manages safely the automated insulin delivery 
system, that all procedures are performed according to the protocol, to control the upload of data on the 
t:connect® platform and to resupply the patient with all materials required i.e., Dexcom G6 CGM sensors 
and transmitter and Tandem t:slim X2 insulin pump catheters and cartridges.   
VI.5.1 -  ROLES OF THE INVESTIGATOR  
During the follow-up period, the Investigator will perform a remote follow-up of glycaemic and insulin data.  
Specific vigilance during the first 10 days   
During the first 10 days: the Investigator will verify glycaemia on the t:connect® platform twice a day at 
6 hours minimum interval to ensure optimal settings of the pump and patient’s safety. If pump settings 
have to be modified, the Investigator will contact the family nurse who will modify the pump settings 
according to the new written prescription received. Changes in pump settings and safety information 
must be entered by the Investigator in the e-CRF.  
From 11th day onwards, the Investigator will analyze the report sent by the HHP after each visit.  

  
  
 
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The Investigator will be immediately notified by the HHP of any adverse event, and/or device 
deficiencies/failure occurring during this period. Safety information will be reported by the Investigator 
in the e-CRF.   
  
VI.5.2 -  ROLES OF THE HOME HEALTHCARE PROVIDER (HHP)  
- 
For patients of the investigational group (Visits 3 to 7):  
● The HHP will visit the patient at home the day after the end of hospitalization (Day 3, visit 3) 
in the presence of the family nurse, the day of the first CGM sensor change (Day 9, visit 4), 
1 month (Day 30, visit 6), and 2 months (Day 60, visit 7) after the set-up of the automated 
insulin delivery system in closed-loop mode.   
● In addition, the HHP will call the patient at Day 15 (Visit 5). The visits 3 to 7 and the phone 
call at day 15 are intended to:  
o 
Ensure that the patient enters meal information in the Pump for bolus insulin 
delivery and knows how to do it.  
o 
Remind the patient of the management of alerts, alarms and emergency issues. 
The contact details of the persons to be contacted in case of safety or technical 
issues will be reminded to the patient. The HHP will ensure that adverse events 
and/or device deficiencies will be reported by the patient in his/her diary. Any 
mismanagement of the system will be reported to the Investigator.  
o 
Ensure that data are uploaded on the t:connect® platform and remind the family 
nurse of the procedures for data upload (performed twice a day with 6 hours 
minimum interval during the first 10 days following patient hospital discharge 
and at each visit afterwards).  
● In addition, the HHP will provide the patient every month with required supplies for 
automated insulin delivery system.  
● The HHP will collect the patient questionnaires at Day 30 (Visit 6) and will remind the patient 
to complete the next questionnaires before Visit 9.  
  
  
● During the follow-up period, the HHP will also perform a remote follow-up of glycaemia and 
insulin data. Serious adverse events, non-serious adverse events possibly related to the IMD, 
to investigation procedures or to diabetes and device deficiencies/failure will be 
immediately notified to the Investigator.  
  
- 
For patients of the control group (Visit 8):  
● An appointment for Visit 8 will be planned 20 days before the study end visit to set up a new 
Dexcom G6 system for a 20-day continuous glucose monitoring period. This visit will be 
performed with the family nurse.  
  
● The patient will be reminded of the precautions of use of the Dexcom G6 CGM, on 
management of emergency problems and device deficiencies/failure. The HHP will also 

  
  
 
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remind the patient of completing the patient diary, of the date of the next visit at hospital 
(Visit 9) and of completing the next questionnaires before Visit 9.  
● The HHP will configure the CLARITY® account and remind the family nurse of the process of 
data upload on the CLARITY® platform. The family nurse will also be reminded to check that 
the patient fills in the patient diary and to report any adverse event or device 
deficiencies/failure to the HHP.  
- 
The HHP will complete the e-CRF and provide required medico-economic information (detailed in 
section VII.2.6).  
VI.5.3 -  ROLES OF THE FAMILY NURSE  
- 
For patients of the investigational group:  
On Day 3, the family nurse will be trained by the HHP to the upload of data and to data visualisation on the 
t:connect® platform.  
  
Specific vigilance during the first 7 to 10 days   
From the first day after patient discharge (Day 3) to the day of first CGM sensor change, the family nurse 
will visit the patient at least twice a day at 6 hours minimum interval to ensure the patient uses the 
pump safely, to upload data from the pump to the t:connect® platform, to ensure the patient enters the 
fixed bolus corresponding to 10% to 20% of his(her) total insulin daily dose as the meal value in the Pump 
as instructed by the investigator, and to ensure more globally the patient uses the automated insulin 
delivery system in a right way.  
  
- 
From 11th day onwards (after the first CGM sensor change), the family nurse will visit the patient 
every 3 days.    
● At each visit, the family nurse will:  
o change the Pump catheter and refill the cartridge,  
 
▪  control the charge of the battery and charge it if necessary,   
 
▪  ensure that the patient enters meal value in the pump,  
▪ ensure that adverse events and device deficiencies/failure are reported by 
the patient in his/her diary. Any adverse event and/or device 
deficiencies/failure must be reported by the family nurse to the HHP. ▪ Every 
3 visits, the family nurse will change the CGM sensor.  
o upload data from the Pump to the t:connect® visualisation platform.  
- 
For patients of the control group:  
● The frequency of visit(s) at the patient’s home will remain the same as before study initiation, 
as defined by the medical prescription. In addition to usual diabetes care, the family nurse 
will ensure that adverse events and device deficiencies are reported by the patient in his/her 
diary.   
The family nurse will immediately inform the investigator of any adverse event occurring 
during the trial. The family nurse will also ensure that the patient questionnaires are 
completed before Visit 9.  

  
  
 
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● Visit 8 at the patient’s home will be planned with the HHP.  
● Twenty days before the study end (D70, visit 8), a new Dexcom G6 CGM system provided by 
the HHP will be installed for a 20-day continuous glycaemia recording period. During Visit 8, 
in addition to usual care, the family nurse will:  
o Install the new blinded Dexcom G6 CGM system,  
o Be trained by the HHP to the procedure of data upload and data visualisation on the 
CLARITY® platform,   
o Be reminded by the HHP on the precautions to use the Dexcom G6 CGM system and on 
the procedures in case of emergency or technical issues.  
- 
The family nurse will provide required medico-economic information to the HHP (detailed in section 
VII.2.6).  
- 
The family nurse will complete the family nurse’s satisfaction questionnaire.  
VI.6 -  END OF STUDY VISIT (V9)  
The end of study visit will be performed at the hospital to unequip and remove the devices, and perform 
the evaluations required by the protocol. All patient materials will be collected and the patient will be 
switched back to MDI T2D care as per investigator’s prescription.   
VI.6.1 -  ROLES OF THE INVESTIGATOR  
At the end of study visit, the Investigator will:  
- 
Remove the Dexcom G6 CGM (for every patient) and the Tandem t:slim X2 Insulin Pump (for patients 
of the investigational group only). Before removing the devices, the Investigator will ensure that data 
have been collected by the HHP.  
- 
Perform the following evaluations:  
● Adverse events and device deficiencies/failure.  
● Concomitant medications.  
● Physical examination, blood pressure and body weight.  
● Laboratory data: HbA1c, blood glucose, total cholesterol, triglycerides, HDL-Cholesterol, LDL-
Cholesterol, serum albumin, AST, ALT, gamma GT and serum Creatinine, blood counts (Red Blood 
Cells (RBC), White Blood Cells (WBC), platelets, haemoglobin, hematocrit) with their sampling 
date, fasting status, unit and normal range in use.  
- 
Collect the patient questionnaires, the patient diary and study documentation.  
- 
Complete the e-CRF and provide required medico-economic information (detailed in section  
VII.2.6).  
- 
Complete the Investigator’s satisfaction questionnaire.  
  
  
VI.6.2 -  ROLES OF THE HOME HEALTHCARE PROVIDER (HHP)  
The HHP will attend the end of study visit at the hospital to:  

  
  
 
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- 
Upload data from the Dexcom G6 receiver to the CLARITY® platform for patients of the control 
group, and data from the Tandem t:slim X2 Insulin Pump to the t:connect® platform for patients 
of the investigational group,  
- 
Collect and return Dexcom G6 CGM, Tandem t:slim X2 Insulin Pump devices and dedicated laptop 
(as detailed in section V.4).  
VI.6.3 -  ROLES OF THE FAMILY NURSE  
The family nurse will not attend the end of study visit at the hospital. The HHP will contact the family nurse 
to provide her (him) with information regarding the new patient MDI T2D care as per investigator’s 
prescription. The family nurse will provide the medico-economic information to the HHP (detailed in section  
 
VII.2.6).   
  
 

  
  
 
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VI.7 -  ASSESSMENTS AND PROCEDURES  
VI.7.1 -  PATIENT’S ASSESSMENTS AND PROCEDURES  
Figure 2: STUDY FLOWCHART of EXAMINATIONS and EVALUATIONS Figure 
2A-Investigational Group  
 
   
 
   
 
 

  
  
 
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Figure 2B: Control Group  
            
  
VI.7.1.1 -  
DEMOGRAPHICS AND CHILD-BEARING POTENTIAL  
Patients’ demographics (age, gender) will be collected at selection visit.  
A blood pregnancy test will be performed at selection visit for women of child-bearing potential to verify that 
no pregnant female patient is included in the study. Breastfeeding information will also be collected.  
VI.7.1.2 -  
MEDICAL AND SURGICAL HISTORY  
Relevant medical and surgical history and comorbidities will be collected at selection visit. The 
T2D must have been diagnosed for at least 6 months prior to the selection visit.  
    
VI.7.1.3 -  
PHYSICAL EXAMINATION, BLOOD PRESSURE, BODY WEIGHT AND HEIGHT  
The following examinations and assessments will be performed at each visit at hospital:  
- 
Height (at selection visit only)  
- 
Body weight  
- 
Blood pressure: both systolic and diastolic resting blood pressures will be measured after 5 minutes 
rest in supine position. The arm with the highest mean diastolic blood pressure at selection will be 
recorded in the e-CRF and used for all subsequent measurements  
- 
Physical examination including cognitive assessment (MoCA and/or MMSE score at selection visit 
only).  

  
  
 
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VI.7.1.4 -  
TREATMENTS  
- 
T2D treatment history  
History of T2D treatments (trade name, start/end date) will be collected at selection visit. Patients must 
have been treated with insulin for at least 6 months prior to their selection visit. Patients prescription for 
daily insulin treatment and glycaemic control by a home family nurse will be collected at selection. Patients 
must require daily home nurse care for their insulin treatment at the time of their selection visit.  
- 
Concomitant medication  
Current treatments (trade name, start/end date) for comorbidities will also be collected at each visit 
performed at hospital.  
- 
Insulin  
Insulin (trade name, start/end date) used during the study will be collected. Of note, the automated insulin 
delivery system is intended to be used with U100 Humalog® or NovoRapid® rapid-acting insulin analogues 
only.  
- 
IMD use (for patients in the investigational group only)  
Time on auto-mode defined as the percentage of time spent with activated closed-loop of the insulin 
administration system over 24-h day will be computed based on the data continuously recorded into the 
Pump. In addition, patient compliance to the IMD will be collected at each visit by the investigator both on 
patient medical file and in the e-CRF by asking questions to the patients and checking the patient diary. The 
reason for any non-compliance, including treatment and/or study discontinuation will be recorded in both 
patient medical file and e-CRF by the Investigator.  
VI.7.1.5 -  
FUNDUS EXAMINATION OR RETINAL PHOTOGRAPHY  
Patients with proliferative retinopathy can not be included in the study. If the last fundus examination or 
retinal photography examination is dated more than 6 months, a new fundus examination or retinal 
photography will be requested by the investigator. The examination must be performed before 
randomisation.  
    
VI.7.1.6 -  
PREGNANCY TEST  
A blood pregnancy test will be performed at selection visit for women of child-bearing potential.  
VI.7.1.7 -  
LABORATORY DATA  
The following assessments will be performed at Selection, Initiation and End of study visits:  
- 
Glycaemic control: blood HbA1c, blood glucose.  
- 
Lipid profile: total cholesterol, triglycerides, HDL-Cholesterol, LDL-Cholesterol.  
- 
Hepatic function: serum albumin, AST, ALT, gamma GT.  
- 
Kidney function: serum creatinine.  

  
  
 
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- 
Blood counts (Red Blood Cells (RBC), White Blood Cells (WBC), platelets, haemoglobin, and 
hematocrit).  
VI.7.1.8 -  
GLYCAEMIC CONTROL AND GLYCAEMIC VARIABILITY  
In addition to HbA1c assays, the glycaemic control and variability will be computed based on the continuous 
measurement of the glucose values recorded after wearing the CGM device in blinded mode during the 14 
consecutive days of the selection period and every day from D70 to D90.  
VI.7.1.9 -  
ADVERSE EVENTS/DEVICE DEFICIENCIES/FAILURE  
Safety assessments will consist in evaluating all serious and non-serious adverse events (AE), and device 
deficiencies/failure occurring from the Informed Consent Form (ICF) signature until the end of the study.  
At each visit, occurrence of AEs and device deficiencies/failure should be inquired and follow-up of 
previously reported AEs and device deficiencies/failure should be performed. Related essential data should 
be recorded in the patient's medical file and in the e-CRF by the Investigator.  
For the AEs, the following data will be recorded in the e-CRF:  
- 
Description of the AE  
- 
Seriousness of the event  
- 
Onset and resolution dates of the AE  
- 
Severity of the AE (mild, moderate or severe)  
- 
Causality with regards to IMD  
- 
Causality with regards to investigation procedures  
- 
Action(s) taken regarding the IMD -  
Corrective treatment/therapy given -  Event outcome.  
    
In addition, the following parameters will be considered for assessment of the safety profile of automated 
insulin delivery system:  
- 
Hypoglycaemic events defined as at least 10 min of continuous CGM readings below the thresholds 
of (1) 70 mg/dL (3.9 mmol/L) or (2) 54 mg/dL (3.0 mmol/L),  
- 
Non severe hypoglycaemic events, being defined by CGM readings between < 70 mg/dL (3.9 mmol/L) 
and ≥ 54 mg/dL (3.0 mmol/L),  
- 
Severe hypoglycaemic events being defined by CGM readings < 54 mg/dL,  
- 
Severe hypoglycaemic events requiring third party assistance,   
- 
Severe hypoglycaemic events requiring hospitalization,  
- 
Severe hyperglycaemic events being defined by CGM readings ≥ 300 mg/dL for over 1 hour,  - 
 Device incidents and deficiencies.  
  
A Data Safety Monitoring Board (DSMB) will review the safety data of the five first patients of each group, 
then 25 patients having completed the study, and more frequently if judged necessary by the DSMB.  

  
  
 
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VI.7.1.10 - PATIENT REPORTED OUTCOMES AND EXPERIENCES   
- 
Quality of life  
EQ-5D is a standardized instrument developed by the EuroQol Group (1990) as a measure of health-related 
quality of life that can be used in a wide range of health conditions and treatments [37-42]. The EQ-5D 
consists of a descriptive system and the EQ VAS. The validity and reliability of the EQ-5D have been assessed 
for different language versions, including French, and various health conditions, including cancer, Type 2 
Diabetes, and cardiovascular disease. The 5L system showed improved responsiveness compared to the 3L 
system, and also good validity and reliability.   
The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. For each dimension, the patient self-rates the level of severity using a five-level (EQ5D-
5L) scale from having no problems (= 1), slight problems (= 2), moderate problems (= 3), severe problems 
(= 4) or being unable to do/having extreme problems (= 5). The EQ-5D can be used as a quantitative measure 
of health outcome that reflects the patient’s own judgement. The scores on these five dimensions can be 
presented as a health profile or can be converted to a single summary index number (utility) reflecting 
preferability compared to other health profiles. As a result, a person's health status can be defined by a 5-
digit number, ranging from 11111 (having no problems in all dimensions) to 55555 (having extreme 
problems in all dimensions). There are potentially 3,125 (=55) different health statuses.   
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints 
100 and 0 are respectively labelled ‘The best health you can imagine’ and ‘The worst health you can 
imagine’. The VAS can be used as a quantitative measure of health outcome that reflects the patient’s own 
judgement.  
    
- 
Hypoglycaemia Fear Experience  
The original Hypoglycaemia Fear Survey (HFS) was developed to measure behaviors and worries related to 
fear of hypoglycaemia in adults with Type 1 and Type 2 diabetes developed [43]. Both the original HFS (HFSI) 
and the revised version (HFS-II) are composed of 33 items divided into two subscales: Behavior (HFS-B) and 
Worry (HFS-W):   
● HFS-B: 15 items that describe behaviors in which patients may engage to avoid hypoglycaemic 
episodes and/or their negative consequences (e.g., keeping blood glucose [BG] levels above 
150 mg/dL, making sure other people are around, and limiting exercise or physical activity).  
● HFS-W: 18 items that describe specific concerns that patients may have about their 
hypoglycaemic episodes (e.g., being alone, episodes occurring during sleep, or having an 
accident).   
The questionnaire uses a 5-point Likert format ranging from Never to Always items. Scores are then summed 
to yield the two subscale scores and the total score.  
The HFS-II is a valid and reliable measure of fear of hypoglycaemia [44]. It has been validated for use in many 
languages and countries, including France.   
- 
Patient’s Experience  
An ad-hoc questionnaire entitled “CLOSE AP+_Patient’s Experience questionnaire” developed by the French 
Federation of Diabetics (FFD) will be used to assess the patient’s experience.  
The questionnaire assesses the patient’s perception of his/her experience during the study. This 
questionnaire is composed of 14 questions. Ten of them can be answered based on 5 modalities 
(Strongly agree to Strongly disagree), and the last four on 3 modalities (2 choices and none of them).   

  
  
 
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There is no specific score, the answers to each question are evaluated independently of each other.  
  
- 
Usability (for patients in the investigational group only)  
The System Usability Scale (SUS) is a quick, low-cost usability scale that can be used for global assessments 
of systems usability originally created by John Brooke in 1986 [45]. It is a valid (i.e., it can effectively 
differentiate between usable and unusable systems) and reliable tool, even in small sized samples 
(https://www.usability.gov/how-to-and-tools/methods/system-usability-scale.html) [46].   
It consists of a 10-item questionnaire with five response options for patients; from Strongly disagree to 
Strongly agree, with values from 1 to 5 respectively.   
It has become an industry standard with references in over 600 publications in a wide variety of products 
and services, including hardware, software, mobile devices, websites and applications.  
The patient’s scores for each question are converted to a new number, added together and then multiplied 
by 2.5 to convert the original scores of 0-40 to 0-100. Though the scores are 0-100, these are not 
percentages and should be considered only in terms of their percentile ranking.   
    
VI.7.2 -  HHP SERVICES UTILISATION  
The HHP activities related to study conduct will be assessed. For each planned contact, the following 
information will be collected in the e-CRF by the HHP:  
- 
Type of contact: home or hospital visits / phone calls / email  
- 
Person contacted: patient, investigator, family nurse or caregiver  
- 
Study period: selection, initiation, run-in, follow-up, ending In case of visit,   
- 
Location: home or hospital  
- 
Date of contact  
- 
Time spent: start time and end time  
- 
Usefulness of the contact from the patient perspective, and if so, in what  
- 
Next visit scheduled  
- 
Written report sent to the investigator  
- 
Adverse event    
Depending on whether the contact is for selection, initiation, run-in, follow-up or ending periods, the 
following information may be requested:  
Main and secondary reasons of the contact such as:  
- 
Need additional training/education on the automated insulin delivery system and/or platforms, and 
if so, on which components (CGM, Pump, CLARITY® platform, t:connect® platform)   
● 
Motivational support or need to be reassured  
● 
Information on the lifestyle of the patient  
● 
Medical situation requiring contact with the investigator / other ●    Other  
Any unplanned contact will be also recorded in the e-CRF. The following information, in addition to those 
mentioned above, will be collected by the HHP:  
- 
Person at the origin of the contact (patient, investigator, HHP, family nurse or other) -  Reason(s) 
of the unplanned contact, in addition to those already listed above, such as:  

  
  
 
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● 
Device deficiency/failure, and if so, the type and nature  
● 
Difficulty in declaring a meal  
● 
Alarm or alert management  
● 
Need resupply and type (Pump, CGM components, consumables, sensors, ...)  
● 
Study procedure information  
● 
Other  
- 
Additional information on the nature and reason of the contact, namely:  
● 
Resolving the problem after contact  
● 
Need for home intervention, and if so, for what action and reason  
● 
Identification of a device deficiency/failure  
● 
Information on the use of the system by the patient (management, replacement scheme, ...)   
- 
For all contacts, planned or unplanned, regarding the CGM or Pump intervention, the type of 
intervention will be specified and collected as described below:   
    
- 
For CGM support:  
● 
Patient equipment & training  
● 
CGM initialization  
● 
CGM replacement by family nurse  
● 
CGM removal  
● 
CGM data upload  
● 
Change of CGM -  For Pump support:  
● 
Patient equipment & training  
● 
Pump initialization  
● 
Catheter & cartridge changes, battery charge  
● 
Pump data upload  
● 
Unplanned change of pump, if necessary.  
VI.7.3 -  ASSESSMENT OF INVESTIGATORS SATISFACTION  
The satisfaction of investigators will be evaluated via an ad-hoc questionnaire developed by Air Liquide 
Santé International. Each investigator having included at least 1 patient will complete the questionnaire 
only once after the last visit of the last patient of the investigational site, thus collecting his/her overall 
satisfaction towards the automated insulin delivery system, unrelated to a specific patient.  
The questionnaire has 5 parts:  
- 
Care management  
- 
Patient benefits   
- 
Evaluation of automated insulin delivery system implementation  -  Telemonitoring 
through 
data 
visualization platforms -  
Overall satisfaction.  
The answers will be evaluated independently of each other, no score will be provided for this questionnaire. 
Each item will be collected through a paper questionnaire which will be sent to the CRO (ICTA PM) and data 
entered in the study database.  

  
  
 
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VI.7.4 -  ASSESSMENT OF FAMILY NURSES SATISFACTION  
The satisfaction of family nurses will be assessed by an ad-hoc questionnaire developed by Air Liquide Santé 
International. Each nurse, who will take care of patients from the investigational group only, will complete 
the questionnaire only once after the last visit of their last patient, thus collecting his/her overall satisfaction 
towards the automated insulin delivery system, unrelated to a specific patient.  
The questionnaire has 6 parts:  
- 
Patient benefits  
- 
Training received/performed on the automated insulin delivery system  
- 
Evaluation of automated insulin delivery system implementation  
- 
Telemonitoring through data visualization platforms -  
Relationship 
with 
other 
healthcare 
professionals -  
Overall satisfaction.  
The answers will be evaluated independently of each other, no score will be provided for this questionnaire.  
Each item will be collected through a paper questionnaire which will be sent to the CRO (ICTA PM) and data 
entered in the study database.   
    
 

  
  
 
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VII -  ENDPOINTS  
VII.1 -  PRIMARY ENDPOINT  
The primary endpoint will be Time In Range (TIR) at D90, defined as the percentage of time spent with CGM 
glucose measurements at 70-180 mg/dL (including boundaries), during the last 14 days completed of CGM 
recording between D70 and D90 at the end of the study period.  
For any of the 14 days to be eligible, ≥ 70% of the data points have to be non missing. Full 24-hour periods 
available only will be used, thus excluding from the calculation all days with CGM sensor installation or 
desinstallation.  
For data analysis and calculation of the TIR at baseline and at D90, gaps in the CGM recording for incomplete 
days will be imputed using a linear interpolation approach of the planned 14 days [51].  
The primary endpoint will be computed at D90 for the full 24-h day. In a complementary way, the TIR will 
also be computed separately considering the diurnal period (from 06.00 H to 23.59 H) and the nocturnal 
period (from 00.00 H to 05.59 H).  
VII.2 -  SECONDARY ENDPOINTS  
VII.2.1 -  EFFICACY ENDPOINTS  
- 
HbA1c absolute change from baseline: HbA1c will be assayed for all patients at baseline and  
D90. The absolute change from Baseline, i.e., HbA1c at D90 – HbA1c at Dbaseline will be calculated for 
each patient.  
- 
Absolute change of glucose variability from baseline:  
● The percentage coefficient of variation (%CV) will be computed at baseline (%CVBasl) and 
D90 (%CVD90), as well as the absolute difference (%CVD90 -%CVBasl) for each patient [52]. For a given 
patient, the %CVBasl will be calculated by dividing the Standard Deviation (SD) by the corresponding mean 
of the CGM recordings during the 14 days at the end of the selection period.  
In the same manner, for each patient, the %CVD90 will be calculated by dividing the Standard Deviation (SD) 
by the corresponding mean of the CGM recordings during the last 14 days of the D70 to D90 period.  
For each patient, %CVBasl, %CVD90 and the (%CVD90 -%CVBasl) difference will be computed 3 
times:  
 Considering the full 24-h day,    
 the diurnal period (from 06.00 H to 23.59 H),   
 or the nocturnal period (from 00.00 H to 05.59 H) separately,  
- 
Absolute change of Time In Range from the 14 days completed CGM recording at the end of the 
selection period (baseline) to the last 14 days completed CGM recording from D70 to D90 at the 
end of the study period: time in range is defined in section VII.1 as the percentage of time spent 
in target range of glucose level (CGM measurements in 70-180 mg/dL (including boundaries)). 
At baseline, as well as from D70 to D90, any day of the considered period need to have ≥ 70% 
non missing data points to be eligible for the TIR computation. The absolute change in TIR from 
Baseline, i.e., D90– D0 will be calculated 3 times for each patient: (1) for the full 24-h day, (2) for 
the diurnal period (from  

  
  
 
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06.00 H to 23.59 H) and (3) for the nocturnal period (from 00.00 H to 05.59 H),  
- 
Time below target range is defined as the percentage of time spent with CGM glucose 
measurements (1) <70 mg/dL, and (2) <54 mg/dL, during the last 14-day CGM completed 
recording from days 70 to 90. The time below target range will be computed for the full 24-h 
day, the diurnal period (from 06.00 H to 23.59 H) and the nocturnal period (from 00.00 H to 
05.59 H) separately,  
- 
Time above target range is defined as the percentage of time spent with CGM glucose 
measurements (1) >180 mg/dL, and (2) ≥250 mg/dL, during the last 14-day CGM completed 
recording from days 70 to 90. The time above target range will be computed for the full 24-h 
day, the diurnal period (from 06.00 H to 23.59 H) and the nocturnal period (from 00.00 H to  
05.59 H) separately,  
- 
Total daily insulin dose change from baseline to D90 (sum of basal and bolus insulin injection), - 
 Body weight absolute change from baseline (end of period of selection) to D90.  
VII.2.2 -  PATIENT REPORTED OUTCOMES, EXPERIENCES AND USABILITY  
Patient reported outcomes, experiences and usability questionnaire are detailed in section VI.7.1.10. They 
will be collected through paper self-questionnaires and they include:  
For patients in the control group  
- 
Patient quality of life which will be assessed with EQ-5D-5L at baseline and D90,  
- 
Patient fear experience which will be assessed with the Hypoglycaemia Fear Survey (HFS-II) at 
baseline and D90,  
- 
Patient experience which will be assessed with an ad-hoc Patient questionnaire at baseline.  
For patients in the investigational group  
- 
Patient quality of life which will be assessed with EQ-5D-5L at baseline, D30 and D90,  
- 
Patient fear experience which will be assessed with the Hypoglycaemia Fear Survey (HFS-II) at 
baseline, D30 and D90,  
- 
Patient experience which will be assessed with an ad-hoc Patient questionnaire at baseline, D30 and 
D90,  
- 
Usability which will be assessed with the System Usability Scale (SUS) at D90,  
- 
Time on auto-mode defined as the percentage of time spent with activated closed-loop of the insulin 
administration system over 24-h day which will be computed based on the data continuously 
recorded into the Pump for patients in the investigational group only.  
    
VII.2.3 -  HEALTH RESOURCE UTILISATION AND MEDICAL DEVICES CONSUMPTION  
Costs related to health resource utilisation and medical devices consumption are part of section VII.2.6.  
- 
HHP visit duration (per type of visit),  
- 
HHP training and educational session duration (per type of session),  
- 
Number of hospital visits of the HHP,  
- 
Number of HHP and family nurse planned contacts (per type of contact) with the patient and/or 
caregiver (defined as home visit and/or phone and/or email planned in the protocol), realized versus 
planned,  

  
  
 
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- 
Number of HHP and family nurse unplanned contacts (per type of contact) with the patient and/or 
caregiver (defined as home visit and/or phone and/or email not required by the protocol 
procedures),  
- 
Reason of unplanned contacts,  
- 
Number of study devices and their consumables (by type of device) used versus planned to be used,  
- 
HHP training satisfaction according to investigator and family nurse questionnaires at D90.  
HHP services utilisation will be assessed with collected data during the study conduct as detailed in section 
VI.7.2.   
VII.3 -  SATISFACTION  
Family nurse and investigator satisfaction will be assessed with ad-hoc questionnaires at the end of the study 
as detailed in sections VI.7.3 and VI.7.4.  
VII.3.1 -  SAFETY PARAMETERS  
Safety assessments are detailed in section VI.7.1.9. They include:  
- 
Number of diabetes-related hospital admissions and their length of stay: the frequency of scheduled 
and unscheduled diabetes-related hospital admissions will be calculated for each study patient from 
baseline to D90.  
- 
Number of hypoglycaemic events  
- 
Number of diurnal hypoglycaemic events (i.e., occurring from 06.00 H to 23.59 H)  
- 
Number of nocturnal hypoglycaemic events (i.e., occurring from 00.00 H to 05.59 H)  
- 
Number of non severe hypoglycaemic events  
- 
Number of severe hypoglycaemic events  
- 
Number of severe diurnal hypoglycaemic events (i.e., occurring from 06.00 H to 23.59 H)  
- 
Number of severe nocturnal hypoglycaemic events (i.e., occurring from 00.00 H to 05.59 H)  
- 
Number of severe hypoglycaemic events requiring third party assistance  
- 
Number of severe hypoglycaemic events requiring hospitalization  
- 
Number of severe hyperglycaemic events (≥ 300 mg/dL for over 1 hour).  
Adverse events and device deficiencies/failure will be collected from the signature of the informed consent 
to study end.  
  
A Data Safety Monitoring Board (DSMB) will review the safety data of the five first patients of each group, 
then 25 patients having completed the study, and more frequently if judged necessary by the DSMB.  
Composition, role and frequency of DSMB meetings will be detailed in the separate DSMB Charter.   
VII.3.2 -  MEDICO-ECONOMIC DATA   
- 
Costs related to family nurse intervention   

  
  
 
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In general, costs are not collected directly but they are calculated from the number of visits and/or phone 
calls made by the family nurse to perform the service in the different cases mentioned (detailed in section 
VI). The overall cost includes the cost of the family nurse in the hospital, at the patient's home and remotely.  
For each patient in the investigational and control groups.  
Costs charged to the French National Health System per patient in the control group.  
    
- 
Time estimation of family nurse intervention  
Duration of training session(s)  
Number of contacts (visits, phone, training, emails) and average duration of contacts at the patient’s home.  
- 
Costs related to hospitals  
Cost per patient in the investigational and control groups  
- 
Time estimation related to hospitals  
Number of study visits and hospital stays per patient in the investigational and control groups.  
Number of connection to CLARITY® and/or t:connect® platforms with the estimated time spent by patient in 
the investigational group.  
- 
Costs related to Home Healthcare Providers (HHP)  
In general, costs are not collected directly but they are calculated from the number of visits and/or phone 
calls made by the HHP to perform the service in the different cases mentioned (detailed in section VI). The 
overall cost includes the cost of the HHP in the hospital, at the patient's home and remotely.  
● Cost and type of diabetes treatment-related medical devices and consumables per patient in the 
investigational and control groups  
● Number, duration and cost of intervention(s) per patient in the investigational and control groups  
- 
Time estimation related to HHP  
Number and duration of planned and unplanned contacts, training, educational session per patient in the 
investigational and control groups. With a subtotal of contacts with the patient him- or her-self, with the 
patient family nurse and with the hospital.  
- 
Costs of IMDs  
Cost of IMDs and their associated consumables per patient in the investigational group.  
- 
Costs charged directly to National Health System  
Cost for medications, medical devices and their associated consumables, per patient in the investigational 
and control groups.  
  
- 
Service Quality measures  
● 
In case of incident o Time to HHP incident intervention following patient/family nurse 
notice  o Time to HHP incident resolution following patient/family nurse notice   
● 
Training attendance during the follow-up period after the patient went back home  
● 
Number of patients with validated training at Visit 2  
● 
Number of calls to HHP and their types with or without attendance to training at D3,  
 
D+1 month and D+3 months  
  
 

  
  
 
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VIII -  SAFETY AND DEVICE DEFICIENCIES  
VIII.1 -  DEFINITIONS  
Adverse Event (AE)  
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
clinically significant abnormal laboratory findings) in patients, users or other persons, whether or not 
related to the investigational medical device.  
This definition includes events related to the procedures involved (see definition below).  
For users or other persons, this definition is restricted to events related to investigational medical devices.  
Investigation Procedure  
Any procedure specific to the clinical investigation. All activities related to the use of a medical device may 
be considered investigation procedures.   
Note: “Preceding investigation procedure” shall be understood as a procedure which is imposed by the 
Clinical Investigation Plan and which has taken place before (or coincided in time) with the serious adverse 
event.   
Adverse Device Effect (ADE)  
Adverse Event related to the use of an investigational medical device.  
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device.  
This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device.  
Abnormal laboratory value  
All abnormal laboratory values that the investigator is aware of will be reported as Adverse Events if the 
investigator categorizes their values as « Clinically Significant » (CS).  
Serious Adverse Device Effect (SADE)  
Adverse Device Effect that has resulted in any of the consequences characteristic of a Serious Adverse Event.  
SAEs related to procedures imposed by the clinical investigation plan but not with the use of the device 
should not be considered Serious Adverse Device Effects.  
    
Serious Adverse Event (SAE)  
Adverse Event that led to any of the following:  - 
 
death   
- 
serious deterioration in the health of the patient, that either resulted in:  
- 
a life-threatening illness or injury, or  

  
  
 
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- 
a permanent impairment of a body structure or a body function, or  
- 
in-patient or prolonged hospitalization, or  
- 
medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, or  
- 
chronic disease,  
- 
foetal distress, foetal death or a congenital physical or mental impairment or birth defect.  
Note: planned hospitalization for a pre-existing condition, or a procedure required by the protocol, without 
serious deterioration in health, is not considered as a Serious Adverse Event.  
The following reasons for hospitalization are exempted from being reported:  
- 
Hospitalization for social and/or convenience reasons.  
- 
Hospitalization for pre-planned (i.e., planned prior to signing informed consent) surgery or 
standard monitoring of a pre-existing disease or medical condition that did not worsen.  
However, complications that occur during hospitalisation are AEs or SAEs (for example, if a complication 
prolongs hospitalization).  
Use Error  
Act or omission of an act that results in a different medical device response than intended by the 
manufacturer or expected by the patient.  
Use Errors include slips, lapses, and mistakes.  
Note: an unexpected physiological response of the patient does not in itself constitute a Use Error.  
Device Deficiency  
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance.  
Note: Device Deficiencies include malfunctions, use errors, and inadequate labelling.  
Unanticipated Serious Adverse Device Effect (USADE)  
Serious Adverse Device Effect which by its nature, incidence, severity or outcome has not been identified in 
the current version of the Risk Analysis report.  
Note: Anticipated Serious Adverse Device Effect (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the Risk Analysis report.   
VIII.2 -  COLLECTION, ASSESSMENT AND FORWARDING/REPORTING BY THE INVESTIGATOR   
VIII.2.1 -  COLLECTION AND ASSESSMENT  
All Adverse Events (serious and non-serious, related and not related) and device deficiencies occurring 
during the study from the informed consent signature until the end of study i.e., the last study evaluation 
will be reported by the investigator in the e-CRF. Related SAEs may be reported at any time.  
  

  
  
 
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Adverse Events, ADEs and Device Deficiencies will be entered by the Investigator in the corresponding 
section of the e-CRF. SAEs, ADEs and Device Deficiencies will be reported by the Investigator by the means 
of specific forms. Depending on the situation, both forms may have to be used for a single event.  
- 
The Investigator will assess the seriousness of every Adverse Event.  
- 
The Investigator will assess the causal relationship between each adverse event and the 
Investigational Medical Device and/or investigation procedures. That causal relationship is assessed 
as being a reasonable possibility or not. A reasonable possibility of a causal relationship between 
the event and the Investigational Medical Device and/or investigation procedures means that there 
are facts (evidence) or arguments to suggest a causal relationship. If a causal relationship is 
suggested between the event and the Investigational Medical Device, the Adverse Event meets the 
definition of the Adverse Device Effect.  
- 
The Investigator will assess, for every device deficiency, if it could have led to a SADE, if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been less 
fortunate.  
VIII.2.2 -  REPORTING TO THE SPONSOR  
The investigator reports to the sponsor, immediately and no later than 3 calendar days  of his/her being 
aware, all SAEs, ADEs and Deficiencies of the Investigational Device and/or investigation procedures, by the 
means of, respectively the “SAE/ADE Form” and/or the “Device Deficiency Form”, that will be sent by email 
to:  
AIR LIQUIDE Santé INTERNATIONAL, Pharmacovigilance Department:  
Email: vigilance.alsi@airliquide.com   
The investigator will answer within 48 hours to any safety query sent by the sponsor.  
VIII.2.3 -  ASSESSMENT BY THE SPONSOR  
For each Serious Adverse Event, the sponsor (Study Physician) will assess the causal relationship between 
the investigational medical device and/or investigation procedures and the event.  
For each device deficiency, the sponsor (Study Physician) will assess if that device deficiency could have led 
to a SADE, if appropriate action had not been taken, intervention had not occurred, or circumstances had 
been less fortunate.  
The assessments given by the investigator cannot be downgraded. In case of disagreement, both opinions 
are provided.  
VIII.2.4 -  REGULATORY SAFETY SUBMISSIONS BY THE SPONSOR  
Regulatory safety submissions (individual cases, annual safety reports) will be done by the sponsor according 
to legal requirements.  

  
  
 
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VIII.3 -  NEW SAFETY EVENTS  
A new safety event is any new data which might lead to:  
- 
A reassessment of the benefit-risk balance of the study or of the IMD,  
- 
A change in the use of the IMD, in the conduct of the study, or in the study documents,  
- 
The interruption, discontinuation or modification of the study protocol or other study conducted on 
the same IMD.  
  
Any new safety event occurring during the study period will be notified by the Sponsor according to legal 
requirements to the French Competent Authority and Ethics Committee.  
 

  
  
 
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IX -  DATA HANDLING  
IX.1 -  ELECTRONIC CASE REPORT FORM (E-CRF)   
An electronic data capture system will be used for this study. An electronic CRF (e-CRF) will be designed to collect 
all the data required by the protocol apart from the automatic recordings of the study IMDs. The e-CRF will be 
developed by the Information Technology Department of ICTA (Dijon, France), in compliance with Sponsor 
specifications and regulatory requirements.   
  
Data entry will be performed by the Investigator or by the designated person from his/her team at the investigator 
site and by the HHP with two different connection profiles, using the e-CRF screens designed with web technologies.   
  
Investigators’, family nurses’ and patients’ paper self-questionnaires data will be entered via Interactive double data 
entry in the study database by Data Entry Operators from ICTA PM.  
  
Patients will be identified with a unique identification code. Two letters for the country code, three digits for the 
site number, dash then the patient number on 3 digits. The last 3 digits will be attributed according to the 
chronological order of selections within each centre.   
  
Data entered via the Internet will be directly recorded in the SQL study database.   
The investigator or the designated personnel from his/her team agrees to complete all documents provided by the 
Sponsor at each patient’s visit and complete the e-CRF as close as possible from the patient’s visit.   
  
All corrections of data on the e-CRF must be made by the investigator (or the designated person from his/her team) 
or by the HHP according to the provided instructions. Any data modification will be recorded in chronological order 
using the audit trail feature of SQL Server database, including who, when and why the modification was done.   
  
In order to ensure confidentiality and security of the data, usernames and passwords will be used to restrict system 
access to authorized personnel only, whether investigator and authorized site members, HHP, Sponsor or third 
parties.   
  
The monitors must make certain that all data are completed on the e-CRF and are according to source.   
After comparing the data to the source documents, the monitor will request corrections/clarifications from the 
investigator using functionalities on line for Source Data Verification (SDV).  
Before the lock of the database by the Data Management Department, the investigator must attest by entering his/her 
username and password:  
- 
The authenticity of the data collected in the e-CRF,   
- 
The coherence between the data in the e-CRF and those in the source documents.   
  
  
  
  
  

  
  
 
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IX.2 -  DATA MANAGEMENT   
SAS® software version 9.2 or later will be used for data management process and data will be recorded in the clinical 
study database stored in a secure folder.  
For the study results evaluation (including the calculation of the primary endpoint as detailed in section VII.1), 
pseudonymised IMDs recordings uploaded from CGM and pumps throughout the patients’ study participation 
periods will be transferred electronically to the study database.   
The Data Management Department of ICTA (Dijon, France) is responsible for data processing including drafting of 
Data Management Plan, development of database structure, drafting the Data Validation Plan (list of edit checks 
and cleaning listings), data transfers and data coding. Medical and surgical history and adverse events will be coded 
using the latest available version of the Medical Dictionary for Regulatory Activities (MedDRA). Prior and 
concomitant medications will be coded using World Health Organization drug dictionary (latest version available).  
A review of the data will be performed according to the CRO Standard Operating Procedure (SOP).   
Database status will be declared as final when all data have been entered, cleaned by the Data Manager, validated 
by the monitor and the investigator or delegate. After declaration of a final database, the data will be exported 
from the SQL source database and converted into SAS datasets in the final database, and both databases will be 
locked and protected from changes. All statistical analyses for the final analysis will be performed on the locked 
SAS database.  
IX.3 -  STUDY COMMITTEES   
A Data Safety Monitoring Board (DSMB) will be established prior to study start (first visit of first patient). All members 
will be independent from the Sponsor.  
A Data Safety Monitoring Board (DSMB) will review the safety data of the five first patients of each group, then 25 
patients having completed the study, and more frequently if judged necessary by the DSMB. The DSMB will make 
recommendations regarding the continuation, temporary suspension or definitive termination of the clinical study.  
Composition, role and frequency of DSMB meetings will be detailed in the separate DSMB Charter.  
X -  STATISTICAL METHODS  
X.1 -  SAMPLE SIZE  
The primary study objective is to demonstrate that the tested therapeutic strategy is superior to the usual care strategy 
on the TIR at D90.  
The required number of assessable patients can be assessed using the standard formula of comparison of 2 means:    
,  
With nA= number of assessable patients/group, s=standard deviation, and Δ= expected difference between both 
groups  
Based on previous studies [53], the difference between the investigational group and the control group is expected 
to be between 14% and 24%, and the standard deviation corresponding to the mean TIR is expected to be equal to 
16 (identical in both groups).  
Based on a difference of 17% in the mean TIR at D90 between the investigational group and the control group, a 
standard deviation = 16 (identical in both groups) for the mean TIR at D90, a type 1 error (α) = 5.0%, a type 2 error 

  
  
 
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(β) = 10.0% (statistical power = 90.0%), the sample size estimation yields n=21 valid patients per study group 
including a 10.0% account for the adjusted analysis (primary analysis adjusted on HbA1c value at baseline and TIR 
at baseline). Allowing for a 25.0% rate of non-evaluable patients, a total of 56 patients needs to be randomized (28 
patients in each study group).  
  
Table 1: Estimated sample size needed to show the statistical significance of a difference ∆ in TIR at D90 varying from 14% to 24% at the 5% 
level with a power of 90%  
Δ
Number of  
assessable patients 
(+10.0%)  
% Loss  
Number of patients to 
recruit by group  
14%  
31  
25.0%  
42  
15%  
27  
25.0%  
36  
16%  
25  
25.0%  
34  
17%  
21  
25.0%  
28  
18%  
19  
25.0%  
26  
19%  
17  
25.0%  
23  
20%  
16  
25.0%  
22  
21%  
15  
25.0%  
20  
22%  
14  
25.0%  
19  
23%  
13  
25.0%  
18  
24%  
11  
25.0%  
15  
X.2 -  DATA SETS ANALYSED   
X.2.1 -  PATIENTS DATA SETS  
The five following data sets analysed will be considered and exhaustively defined prior to the database lock: 
[1] The Selected data set will include all patients who signed an informed consent.  
[2] The Randomised Intention-to-treat (ITT) data set will include all patients who were randomised to study IMD.  
[3] The Safety data set will include all randomised patients continuing their study participation at the end of their 
initiation visit (V1).   

  
  
 
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[4] The modified Intention-To-Treat (ITT) efficacy data set will include all patients from the safety data set with 
at least 3 days with ≥ 70% of non missing data points recording at baseline (selection period), as well as at the 
end of the study (planned from D70 to D90).   
[5] The Per Protocol (PP) data set will include all patients in the modified ITT efficacy data set who completed the 
90-day study period without any major protocol deviation.  
Safety analysis will be performed on the safety data set.  
Efficacy parameters and medico-economic endpoints will be analysed in the modified ITT efficacy data set. The primary 
efficacy endpoint will also be analysed in the PP data set, the PP analysis serving as sensibility analysis.  
According to ICH recommendation, modified ITT efficacy and PP analyses will be conducted according to the IMD 
assigned by the IWRS.  
Safety analyses will be conducted according to the IMD actually equipped with rather than according to the IMD 
assigned.  
The definition of the data sets analysed will be finalized during the final Data Review Meeting (DRM), before the 
database lock. During this DRM, all protocol deviations encountered throughout the study will be reviewed and 
their consequences on the efficacy evaluations performed will be evaluated.  
A deviation will be considered major and thus, resulting to the exclusion of the concerned patient from the Per 
Protocol data set, when it is likely to bias significantly the interpretation of the efficacy results, especially the 
primary efficacy endpoint (i.e., the TIR at D90). All other protocol deviations will be considered minor.  
A listing of all protocol deviations will be provided for all randomised patients, including the type (major/minor) of 
protocol deviations according to the decisions made during the DRM. The number and percentage of patients with 
protocol deviations will be tabulated by study group (and overall) and type of protocol deviations on the modified 
ITT efficacy data set.  
Protocol deviations which will be evaluated will include, but will not be limited to:  
- deviations in selection, inclusion and exclusion criteria,  
- deviations in dates of visits and assessments, including study premature withdrawals, -  
deviations in the allocation and/or the schedule of the study IMDs equipment.   
  
  
X.2.2 -  INVESTIGATORS DATA SET  
The reference data set for the investigator’s satisfaction analysis will be the set of all investigators having randomised 
at least one patient within the study.  
X.2.3 -  FAMILY NURSES DATA SET  
The reference data set for the family nurse’s satisfaction analysis will be the set of all family nurses having taken care 
of at least one patient from the investigational group.  

  
  
 
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X.3 -  STATISTICAL ANALYSES   
A Statistical Analysis Plan (SAP) will be prepared by the CRO and validated by the Sponsor. Its final version will be 
approved after the DRM. After database lock, statistical analyses will be performed by the CRO under the 
supervision of the Sponsor with SAS® version 9.2 or higher (SAS institute, North Carolina, USA).  
X.3.1 -  GENERAL CONSIDERATIONS  
Analyses will be adjusted on the HbA1c level at baseline (<10.0% or ≥10.0%) if the study recruitment allows it.  
Thorough description of all parameters recorded will be presented separately by study group, using the observed 
case approach (apart from the primary endpoint as detailed in section VII.1). Summary tabulated results will be 
provided by group and assessment time/visit, if relevant or they will be replaced by the corresponding individual 
data listings if too few patients are concerned.  
Quantitative variables will be summarized in tables displaying number of patients, means, standard deviations, 
medians and percentiles when appropriate, and extreme values. When applicable, the Wald two-tailed 95.0% 
Confidence Interval (95%CI) of the means will be provided.  
Qualitative variables will be described in terms of frequencies and percentages of the total number of non-missing 
recordings described. When applicable, the Agresti-Coull [54] 95%CI of the percentages will be provided.  
The primary analysis of the primary efficacy endpoint is detailed in section X.3.3. All other efficacy, medicoeconomic 
and safety statistical results provided will be exploratory and exclusively descriptive. They may not lead to any 
causal interpretation. As a consequence, the statistical significance level of the various two-sided tests performed 
will be 5.0%. No adjustment for multiplicity will be made.  
Gaussian quantitative variables will be analysed using parametric ANCOVA model and HbA1c category level at 
baseline as a cofactor.  
Non-gaussian quantitative variables and ordinal qualitative variables will be analysed using a non-parametric ANCOVA 
model and HbA1c category level at baseline as a cofactor (performed on ranks).  
Depending on the analysed parameter and its frequency of collection in both study groups, ANCOVA will be performed 
with or without repeated measures.  
Nominal qualitative variables will be analysed using Cochran-Mantel-Haenszel (CMH) chi-squared tests.  
    
X.3.2 -  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS  
Demographic and other baseline characteristics recorded up to D0 will be tabulated by study group (and IMD 
actually equipped with) and overall in the safety data set. No systematic statistical test will be performed to 
compare both groups at baseline.  
Comorbidities, as well as medical and surgical history separately at selection will be summarised by study group and 
overall using the MedDRA codes of System Organ Classes (SOC) and Preferred Terms (PT).  
Clinical laboratory evaluation at selection and Visit 1 separately will be summarised by study group and overall as 
both quantitative parameters (raw values converted in international units, if necessary) and qualitative parameters 
(relative positions regarding normal ranges in use in each laboratory involved).  
All concomitant treatments with start date at the latest on the day before the initiation visit will be tabulated 
descriptively by study group and overall using the WHO DRUG dictionary and the Anatomical Therapeutic Chemical 
(ATC) classification. Three (3) tables will be provided:  

  
  
 
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- 
one table showing the number and percentage of patients with at least 1 concomitant treatment with start 
date at the latest on the day before the initiation visit, by therapeutic area (ATC1 code corresponding to 
ATC system main group),  
- 
one table by both ATC1 code and ATC system subgroup (ATC2 code),  
- 
and one table showing the number and percentage of patients with at least 1 metabolic system 
concomitant treatment with start date at the latest on the day before the initiation visit, by ATC system 
subgroups (ATC2, ATC3 and ATC4 codes).  
X.3.3 -  PRIMARY EFFICACY ENDPOINT ANALYSIS  
The primary efficacy endpoint is the TIR at D90 for the full 24-h day (as detailed in section VII.1).  
The primary analysis of this primary endpoint will be performed on the modified ITT efficacy data set (defined in 
section X.2.1). The TIR at D90 will be compared between both study groups using a parametric ANalysis of 
COVAriance (ANCOVA) model with 3 factors: HbA1c category level at baseline, TIR value at baseline as covariate 
and study group assigned by the IWRS.  
This ANCOVA model corresponding to the primary analysis of the primary efficacy endpoint will allow testing the 
following set of hypotheses:  
- 
H0 (the null hypothesis of interest): mean TIR values at D90 are equal in the two groups,  
- 
against H1 (the alternative two-sided hypothesis): mean TIR values at D90 differ between the two groups.  
This primary ANCOVA model will be repeated in a secondary supportive step, including the interaction between 
the HbA1c category level at baseline and the study group as fixed effect, if the study recruitment allows further 
exploration of the HbA1c category level effect on the TIR at D90.  
If this interaction term is significant (p ≤ 0.10) and if it appears potentially relevant from a clinical point of view, further 
analyses and/or graphs might be produced to interpret this statistically significant interaction.  
Both ANCOVA models with and without interaction term (if relevant) will be repeated on the TIR at D90 considering 
the diurnal period (from 06.00 H to 23.59 H) and the nocturnal period (from 00.00 H to 05.59 H) separately as 
supportive analyses of the primary efficacy endpoint.  
Moreover, all 3 ANCOVA models with and without interaction term (if relevant) will be performed in the PP data set 
to check their robustness.  
  
X.3.4 -  SECONDARY EFFICACY ENDPOINTS ANALYSIS  
The secondary efficacy endpoints and patient reported outcomes will be analysed in the modified ITT efficacy data 
set.  
Each secondary efficacy endpoint will be summarised at each time point using descriptive statistics and compared 
between study groups using Cochran-Mantel-Haenszel chi-squared tests adjusted on the HbA1c level at baseline 
(2-categories stratification variable) or analyses of covariance with or without repeated measures (depending on 
the analysed parameter and its frequency of collection in both study groups) adjusted on the HbA1c level at 
baseline.   
When appropriate, analyses based on CGM measures will be performed considering (1) the full 24-h day, (2) diurnal 
period (from 06.00 H to 23.59 H) and (3) nocturnal period (from 00.00 H to 05.59 H) separately.  
When relevant, continuous, longitudinal endpoint data (e.g. HbA1c, Total daily insulin dose, body weight) will be 
analysed using the mixed effects model for repeated measures method based on the restricted maximum 

  
  
 
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likelihood for estimation with several prespecified fixed effects, including first-order interactions with time, and 
the corresponding endpoint as the dependent variable in the model. ANCOVA will be used for analyses of measures 
taken at a single time point post baseline in both study groups.   
X.3.5 -  SAFETY EVALUATION  
Safety data will be tabulated descriptively by study group and assessment time, when relevant. Extent of exposure 
and Adverse Events will be tabulated in the Randomised ITT and the safety data sets (defined in section X.2.1). No 
statistical test will be performed.  
X.3.5.1 -  
EXTENT OF EXPOSURE  
Duration of the 4 study periods (Selection, Initiation, Run-in and Follow-up periods) and overall study duration will be 
tabulated (expressed in days) by study group (and globally), as both quantitative and categorical data.  
Overall study duration is defined as the time interval between the actual date of the selection visit (V0 included) 
and the actual date of the end of study visit (V9 excluded) whether the end of study occurred at the time of 
premature withdrawal or on visit date corresponding to D90 as planned, i.e., as the time interval equal to “date of 
end of study visit (V9) - date of selection visit (V0)”.  
X.3.5.2 -  
ADVERSE EVENTS (AES)  
The time period for the recording of Adverse Events (AEs) is the time interval between selection (V0) and end of 
study (V9) divided in 2 periods, either before or after the initiation visit (V1). All reported AEs will be classified in 
one of these 2 periods, according to their start date.   
AEs tabulated evaluations described below will be performed on Study Emergent Adverse Events (SEAEs). AEs 
occurring before the initiation visit (V1) will be tabulated in the Randomised ITT and the safety data sets separately, 
if relevant, or they will be listed if too few patients are concerned.   
    
Each AE (whether serious or not serious, according to their regulatory definition provided in section VIII.1) having 
been reported throughout the study for a given patient will be classified by Preferred Term (PT) and corresponding 
primary System Organ Class (SOC), using the MedDRA terminology, prior to the study database lock.  
An AE will be categorised as Study Emergent if it begins at the earliest on the day of the initiation visit (V1). In case of 
missing or partial AE start date, an AE will be considered as Study Emergent (SE):  
         (1) if the AE start date is unknown,  
   or  (2) if the partial AE start date is on or after the date of the initiation visit (V1) (i.e., ‘year‘ or ‘year and             
month’ is/are ’the same as’ or ‘after’ those of the date of Visit 1).  
  
An overall summary of AEs will be provided by study group, including:  
- the number and percentage of patients with at least 1 AE and the total number of AEs,  
- the number and percentage of patients with at least 1 SEAE and the total number of SEAEs,  
- the distribution of the number of SEAEs reported by patient (in 5 categories, if relevant: 1 SEAE, [2 - 3] SEAEs, 
[4 - 6] SEAEs, [7 - 9] SEAEs or 10 or more SEAEs),  
- the number and percentage of patients with at least 1 Serious SEAE and the total number of Serious SEAEs,  

  
  
 
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- the number and percentage of patients with at least 1 possibly IMD related SEAE (possibly IMD related SEAEs 
being defined as SEAEs for which the investigator has reported at least once either ‘Causal relationship’ or 
‘Probable’ or ‘Possible’ for the relationship to the IMD) and the total number of those possibly IMD related  
SEAEs,  
- the number and percentage of patients with at least 1 SEAE possibly related to investigation procedures 
(SEAEs possibly related to investigation procedures being defined as SEAEs for which the investigator has 
reported at least once either ‘Causal relationship’ or ‘Probable’ or ‘Possible’ for the relationship to the 
investigation procedures) and the total number of those SEAEs possibly related to investigation procedures,  
- the number and percentage of patients with at least 1 AE leading to study premature withdrawal and the 
total number of those significant AEs.  
This summary table will also be provided for Serious Adverse Events (SAEs) separately.  
The number and percentage of patients with at least 1 SEAE will be tabulated by study group, System Organ Class 
(SOC) and Preferred Term (PT) on the safety data set, as well as:  
- the number and percentage of patients with at least 1 most common SEAE (defined as those occurring in at 
least 5.0% of the patients from the safety data set), if it appears to be relevant,  
- the number and percentage of patients with at least 1 SEAE by most severe intensity,  
- the number and percentage of patients with at least 1 SEAE by worst recorded relationship to the IMD,  
- the number and percentage of patients with at least 1 SEAE by worst recorded relationship to investigation 
procedures.  
  
The number and percentage of patients with at least 1 SEAE will also be tabulated by study group and SOC only on the 
safety data set.  
  
For the overall evaluation of AEs (including counting of the number of AEs reported), recurring AEs (i.e., AEs 
classified under the same Preferred Term (PT)) for a given patient in a given period will be counted only once for 
the patient concerned in the period concerned.  
  
If relevant, the number and percentage of patients with at least 1 SAE will be tabulated by study group, System Organ 
Class (SOC) and Preferred Term (PT), separately from all AEs, in a second step.  
Moreover, SEAEs occurring during the Run-in period (which only concerns patients allocated to the investigational 
group) will be tabulated in the safety data set separately, if relevant, or they will be listed if too few patients are 
concerned.   
  
All SAEs reported throughout the study (i.e., from the date of the selection visit (V0) onwards), all AEs leading to 
study premature withdrawal (which constitute significant AEs) and deaths if applicable will be listed separately by 
study group. They will be exhaustively described on an individual basis, including all reported information in the 
section devoted to AEs in the e-CRF, as well as their start date (i.e., both (1) the time interval between the date of 
the selection visit (V0) and the occurrence of the AE and (2) the timing of onset of the AE in relation to D0), and 
duration of the AE.  
  
Adverse Device Effects and Device Deficiencies will be listed separately and they will be exhaustively described on an 
individual basis, in a similar manner to SAEs, if relevant.  
  
Unplanned hospitalisations whatever their reason (which will be reported as SAEs) will also be listed separately 
from all SAEs and they will be tabulated by study group, including the number and percentage of patients 

  
  
 
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hospitalised at least once during their study participation and the number of hospitalisations per patient (as both 
quantitative and categorical data).  
X.3.5.3 -  
CLINICAL LABORATORY EVALUATION  
In the safety data set, for each laboratory parameter (apart from HbA1c which is part of the secondary efficacy 
endpoints described in section X.3.4), laboratory results and their absolute variations from baseline (i.e., initiation 
visit (V1)) will be summarised as quantitative parameters using descriptive statistics by study group at the end of 
study visit (V9) planned to be performed at D90, using the observed case approach.  
Number and percentage of patients above, below or within normal ranges in use in each laboratory involved will also 
be tabulated by study group for each parameter at study end.  
A shift table will also be provided for each parameter at study end to depict the number and percentage of patients 
with post baseline decreased laboratory values (from Within Normal Ranges to Below, from Above normal ranges 
to Within Normal Ranges or from Above normal ranges to Below), the number and percentage of subjects without 
changes (either always Within Normal Ranges or Above or Below) and the number and percentage of patients with 
post baseline increased laboratory values (from Below to Within Normal Ranges, from Within Normal Ranges to 
Above or from Below normal ranges to Above) by study group.  
X.3.5.4 -  
VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY  
For systolic and diastolic resting blood pressure separately, quantitative descriptive statistics will be tabulated on the 
safety data set by visit planned and study group, using the observed case approach.  
For each parameter separately, the absolute variations “post-initiation period – baseline (recorded at initiation visit 
(V1))” will also be tabulated by visit planned and study group. 
    
X.3.5.5 -  
CONCOMITANT TREATMENTS  
All concomitant treatments with start date at the earliest on the day of the initiation visit will be tabulated 
descriptively by study group in the safety data set using the WHO DRUG dictionary and the Anatomical Therapeutic 
Chemical (ATC) classification. Three (3) tables will be provided:  
- one table showing the number and percentage of patients with at least 1 concomitant treatment with start 
date at the earliest on the day of the initiation visit, by therapeutic area (ATC1 code corresponding to ATC 
system main group),  
- one table by both ATC1 code and ATC system subgroup (ATC2 code),  
- and one table showing the number and percentage of patients with at least 1 metabolic system concomitant 
treatment with start date at the earliest on the day of the initiation visit, by ATC system subgroups (ATC2, ATC3 
and ATC4 codes).  
X.3.6 -  MEDICO-ECONOMIC EVALUATIONS  
Medico-economic data will be tabulated descriptively by study group in the modified ITT efficacy data set (defined in 
section X.2.1) using the observed case approach, without any extrapolation of missing data.  

  
  
 
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X.3.6.1 -  
COSTS AND TIME ESTIMATION  
Overall costs will be estimated for each randomised patient from the collective perspective. The unit will be the 
patient.   
Costs will be recorded at all levels where they are generated: hospitals, HHP, family nurses and any other cost related 
to any adverse event.   
Costs include all healthcare direct costs, including transportation cost when relevant. They will be recorded 
prospectively alongside the study by the study personnel. This means that overall medical consumables, as well as 
resources consumed associated to medical interventions, home healthcare provider interventions and clinical 
events associated to diabetes (including hospitalisations) during the trial will be recorded.  
The costs associated with the resources used specifically in the study context but not planned for the treatment 
therapy once on the market (i.e., planned investigators visit only for the purpose of the trial) will be recorded but 
not part of the economic analysis.  
Time estimation means the duration of an event, linked or not to a cost estimation.  
    
Costs related to family nurse intervention   
- 
For the family nurse taking care of the patients in the investigational group and for each scheduled 
training session: the date of the session performed, its type and location will be recorded.  
- 
For each study participation day from V1 to V9, all family nurses acts will be recorded for each 
randomised patient in both control and investigational groups.  
- 
Costs will be valued according to the so called NGAP (French ‘Nomenclature Générale des Actes 
Professionnels), which is the tariff of the French National Health System.  
- 
For the total costs evaluation, it will be important to separate diabetes-related acts from those which 
are not. Specific invoicing elements, such as transportation compensations (indemnité forfaitaire de 
déplacement, indemnité forfaitaire kilométrique), and tariff for unique act (majoration pour acte 
unique) will be considered and possibly re-assessed in the economic model.  
Time estimation for family nurse intervention  
The duration will be estimated for training sessions and daily sessions at patient’s home separately and 
added globally for each study patient, including the family nurse transportation time to reach the patient’s 
home.  
Costs related to hospitals  
Recorded costs at hospitals are:  
- 
Patient study visits at all 4 periods, e.g. selection, initiation, run-in and follow-up  -  
Scheduled 
hospital stay for IMD (investigational medical device) initiation -  Any diabetes-related hospital stay.  
Hospital costs will be valued based on the latest National Cost Study method (French ‘Echelle Nationale de 
Coûts à méthodologie Commune’, ENCC).  
Time estimation related to hospitals  
The duration of each patient hospital visit and hospitalisation length of stay throughout their study 
participation will be calculated separately based on the recorded dates and times of each hospital 
arrival/admission and departure/discharge and added globally for each patient during their study 
participation.  

  
  
 
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Costs related to HHP  
Recorded costs of HHP services are:  
- 
All medical devices and their associated consumables as detailed in IMD section V.1  -  Costs 
charged to the French National Health System.  
Time estimation related to HHP  
The duration of each HHP intervention will be estimated for the 4 study periods: selection, initiation, run-in 
and follow-up separately.  
It will be done for all relevant interventions separately: at hospital, at home, by phone or by email and added 
globally for each study patient.  
Types and outcomes (activities) of calls will be written down.  
Costs charged directly to National Health System  
Recorded costs charged directly to National Health System are:  
- 
The insulin  
- 
Any medication or medical device and their consumables apart from those used by the HHP.  
  
Analysis  
The cost analysis will be performed in two steps:  
- 
Assessment of the real cost in the investigational and control groups, -  Reevaluation of the cost 
based on real life.  
X.3.6.2 -  
COST-EFFECTIVENESS  
The cost-effectiveness evaluation performed will relate the estimated difference in costs between both study 
groups in the perspective of the national healthcare payer to a difference in medical outcome over the 3-
month follow-up period. The expression of the results of the cost-effectiveness evaluation will be:  
- 
for patients with a high risk of severe hypoglycaemia (hypoglycaemia implicating a medical 
intervention in emergency within the 6 previous months before selection): cost/ severe 
hypoglycaemia event avoided,  
- 
for all patients: cost/average TIR.   
X.3.6.3 -  
COST-UTILITY  
An incremental cost per Quality-Adjusted Life Year (QALY) gained will be estimated by calculating the ratio 
between the incremental cost of the investigational group and the control group and the incremental utility.  
The incremental cost will be estimated by calculating the difference between the average total costs per 
patient in both study groups.  
Incremental utility will be estimated by calculating the difference in utility between the two study groups. In 
health economics, utility is the measure of the preference or value that an individual or society gives a 
particular health status. It is generally a number between 0 (representing death) and 1 (perfect health). This 
utility score is obtained by using the self-evaluations of the EQ-5D-5L health-related quality of life instrument 

  
  
 
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and the French specific scoring algorithm associated to a disutility related to hypoglycaemia fear 
documented with the worry subscale (HFS-W) of the Hypoglycemia Fear Survey (HFS-II).  
QALYs per patient in both study groups will be compared.   
X.4 -  HANDLING OF DROPOUTS OR MISSING DATA  
For data analysis and calculation of the TIR at baseline and at D90, gaps in the CGM recording for incomplete 
days will be imputed using a linear interpolation approach of the planned 14 days.  
Missing observations at D90 will be imputed as “non-response” in the Cochran-Mantel-Haenszel analyses.  
The number and percentage of patients prematurely withdrawn from the study after their randomisation 
will be provided by study group and overall in the Randomised ITT and the safety data sets (defined in section 
X.2.1).  
All withdrawn patients will be further described by study group and overall regarding their time to dropout, 
study period and reason for premature withdrawal. Particular attention will be paid to the description of 
Adverse Events (either serious or not serious, according to their regulatory definition provided in section 
VIII.1) leading to study premature withdrawal, as detailed in section X.3.5.2.  
  

  
  
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X.5 
HANDLING OF MODIFICATIONS TO THE INITIAL STATISTICAL METHODS  
Any modification of the initial statistical method previously described and the reason why they were 
performed will be described in a specific section of the study Statistical Analysis Plan (SAP), as well as in the 
clinical study report.  
XI -  QUALITY CONTROL/MONITORING  
Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, 
recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good 
Clinical Practice (GCP), and the applicable regulatory requirements.  
The study will be subjected to regular monitoring (visits and/or telephone monitoring) by the sponsor or any 
person appointed by the sponsor. During the monitoring visits, the Clinical Research Associate (CRA) will 
verify Investigators’ adherence to the Good Clinical Practice and the protocol and that informed consent is 
obtained and recorded for all patients prior to implementation of any study procedure.  
The CRA will contact and visit the Investigator at regular intervals during the study. He/she will compare the 
e-CRFs with medical records and other relevant documentation through direct access, during the on-site 
monitoring visits. He/she ensures the completeness, consistency and accuracy of the data being recorded in 
the e-CRF by the Investigator.  
The sponsor or any person appointed by the sponsor (such as the CRA) will explain the protocol and study 
related procedures to all study staff, including the Investigator. If new collaborators are included during the 
course of the study, additional training sessions will be organised by the investigator and/or the CRA.  
As part of the supervision of the study progress, other sponsor personnel or the CRO may, on request, 
accompany the CRA on visits to the study site. The investigator and his/her collaborators commit to 
cooperate with the CRA to resolve any problems, corrections, or possible misunderstandings concerning the 
findings detected in the course of these monitoring visits.  
XI.1 -  ACCESS TO SOURCE DATA  
The Investigator must authorize the Clinical Research Associate (CRA) to have direct access to all source 
documents concerning the patient necessary for the verification of data listed in the e-CRF. The Investigator 
must authorize the manufacturer representative to have direct access to IMD data concerning the patient 
necessary for the verification of proper use of IMD.  
In case of requests from the Health Authorities, it is also indispensable to have access to all study data.  
According to ICH-GCP requirements, the patient will be informed in writing about the need for Source Data 
Verification (SDV) for quality control, and audits/inspections.  
  
  

  
  
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XI.2 
AUDIT AND INSPECTION  
An inspection may be conducted by a regulatory authority. An audit might be carried out by the sponsor to 
ensure that the study is conducted as per the protocol and in accordance with the applicable regulatory 
requirements.  
The audit consists of the visit of the facilities together with the review of the study related activities and 
documentation (subject’s medical file, study specific records, case report forms, …). The investigational study 
team and documentation should be available for any audit and inspection.  
Investigators will have to accept that participation in the study implies agreement with regard to inspection 
and audit.  
In case of inspection, the Investigator will inform the Sponsor who can participate in the inspection at the 
investigator’s request.    
 

  
  
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XII RESPONSIBILITIES  
XII.1 -  SPONSOR’S RESPONSIBILITIES  
The Sponsor will submit an application to Independent Ethics Committee and the French Competent 
Authority (ANSM) for approval of the clinical study. A copy of the Ethics Committee and Competent Authority 
approvals must be received by the sponsor before the study starts.  
In accordance with the provisions of the law and the GCP, the Sponsor will have an insurance policy intended 
to guarantee against possible damage resulting from the research.  
The studies and/or experiments performed on behalf of the sponsor will be specifically and expressly 
guaranteed. It is advisable to underline that noncompliance with the Research Legal Conditions is a cause 
for guarantee exclusion.  
XII.2 -  INVESTIGATOR RESPONSIBILITIES  
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner and kept up-to-date to ensure 
accurate interpretation of data.  
The Investigator will maintain adequate and accurate records in accordance with ICH Good Clinical Practice 
and this Clinical Investigation Plan to enable the conduct of the study to be fully documented and the study 
data to be subsequently verified for trial-related monitoring, audits, EC review, and regulatory inspection.  
Agreement of the investigator to conduct and administer this study in accordance with the protocol will be 
documented in separate study agreements.  
The Investigator will be responsible for giving information and training about the study to all staff members 
involved in the study or in any element of patients management, both before starting the practical 
performance of the study and during the course of the study (e.g., when new staff becomes involved).  
The Investigator will maintain a record of all individuals involved in the study (medical, nursing and other 
staff) and will specify, for each person, the tasks delegated for the study. The investigator is responsible for 
ensuring the privacy, health, and welfare of the patients during and after the study.  
The Investigator must be familiar with the background and requirements of the study and with the properties 
of the investigational medical device as described in the technical documentation and any relevant health 
product information.  
  
  
XIII 
ADMINISTRATIVE AND REGULATORY ASPECTS  
XIII.1 -  GOOD CLINICAL PRACTICES/ DECLARATION OF HELSINKI  
The study will be conducted in compliance with ICH Harmonized Tripartite Guidelines for Good Clinical  
Practice (ICH E6), the provisions of the Declaration of Helsinki (Appendix 3) and the European Directive 
2001/20/EC, as well as with applicable local regulatory requirements.  

  
  
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XIII.2 -  INDEPENDENT ETHICS COMMITTEE AND COMPETENT AUTHORITY  
Prior to the commencement of the study, the study protocol (and its substantial amendments if any) will be 
reviewed and approved by concerned Independent Ethics Committee (IEC) and competent authority(ies) of 
participating country(ies). The study protocol, informed consent form, subjects’ recruitment procedures and 
any written information to be provided to the subjects will be reviewed by the IEC for opinion.  
The study protocol cannot be implemented until the approvals by IEC and competent authority, in 
accordance with the applicable regulatory requirements, have been obtained.  
During the study, the sponsor should notify the investigator, the IEC and the competent authority(ies) of any 
relevant information that could affect the safety of the subjects and/or could impact the conduct of the 
study.  
XIII.3 -  PERSONAL DATA PROTECTION AND CONFIDENTIALITY  
The Investigator must assure that the personal data of patients, including their identity and all other personal 
medical information, will be kept confidential at any time.  
Patient number and initials will identify the patients in the e-CRF. On other documents submitted to the 
sponsor, patients will not be identified by their names but by an identification code (e.g. patient number).  
By signing this protocol, the Investigator undertakes that the protocol and all attached information are and 
will remain confidential. The Investigator agrees that after providing the protocol and all information 
necessary for the personnel involved, he/she remains responsible for their total confidentiality. Such 
obligation is detailed in the confidentiality agreement signed by the Investigator before the initiation of the 
study.  
The Investigator agrees that, subject to local regulations and ethical considerations, a Sponsor representative 
or any regulatory agency may consult directly and/or copy study documents in order to verify a case report.  
The Investigator undertakes to treat all patients data used or disclosed in connection with the conduct of 
study in compliance with European and local applicable laws relating to data protection.  
The Investigator will be responsible for keeping a list of all enrolled patients including patient numbers, full 
names and dates of birth.  
All data received during the study will be collected in a computer system and shall remain strictly 
confidential. Access to the database will only be allowed to the study team, persons duly authorized by the 
sponsor and if necessary, by the representatives of regulatory authority(ies), which are all subjected to 
professional secrecy.  
The collected data will be analyzed in order to be able to achieve the objectives of the study.  
Confidentiality will be guaranteed by the fact that the subject file number will appear in the written 
analyses/documents and that the complete name of the subject will never appear in the study documents.  

  
  
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The sponsor will be entitled to use and to analyze all of the data collected during this study. The information 
will be controlled, in accordance with the regulations in force and notably with the Regulation (EU) 2016/679 
of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with 
regard to the processing of personal data and on the free movement of such data (General Data Protection 
Regulation – GDPR), in addition to the Loi n°78-17 “relative à l’informatique, aux fichiers et aux libertés” in 
its current version.  
   
The contact details of the Data Protection Officer designated by the sponsor are:  
Laurence Thomazeau  
AIR LIQUIDE  
Déléguée à la Protection des Données  
75, Quai d’Orsay 75007 
Paris - France  
 https://www.airliquide.com/fr/groupe/contactez-nous-rgpd  
The data may be passed on to companies that act on behalf of the sponsor and are in countries located in or 
outside European Union that could guarantee an adequate level of personal data protection to administer 
the study.  
XIII.4 -  COMMISSION NATIONALE DE L’INFORMATIQUE ET DES LIBERTES (CNIL)  
Data will be recorded and analysed in agreement with the compliance commitment of the CNIL MR-001 
(Méthodologie de référence 001).  
ARCHIVING OF STUDY DOCUMENTS  
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified. The study documents, including patient e-CRFs, 
should be classified in the Investigator's file.  
The Investigator's file will contain the protocol/amendments, independent ethics committee and health 
authorities with correspondence, sample informed consent, IMD records, staff curriculum vitae and 
authorization forms, correspondence, etc.  
The Investigator must keep the Study File until the Sponsor authorization of destruction and by default during 
at least 15 years after the last publication of the study. However, this period may be extended in accordance 
with the applicable regulatory requirements.  
Should the investigator wish to assign the study records to another party or move them to another location, 
the sponsor must be notified in advance. 
XIII.5 -  PATIENT’S INFORMATION AND CONSENT  
The information note must be given to the patients before their decision to participate or abstain from 
participation, according to local requirements and Good Clinical Practice.  

  
  
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This information is based on the elements set out in the Declaration of Helsinki and the ICH-GCP Guideline 
(ICH E6). It must also describe the measures taken to safeguard patient’s privacy and protection of personal 
data, according to European GDPR and French law.  
Restraints and risks must be explained, as well as the right to discontinue participation in the study at any 
stage, without affecting their further relationship with the investigator and/or their future care.  
The information note and written consent form must be submitted by the Investigator to the patient with 
an oral explanation. The investigator should provide the patient ample time and opportunities to inquire 
about details of the trial and to decide whether or not to participate in the trial. All questions about the trial 
should be answered to the satisfaction of the patients.  
The consent must be agreed, dated and signed by the patient before any study-related procedure starts.  
The consent form is made in duplicate: the original copy is kept by the Investigator and one copy is given to 
the patient.  
If any information becomes available during the trial that may be relevant to the patient’s willingness to keep 
on participating in the trial, an updated written informed consent must be submitted to the patient to 
confirm his/her agreement to continue participating.  
XIII.6 -  CONSEIL NATIONAL DE L’ORDRE DES MEDECINS (CNOM)  
A separate financial agreement will be signed between the sponsor and the investigator and/or the institution 
involved.  
According to French national law (article R1121-3-1 du Code de la Santé Publique), the financial agreement 
related to the study will be submitted for information to the CNOM upon financial agreement signature.  
According to French national law (article L.4113.6 du Code de la Santé Publique), the Sponsor will inform the 
CNOM of the agreement implementation.  
According to the 2011-2012 French law dated December 29, 2011 and its implementing decree 2013-414 of 
21 May 2013, the sponsor will publish the existence of this agreement, as well as benefits in kind or in cash 
provided directly or indirectly to the Investigator.  
XIII.7 -  PROTOCOL AMENDMENT  
Neither the Investigator nor the Sponsor may alter the protocol without the authorization of the other party. 
Any amendment that may be issued, must be dated and signed by both parties and must appear as an 
amendment to the protocol before implementation.  
Substantial amendments are submitted for authorization to Competent Authority (CA) and approval to EC 
before implementation.  
Substantial amendments on safety measures are submitted for approval/authorization to EC and CA but could 
be implemented immediately under specific conditions defined with the sponsor.  
XIII.8 -  USE OF INFORMATION AND PUBLICATION OF STUDY RESULTS   
The study data and study results are the exclusive property of the Sponsor. Nevertheless, the sponsor is 
aware that its property rights over the data must not prevent the investigator from communicating the study 

  
  
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results to the scientific community. Provided any such presentations do not prevent recognition of its 
industrial property rights, the Sponsor therefore authorises the investigator to draw up and present any 
scientific papers concerning the study after having received the written Sponsor authorization.   
The study results will be reported into a final clinical study report that will be written according to the ICH E3 
Guideline (Structure and Content of Clinical Study Reports) and according to all applicable regulations.  
  
  
  
 

  
  
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XIV -  BIBLIOGRAPHY  
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France in 18- to 74-year-old individuals: the French Nutrition and Health Survey 2006/2007. Diabet Med. 2011 
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2.Bringer J, Fontaine P, Detournay B, et al. Prevalence of diagnosed type 2 diabetes mellitus in the French general 
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multiple daily injections in the treatment of type 2 diabetes-research design and methods. Diabetes Technol Ther. 2014 
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6.Conget I, Castaneda J, Petrovski G, et al. The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with 
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7.Reznik Y, Cohen O, Aronson R, et al. Insulin pump treatment compared with multiple daily injections for treatment of 
type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet. 2014 Oct 4;384(9950):1265-72.  
8.Ozougwu JC, Obimba, K. C., Belonwu, C. D., and Unakalamba, C. B. The pathogenesis and pathophysiology of type 1 
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diabetes. Diabetes Care. 2013 Aug;36 Suppl 2:S127-38.  
10.Federation ID. IDF DIABETES ATLAS, Eighth edition. 2017:1-150.  
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17.  
12.Mosnier-Pudar H, Hochberg G, Eschwege E, et al. How do patients with type 2 diabetes perceive their disease? 
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Sep;12(5):1029-40.  
14.American Diabetes A. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 
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17.Agency EM. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes 
mellitus. Annual Report. 2018.  
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pour la pratique clinique ». 2013.  
19.Zonszein J, Groop PH. Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the 
Disease. Diabetes Ther. 2016 Dec;7(4):621-39.  

  
  
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20.Blumer I, Clement M. Type 2 Diabetes, Hypoglycemia, and Basal Insulins: Ongoing Challenges. Clin Ther. 2017 
Aug;39(8S2):S1-S11.  
21.Beck RW, Riddlesworth TD, Ruedy K, et al. Continuous Glucose Monitoring Versus Usual Care in Patients With Type 
2 Diabetes Receiving Multiple Daily Insulin Injections: A Randomized Trial. Ann Intern Med. 2017 Sep 19;167(6):365-74.  
22.Munoz-Velandia O, Guyatt G, Devji T, et al. Patient Values and Preferences Regarding Continuous Subcutaneous 
Insulin Infusion and Artificial Pancreas in Adults with Type 1 Diabetes: A Systematic Review of Quantitative and 
Qualitative Data. Diabetes Technol Ther. 2019 Apr;21(4):183-200.  
23.Weisman A, Bai JW, Cardinez M, Kramer CK, Perkins BA. Effect of artificial pancreas systems on glycaemic control in 
patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials. Lancet 
Diabetes Endocrinol. 2017 Jul;5(7):501-12.  
24.Bally L, Gubler P, Thabit H, et al. Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 
diabetes receiving hemodialysis. Kidney Int. 2019 Mar 20.  
25.Brown S, Raghinaru D, Emory E, Kovatchev B. First Look at Control-IQ: A New-Generation Automated Insulin Delivery 
System. Diabetes Care. 2018 Dec;41(12):2634-6.  
26.Kumareswaran K, Thabit H, Leelarathna L, et al. Feasibility of closed-loop insulin delivery in type 2 diabetes: a 
randomized controlled study. Diabetes Care. 2014;37(5):1198-203.  
27.Taleb N, Carpentier AC, Messier V, et al. Efficacy of Artificial Pancreas Use in Patients With Type 2 Diabetes Using 
Intensive Insulin Therapy: A Randomized Crossover Pilot Trial. Diabetes Care. 2019 Jul;42(7):e107-e9.  
28.Thabit H, Hartnell S, Allen JM, et al. Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, 
parallel-group trial. Lancet Diabetes Endocrinol. 2017 Feb;5(2):117-24.  
29.Battelino T, Danne T, Bergenstal RM, et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: 
Recommendations From the International Consensus on Time in Range. Diabetes Care. 2019 Aug;42(8):1593-603.  
30.Danne T, Nimri R, Battelino T, et al. International Consensus on Use of Continuous Glucose Monitoring. Diabetes 
Care. 2017 Dec;40(12):1631-40.  
31.Lu J, Ma X, Zhou J, et al. Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic 
Retinopathy in Type 2 Diabetes. Diabetes Care. 2018 Nov;41(11):2370-6.  
32.M. Z. Appropriateness of Time in Range as a Measure of Diabetes. Outcomes Diabetes in Control. 2018.  
33.https://www.has-sante.fr/jcms/c_2826867/fr/amelioration-de-la-qualite-de-vie-des-patients-et-acces-al-
innovation-deux-priorites-dans-les-evaluations-des-dispositifs-medicaux-15-mars-2018#toc_1_1.158.  
34.Ekhlaspour L, Forlenza GP, Chernavvsky D, et al. Closed loop control in adolescents and children during winter sports: 
Use of the Tandem Control-IQ AP system. Pediatr Diabetes. 2019 May 17.  
35.Forlenza GP, Ekhlaspour L, Breton M, et al. Successful At-Home Use of the Tandem Control-IQ Artificial Pancreas 
System in Young Children During a Randomized Controlled Trial. Diabetes Technol Ther. 2019 Apr;21(4):159-69.  
36.Schliess F, Heise T, Benesch C, et al. Artificial Pancreas Systems for People With Type 2 Diabetes: Conception and 
Design of the European CLOSE Project. J Diabetes Sci Technol. 2019 Mar;13(2):261-7.  
37.Brooks R. EuroQol: the current state of play. Health Policy. 1996 Jul;37(1):53-72.  
38.Buchholz I, Janssen MF, Kohlmann T, Feng YS. A Systematic Review of Studies Comparing the Measurement 
Properties of the Three-Level and Five-Level Versions of the EQ-5D. Pharmacoeconomics. 2018 Jun;36(6):645-61.  
39.EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990 
Dec;16(3):199-208.  
40.Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36.  

  
  
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41.Janssen MF, Bonsel GJ, Luo N. Is EQ-5D-5L Better Than EQ-5D-3L? A Head-to-Head Comparison of Descriptive 
Systems and Value Sets from Seven Countries. Pharmacoeconomics. 2018 Jun;36(6):675-97.  
42.Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001 Jul;33(5):337-43.  
43.Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of hypoglycemia: quantification, validation, and 
utilization. Diabetes Care. 1987 Sep-Oct;10(5):617-21.  
44.Gonder-Frederick LA, Schmidt KM, Vajda KA, et al. Psychometric properties of the hypoglycemia fear survey-ii for 
adults with type 1 diabetes. Diabetes Care. 2011 Apr;34(4):801-6.  
45.Brooke J. SUS: A Quick and Dirty Usability Scale. 1986.  
46.Sauro J. Measuring Usability with the System Usability Scale (SUS)  
47.Patek SD, Lv D, Ortiz EA, Hughes-Karvetski C, Kulkarni S, Zhang Q, Breton MD. Empirical representation of blood 
glucose variability in a compartmental model. InPrediction Methods for Blood Glucose Concentration 2016 (pp. 
133157). Springer, Cham.    
48.Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular 
complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year 
study. Diabetes Res Clin Pract 1995;28: 103–117  
49.Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International 
Consensus on Time in Range Diabetes Care Volume 42, August 2019   
50.Améliorer la qualité du système de santé et maîtriser les dépenses 7 juillet 2016 Propositions de l’Assurance Maladie 
pour 2017. Rapport au ministre chargé de la Sécurité sociale et au Parlement sur l’évolution des charges et des produits  
de  
l’Assurance  
Maladie  
au  
titre  
de  
2017  
(loi  
du  
13  
août  
2004).  
https://assurance- 
maladie.ameli.fr/sites/default/files/rapport-activite-charges-produits-17_assurance-maladie.pdf Accédé le 16 Août  
2019  
51.Usage Note 24560: How can I linearly interpolate between the values in my datA?” SUPPORT / SAMPLES & SAS 
NOTES (« http://support.sas.com/kb/24/560.html)  
52.G. E. Umpierrez and B.P. Kovatchev. Glycemic Variability: How to Measure and Its Clinical Implication for Type 2 
Diabetes. Am J Med Sci 2018;356(6):518−527  https://www.amjmedsci.org/article/S0002-9629(18)30373-2/pdf  
53.L. Bally, H. Thabit, S. Hartnell, E. Andereggen, Y. Ruan, M.E. Wilinska, M.L. Evans, M.M. Wertli, A.P. Coll, C. Stettler, 
and R.Hovorka. Closed-Loop Insulin Delivery for Glycemic-Control in Noncritical Care. N Engl J Med 2018;379:547-56  
54.J. T. Casagrande; M. C. Pike; P. G. Smith. An Improved Approximate Formula for Calculating Sample Sizes for  
Comparing Two Binomial Distributions. Biometrics, Vol. 34, No. 3. (Sep., 1978), pp. 483-486  
  
XV -  APPENDICES  
  
  
  
  
  
  
  
  

  
  
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APPENDIX 1- PATIENT VALIDATION OF KNOWLEDGES AND SKILLS ACQUIRED FORM  
For each item, the level “en cours” or “acquis” must be obtained by the patient. Otherwise, these levels must 
have been obtained by the caregiver.  
  
  

 
 
  
  

 
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APPENDIX 2- CODE OF PRACTICE FOR HOME HEALTHCARE PROVIDERS 
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APPENDIX 3- DECLARATION OF HELSINKI  
  
  
 

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APPENDIX 4- HYPERGLYCEMIA AND HYPOGLYCEMIA PROTOCOL INSTRUCTIONS  
HYPERGLYCEMIA PROTOCOL:   
If a participant’s CGM reading is ≥300 mg/dL for over 1 hour, or ≥400 mg/dL at any point, the 
participant or their caregiver will be instructed to take the following steps:  
● Perform a blood ketone measurement with the study ketone meter. Participants will also be 
encouraged to check ketones if they are clinically concerned.  
● Correction insulin may be taken per the participant’s usual routine.   
● Participants will be instructed to change their pump site and administer correction insulin via 
insulin syringe or pen for ketones ≥0.6 mmol/L and to additionally notify study staff for ketones 
≥3.0 mmol/L.  
  
HYPOGLYCEMIA PROTOCOL:   
If a participant receives a CGM hypoglycemia threshold alert or notes that the CGM glucose is below 
the hypoglycemia threshold alert value,   
● A confirmatory fingerstick testing will be performed.   
● The participant or their caregiver will be instructed to treat hypoglycemia with ~16 grams of 
fast-acting oral glucose (corresponding to half of soda can or 3 pieces of sugar n°4).   
● A confirmatory fingerstick testing will be performed 20 minutes after fast-acting oral glucose 
intake, if CGM glucose reading is still < 80 mg/dL.