Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care (CREDOenAP)
Phase: NA
Conditions: Type 2 Diabetes Mellitus (T2DM)
Sponsor: Parc Sanitari Pere Virgili

 
 
 
 
 
 
 
Lifestyle Intervention Clinical Trial for the Remission 
of Type 2 Diabetes Mellitus in Primary Care 
(CREDOenAP) [Ensayo clínico de intervención estilo 
de vida para la reversión de Diabetes Mellitus tipo 2 
en Atención Primaria (CREDOenAP) ] 
 
Protocol Number*: <Number> 
National Clinical Trial (NCT) Identified Number:  <Number, once assigned 
by CT.gov> 
Principal Investigator*: Alexandre Ternianov.  
PhD, Specialist in Family and Community Medicine, Parc Sanitari Pere i Virgili. Primary 
and Community Care Research Group in Barcelona (APICBA), Hospital del Mar 
Research Institute. 
Sponsor: Parc Sanitari Pere i Virgili 
Funded by: Parc Sanitari Pere i Virgili  
Version Number:  Not applicable; this is the first version of the protocol 
Date: 2025-09-04 
 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
Protocol <#> 
 
04 September 2025 
 
 
 
 
Table of Contents 
STATEMENT OF COMPLIANCE .............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE ............................................................................................................................... 2 
1 
Resumen del protocolo ...................................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................. 3 
Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care (CREDOenAP) 
[Ensayo clínico de intervención estilo de vida para la reversión de Diabetes Mellitus tipo 2 en Atención Primaria 
(CREDOenAP) ] ............................................................................................................................................................ 3 
1.2 
SCHEMA ............................................................................................................................................... 6 
1.3 
Schedule of Activities ............................................................................................................................ 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale ...................................................................................................................................... 8 
2.2 
Background ............................................................................................................................................ 9 
2.3 
Risk/Benefit Assessment ...................................................................................................................... 11 
2.3.1 
Known Potential Risks ..................................................................................................... 11 
2.3.2 
Known Potential Benefits ................................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits ..................................................................... 12 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 13 
4 
STUDY DESIGN ............................................................................................................................................ 15 
4.1 
Overall Design ...................................................................................................................................... 15 
4.2 
Scientific Rationale for Study Design .................................................................................................. 17 
4.3 
Justification for Intervention ................................................................................................................ 17 
4.4 
End-of-Study Definition ....................................................................................................................... 18 
5 
STUDY POPULATION ................................................................................................................................. 18 
5.1 
Inclusion Criteria .................................................................................................................................. 19 
5.2 
Exclusion Criteria ................................................................................................................................. 19 
5.3 
Lifestyle Considerations ....................................................................................................................... 19 
5.4 
Screen Failures ..................................................................................................................................... 20 
5.5 
Strategies for Recruitment and Retention ............................................................................................. 20 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .............................................. 21 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration .............................................. 21 
6.1.1 
Study Intervention or Experimental Manipulation Description ........................................ 21 
6.1.2 
Administration and/or Dosing .......................................................................................... 21 
6.2 
Fidelity ................................................................................................................................................. 22 
6.2.1 
Interventionist Training and Tracking .............................................................................. 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................................. 22 
6.4 
Study Intervention/Experimental Manipulation Adherence ................................................................. 22 
6.5 
Concomitant Therapy ........................................................................................................................... 23 
6.5.1 
Rescue Therapy ................................................................................................................ 23 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 23 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ..................................................... 23 
7.2 
Participant Discontinuation/Withdrawal from the Study...................................................................... 24 
7.3 
Lost to Follow-Up ................................................................................................................................ 24 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................................................... 24 
8.1 
Endpoint and Other Non-Safety Assessments ...................................................................................... 24 
8.2 
Safety Assessments .............................................................................................................................. 32 
8.3 
Adverse Events and Serious Adverse Events ....................................................................................... 32 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
Protocol <#> 
 
04 September 2025 
 
 
 
8.3.1 
Definition of Adverse Events ........................................................................................... 32 
8.3.2 
Definition of Serious Adverse Events ............................................................................... 32 
8.3.3 
Classification of an Adverse Event ................................................................................... 33 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ................................. 34 
8.3.5 
Adverse Event Reporting .................................................................................................. 34 
8.3.6 
Serious Adverse Event Reporting ..................................................................................... 34 
8.3.7 
Reporting Events to Participants ....................................................................................... 35 
8.3.8 
Events of Special Interest ................................................................................................. 35 
8.3.9 
Reporting of Pregnancy .................................................................................................... 35 
8.4 
Unanticipated Problems ....................................................................................................................... 35 
8.4.1 
Definition of Unanticipated Problems .............................................................................. 35 
8.4.2 
Unanticipated Problems Reporting ................................................................................... 36 
8.4.3 
Reporting Unanticipated Problems to Participants ........................................................... 36 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................ 36 
9.1 
Statistical Hypotheses ........................................................................................................................... 36 
9.2 
Sample Size Determination .................................................................................................................. 37 
9.3 
Populations for Analyses ...................................................................................................................... 37 
9.4 
Statistical Analyses............................................................................................................................... 38 
9.4.1 
General Approach ............................................................................................................. 38 
9.4.2 
Analysis of the Primary Endpoint(s)................................................................................. 38 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 39 
9.4.4 
Safety Analyses ................................................................................................................ 40 
9.4.5 
Baseline Descriptive Statistics .......................................................................................... 40 
9.4.6 
Planned Interim Analyses ................................................................................................. 41 
9.4.7 
Sub-Group Analyses ......................................................................................................... 41 
9.4.8 
Tabulation of Individual Participant Data ......................................................................... 41 
9.4.9 
Exploratory Analyses ........................................................................................................ 41 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................. 42 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ................................................................... 42 
10.1.1 
Informed Consent Process ................................................................................................ 42 
10.1.2 
Study Discontinuation and Closure .................................................................................. 42 
10.1.3 
Confidentiality and Privacy .............................................................................................. 43 
10.1.4 
Future Use of Stored Specimens and Data........................................................................ 44 
10.1.5 
Key Roles and Study Governance .................................................................................... 45 
10.1.6 
Safety Oversight ............................................................................................................... 46 
10.1.7 
Clinical Monitoring .......................................................................................................... 47 
10.1.8 
Quality Assurance and Quality Control ............................................................................ 47 
10.1.9 
Data Handling and Record Keeping ................................................................................. 48 
10.1.10 
Protocol Deviations .......................................................................................................... 48 
10.1.11 
Publication and Data Sharing Policy ................................................................................ 48 
10.1.12 
Conflict of Interest Policy ................................................................................................. 49 
10.2 
Additional Considerations .................................................................................................................... 49 
10.3 
Abbreviations and Special Terms ......................................................................................................... 49 
10.4 
Protocol Amendment History ............................................................................................................... 51 
11 
REFERENCES................................................................................................................................................ 52 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with the International Council on Harmonisation Good 
Clinical Practice (ICH GCP) guidelines, the Declaration of Helsinki, and applicable European 
Union and Spanish regulations governing clinical research with human participants, including: 
 
Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. 
 
Spanish Royal Decree 1090/2015, of 4 December, regulating clinical trials with 
medicinal products, Ethics Committees for Research with Medicinal Products (CEIm), 
and the Spanish Clinical Studies Registry (REec). 
All investigators and clinical trial site staff responsible for the conduct, management, or 
oversight of the trial have completed training in Human Subjects Protection and ICH GCP. The 
study has been reviewed and approved by the Ethics Committee for Research with Medicines 
(CEIm) of Parc de Salut MAR, Barcelona, Spain. The Committee, both in its composition and in 
its Standard Operating Procedures (SOPs), complies with Good Clinical Practice (GCP) 
guidelines (CPMP/ICH/135/95). 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the CEIm of Parc de Salut MAR for review and approval. Approval 
of both the protocol and the consent form(s) must be obtained before any participant is 
consented. Any amendment to the protocol will require review and approval by the CEIm 
of Parc de Salut MAR before the changes are implemented to the study. All changes to the 
consent form(s) will be CEIm of Parc de Salut MAR approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
2 
INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines, as described in the 
Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name*: Alexandre Ternianov 
 
Title*: PhD, Specialist in Family and Community Medicine  
 
Investigator Contact Information 
Affiliation*: Primary and Community Care Research Group in Barcelona (APICBA), Hospital 
del Mar Research Institute, Parc Sanitari Pere Virgili, Barcelona, Spain. 
Address: 30 Esteve Terradas Street, 08023 Barcelona, Spain 
Telephone: +34 932 59 40 00 
Email: aternianov@perevirgili.cat; ncarrilero@perevirgili.cat; averas@perevirgili.cat 
 
 
 
 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
3 
1 
SUMMARY OF THE PROTOCOL 
1.1 SYNOPSIS  
 
Title: 
Lifestyle Intervention Clinical Trial for the Remission of Type 2 
Diabetes Mellitus in Primary Care (CREDOenAP) [Ensayo 
clínico de intervención estilo de vida para la reversión de 
Diabetes Mellitus tipo 2 en Atención Primaria (CREDOenAP)] 
 
Grant Number: 
N/A 
Study Description: 
Intervention program with intensive lifestyle counseling, added 
to standard pharmacological treatment subsequently adjusted 
according to clinical needs and outcomes. The intervention will 
last 6 months and consists of biweekly in-person and telephone 
visits. Patients will follow a personalized dietary plan with 
carbohydrate restriction, based on the recommendations of the 
American Diabetes Association; engage in moderate and 
accessible physical activity; implement circadian rhythm 
regularization; and receive psychological counseling and 
support. 
 
Objectives*: 
 
Primary objective: 
 
To quantify the proportion of Type 2 Diabetes (T2DM) 
remission among participants without evidence of absolute 
insulinopenia enrolled in the lifestyle intervention program 
(CREDOenAP) at the end of the program (6 months). 
 
Secondary objectives: 
 
- 
To quantify the percentage of T2DM remission among 
participants in the lifestyle intervention program 
(CREDOenAP) one year after completion of the program 
(18 months). 
 
- 
To determine the nutritional, physical activity, and 
quality-of-life 
patterns 
of 
participants 
in 
the 
CREDOenAP program before, at the end of the 
intervention and one year after (18 months). 
 
- 
To assess anthropometric, metabolic, and imaging 
markers of cardiovascular risk in participants in the 
CREDOenAP program before, at the end of the 
intervention (6 months) and one year after completion (18 
months). 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
4 
Endpoints*: 
Primary Endpoint:  
 
- 
Percentage of participants achieving type 2 diabetes 
remission at 6 months, defined as HbA1c <6.5% after 6 
months of intervention and at least 3 months without 
antidiabetic medication. HbA1c will be determined 
through fasting blood analysis (minimum 8 hours). 
- 
Percentage of participants achieving T2DM remission at 
6 months, defined as fasting venous plasma glucose <126 
mg/dL after 6 months of intervention and at least 3 
months without antidiabetic medication. Fasting glucose 
will be measured through venous blood analysis after a 
minimum 8-hour fast. 
 
Secondary Endpoints:  
 
- 
Percentage of participants maintaining type 2 diabetes 
remission at 18 months, defined as HbA1c <6.5% after 
12 months post-intervention and at least 9 months 
without antidiabetic medication. 
 
- 
Percentage of participants maintaining type 2 diabetes 
remission at 18 months, defined as fasting venous plasma 
glucose <126 mg/dL after 12 months post-intervention 
and at least 9 months without antidiabetic medication. 
 
- 
Change in dietary patterns at 6 and 18 months, assessed 
using a validated 24-hour dietary recall questionnaire, to 
evaluate adherence to the nutritional component of the 
intervention. 
 
- 
Change in physical activity level at 6 and 18 months, 
measured using the International Physical Activity 
Questionnaire (IPAQ). 
 
- 
Change in health-related quality of life at 6 and 18 
months, assessed using validated instruments such as the 
SF-36 or EQ-5D questionnaires. 
 
- 
Change in cardiovascular risk factors at 6 and 18 months, 
including blood pressure, total cholesterol, HDL 
cholesterol, LDL cholesterol, Apo B100, triglycerides, 
and presence and size of carotid atherosclerotic plaques. 
 
- 
Change in metabolic indicators at 6 and 18 months, 
including weight, Body Mass Index (BMI), waist 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
5 
circumference, insulin resistance (HOMA-IR index), 
pancreatic beta-cell function (HOMA-B index), and 
fasting insulin. 
 
Study Population: 
The study population consists of patients with type 2 diabetes 
(T2DM) assigned to the Primary Care centers of Barceloneta 
and Larrard at Parc Sanitari Pere Virgili, Barcelona. 
 
 
 
Phase* or Stage: 
N/A. 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Multicenter Study Sites 
Barceloneta Primary Care Center, Parc Sanitari Pere Virgili, 
Barcelona, Spain 
Larrard Primary Care Center, Parc Sanitari Pere Virgili, 
Barcelona, Spain 
 
Description of Study 
Intervention/Experimental 
Manipulation: 
The program consists of biweekly in-person and telephone visits, 
focused on implementing a personalized dietary plan with 
carbohydrate restriction, based on the American Diabetes 
Association recommendations; moderate and accessible physical 
activity; circadian rhythm regularization; and psychological 
counseling and support. 
Study Duration: 
3 years. 
 
Participant Duration: 
18 months (6 months of intervention and follow-up assessments 
one year after completion of the intervention). 
 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
6 
1.2 SCHEME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-screening of potential patients (inclusion/exclusion criteria) Screening visit Schedule 
 
N= 120 
Those who meet the criteria will be provided with the informed consent form and will 
complete the validated questionnaires. See Section 1.3, Schedule of Activities, for the list 
of procedures 
Imaging study (Carotid ultrasonography) + baseline laboratory tests 
 
Randomize 
Grup A 
Intervention 
Grup B  
Control 
1 Session (Individual) 
Intervention Session 
Follow-up sessions (15 min, 
biweekly). Telephone contact 
Standard diabetes treatment 
Assessment 2 (6 months after initiation) End of intervention. 
For the list of procedures, see Section 1.3, Schedule of Activities. 
Assessment 3 (12 months after the end of intervention). 
For the list of procedures, see Section 1.3, Schedule of Activities. 
Selection Visit 
Assessment 1 
Visit 1 
N=60
N=60
Visit 2
Visit 3 
 to 15 
Assessment 2 
Assessment 3 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
7 
1.3 SCHEDULE OF ACTIVITIES  
 
 
 
 
Screening / 
Selection 
 
Assessment  1 
Visit 1: Carotid 
ultrasonography  
+ laboratory 
analyses 
Randomization 
Visit 2: 
Intervention 
session 
Visits 3 to 15: 
Biweekly 
telephone 
contacts 
Assessment  2 
(6 months) 
Assessment  3 
(18 months) 
End of study 
Assessment of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Signing of informed 
consent 
 
X 
 
 
 
 
 
 
 
Collection of 
sociodemographic 
variables 
 
X 
 
 
 
 
 
 
 
Review of medical 
history and current 
medication 
 
X 
 
 
 
 
 
X 
 
Anthropometric 
measurements 
(weight, height, BMI, 
waist circumference) 
 
X 
 
 
 
 
X 
X 
 
Health-related quality 
of life questionnaire 
(SF-36) 
 
X 
 
 
 
 
X 
X 
 
Dietary questionnaire 
(24-hour recall) 
 
X 
 
 
 
 
X 
X 
X 
 
Physical activity 
questionnaire (IPAQ) 
 
X 
 
 
 
 
X 
X 
 
Laboratory analyses 
(HbA1c, glucose, 
insulin, lipids, etc.) 
 
 
X 
 
 
 
X 
X 
 
Imaging studies 
(Carotid 
ultrasonography) 
 
 
X 
 
 
 
X 
X 
 
Randomization 
 
 
 
X 
 
 
 
 
 
Adverse event 
recording 
 
X 
 
 
 
 
X 
X 
X 
Telephone follow-up 
for clinical status 
 
 
 
 
 
X 
 
 
 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
8 
2 
 
INTRODUCTION 
2.1 STUDY RATIONALE  
Type 2 diabetes (T2DM) represents a major public health problem, with its incidence rapidly 
increasing worldwide. In 2014, 8.5% of the global population was affected by this disease. 
(Hambleton et al., 2013).  The results of Di@bet.es (Soriguer et al., 2012), the largest 
epidemiological study conducted in Spain revealed a prevalence of 13.8% for type 2 diabetes 
among adults over 18 years of age (5.3 million people), of whom 43% (2.3 million) were 
undiagnosed at the time of the study. Traditionally, type 2 diabetes (T2DM) has been considered 
a progressive and irreversible disease. This hypothesis was supported by a series of studies 
showing that 50% of individuals required insulin therapy 10 years after T2DM diagnosis, along 
with a progressive loss of insulin production. (“Effect of Intensive Blood-Glucose Control with 
Metformin on Complications in Overweight Patients with Type 2 Diabetes (UKPDS 34). UK 
Prospective Diabetes Study (UKPDS) Group.,” 1998; “U.K. Prospective Diabetes Study 16. 
Overview of 6 Years’ Therapy of Type II Diabetes: A Progressive Disease. U.K. Prospective 
Diabetes Study Group.,” 1995; Rudenski et al., 1988). However, these hypotheses were based on 
studies with small sample sizes (Rahier et al., 2008; Rudenski et al., 1988)  or on data from groups 
of individuals who gained weight steadily (approximately 5 kg in the intensively treated group 
(“Effect of Intensive Blood-Glucose Control with Metformin on Complications in Overweight 
Patients with Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.,” 
1998; “U.K. Prospective Diabetes Study 16. Overview of 6 Years’ Therapy of Type II Diabetes: A 
Progressive Disease. U.K. Prospective Diabetes Study Group.,” 1995). However, this paradigm 
has been shifting due to new evidence suggesting that intensive lifestyle interventions can achieve 
reversal or remission of the disease. 
The objective of this study is to evaluate the effectiveness of the CREDOenAP program 
(Counseling for the Reversal of Diabetes in Primary Care), a multicomponent intervention based 
on intensive lifestyle modification, implemented in the primary care setting. The program focuses 
on four key pillars: a carbohydrate-restricted diet based on whole foods, daily physical activity, 
smoking and alcohol cessation, and psycho-emotional support (Committee ADAPP, 2021). 
The intervention program is based on both WHO and ADA recommendations to address physical 
inactivity, diet, smoking, and alcohol consumption, as well as local dietary habits, prioritizing 
fresh, whole, locally sourced foods rather than processed, prepackaged, or substitute products. The 
program will utilize the usual resources of Family and Community Medicine, including standard 
in-person consultations and telehealth(“5. Facilitating Behavior Change and Well-Being to 
Improve Health Outcomes: Standards of Medical Care in Diabetes—2022,” 2022; Committee 
ADAPP, 2021). 
It is expected that the changes induced by this intervention will result in improved glycemic control 
and, ultimately, partial or complete remission of type 2 diabetes (T2DM), defined according to the 
American Diabetes Association (ADA) consensus criteria as HbA1c <6.5% without 
pharmacological treatment for at least 3 months (“6. Glycemic Targets: Standards of Medical Care 
in Diabetes—2022,” 2022). In addition to potential T2DM remission, improvements in body 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
9 
weight and cardiovascular risk profile are also anticipated, which may translate into reduced 
utilization of healthcare services and resources (Committee ADAPP, 2021). 
It should also be noted that, to date, no methodology for T2DM reversal has been evaluated in 
patients under primary care follow-up in our setting and following a real-food diet. Developing 
such interventions and assessing their effectiveness is crucial for a systematic, multicomponent 
approach based on evidence-based medicine principles, adding value to routine primary care 
practice. 
2.2 BACKGROUND  
This study is based on the recommendations of the World Health Organization (WHO) and the 
American Diabetes Association (ADA). The intervention avoids the use of processed or dietary 
substitute products and promotes the consumption of fresh, locally sourced foods. It relies on the 
usual resources of Family and Community Medicine and can be implemented in primary care 
centers (“5. Facilitating Behavior Change and Well-Being to Improve Health Outcomes: 
Standards of Medical Care in Diabetes—2022,” 2022; Committee ADAPP, 2021). 
Low-Carbohydrate Diet 
 
An available tool, in addition to oral and injectable antidiabetic medications such as insulin 
therapy and/or incretin receptor agonists, for reducing blood glucose levels, is a low-
carbohydrate diet. (Westman et al., 2006). These diets are characterized by a reduced 
carbohydrate content, ranging from 5% to 45% of total daily intake, with a correspondingly 
higher proportion of dietary protein and fat, without restriction of total caloric intake. They can 
be an effective and safe tool for both weight management (Harvey et al., 2019; Hession et al., 
2009), and glycemic control (Sainsbury et al., 2018; Tay et al., 2015). This has led to the 
inclusion of low-carbohydrate diets in the 2019 recommendations of the American Diabetes 
Association (ADA) (ElSayed et al., 2022; Evert et al., 2019).  
 
Several additional beneficial effects of low-carbohydrate diets beyond weight and glycemic 
control have also been described: improvement of lipid profiles compared with high-carbohydrate 
diets (Tay et al., 2015), and also compared with low-fat diets (Gjuladin-Hellon et al., 2019); 
reduction of cardiovascular risk (Harvey et al., 2019; Hession et al., 2009); improvement of 
hepatic steatosis with very low-carbohydrate diets (Dyńka et al., 2024; Jang et al., 2018), as well 
as with low-carbohydrate Mediterranean diets (Gepner et al., 2019); improvement of epileptic 
conditions with very low-carbohydrate diets (García-Peñas, 2016; Paoli et al., 2013); and 
beneficial effects for the prevention and adjuvant therapy of various cancers with very low-
carbohydrate diets (Weber et al., 2018).  
 
Diabetes Reversal – Non-Pharmacological Approaches 
 
In the United Kingdom, within primary care settings, the DiRECT series of studies (Lean et al., 
2018), were conducted, focusing on weight loss through a low-calorie diet. These studies were 
designed to evaluate whether effective weight control could induce sustained remission of type 2 

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
10 
diabetes (T2DM), restricting the participation to individuals aged 20–65 years who had been 
diagnosed with T2DM within the past 6 years, had a body-mass index of 27–45 kg/m², and were 
not receiving insulin. In the DiRECT study (149 participants per group), conducted across 49 
primary care practices in Scotland and England, 24% of participants in the intervention group 
achieved a weight loss of 15 kg or more at 12 months, compared to none in the control group (P < 
0.0001). T2DM remission was achieved in 46% of participants in the intervention group and 4% 
in the control group (odds ratio 19.7; 95% CI 7.8–49.8; P < 0.0001). A clear correlation was 
observed between remission rates and weight loss. The DiRECT program maintained remission at 
24 months in more than one-third of participants with T2DM (Lean et al., 2019)with sustained 
remission associated with maintenance of the achieved weight loss. 
 
This weight-loss-focused approach with dietary caloric restriction has been applied in other 
studies, achieving diabetes remission rates ranging from 47.2% (Yang et al., 2023) to over 60% of 
participants  (Taheri et al., 2020), using various caloric restriction strategies and more restrictive 
inclusion criteria. 
Another research group in the United Kingdom has published several articles in the form of clinical 
audits, reporting beneficial effects of diabetes remission through carbohydrate restriction. These 
effects include improvements in arterial hypertension, renal function, dyslipidemia, weight loss, 
and other metabolic parameters. (Unwin et al., 2020, 2021, 2023; D. J. Unwin et al., 2019). 
In a series of publications, a telemedicine intervention group in the United States demonstrated 
several metabolic benefits of type 2 diabetes (T2DM) reversal through nutritional ketosis, with or 
without weight loss and without intentional caloric restriction. (Athinarayanan et al., 2019; 
Bhanpuri et al., 2018; Hallberg et al., 2018; McKenzie et al., 2017). 
A consensus panel of ADA experts has developed and agreed upon criteria and definitions for the 
terms reversal, partial remission, complete remission, and prolonged remission of type 2 diabetes 
(T2DM) (Riddle et al., 2021). Diabetes remission is defined as achieving glycemic levels (fasting 
plasma glucose and HbA1c) below the minimum thresholds required for a T2DM diagnosis, i.e., 
fasting plasma glucose <126 mg/dL or HbA1c <6.5%. 
To meet remission criteria, participants must be free from any pharmacological therapy or 
procedures (e.g., gastric band adjustments) for at least 3 months. 
 
Lifestyle and Type 2 Diabetes 
 
The WHO Global Action Plan for the prevention and control of chronic diseases, such as type 2 
diabetes (T2DM), hypertension, obesity, and at least 13 obesity-related cancers (CDC, 2017; 
Secretan et al., 2016), recommends focusing efforts on addressing harmful lifestyle factors, 
including tobacco and alcohol use, physical inactivity, and unhealthy diet (World Health 
Organization, 2013).   

Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
11 
According to the ADA, diabetes self-management education and support are essential to achieve 
therapeutic goals for type 2 diabetes (T2DM). These measures include medical nutrition therapy, 
physical activity, counseling for smoking cessation, and psychosocial support (Committee 
ADAPP, 2021). 
Type 2 Diabetes – Current Management and Proposed Improvements 
 
Although nutrition and physical activity are placed at the center of international guidelines for 
diabetes management (ADA/EASD), in clinical practice the pharmacological approach is clearly 
predominant. Economic data indicate that the cost of diabetes is increasing each year, with the 
largest share attributed to pharmaceutical expenditures. (Crespo et al., 2015). Currently, reversal 
and remission of type 2 diabetes (T2DM) are not considered primary treatment goals, with 
management focused on maintaining metabolic values within target ranges. 
In the context of Spain, most interventions follow a pharmacological approach, representing high-
cost measures for the healthcare system. The CREDOenAP intervention could provide evidence 
on lifestyle-focused strategies as a therapeutic pillar for T2DM remission, and evaluate their 
feasibility and effectiveness in primary care. Potential T2DM reversal through lifestyle 
intervention could have economic and organizational impact by reducing pharmaceutical costs and 
decreasing the number of medical visits associated with diabetes management. 
 
2.3 RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
Due to the nature of the study, which focuses on dietary and lifestyle changes in patients, the risks 
associated with this type of intervention are very low. However, potential risks may include: 
 
Immediate risks: Dietary changes and increased physical activity may trigger mild 
adverse effects. For example, participants may experience episodes of constipation, 
fatigue, or minor muscle discomfort related to increased physical activity. 
 
Long-term risks: In individuals with type 2 diabetes (T2DM) who discontinue 
pharmacological treatment due to metabolic improvement, there is a risk of hyperglycemia 
if the long term adherence to lifestyle programm fails. This risk will be minimized through 
close medical monitoring during the study. 
No alternative interventions were proposed due to the low risk of adverse effects and to avoid 
interfering with the intervention as defined in the protocol. 
 
 

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2.3.2 KNOWN POTENTIAL BENEFITS  
The expected benefits of this project, aimed at the remission of type 2 diabetes (T2DM) through 
lifestyle modification, include both immediate benefits for participants and long-term benefits with 
potential societal impact: 
 
Immediate benefits: 
o Improved glycemic control and avoidance of hypoglycemia 
o Weight loss 
o Reduction or discontinuation of antidiabetic medication 
o Improved overall well-being and mood 
 
Long-term benefits: 
o Possible sustained remission of T2DM 
o Improvement or reduction of cardiovascular risk and some types of cancer , (Lakka 
et al., 2000; Nubiola et al., 2015; Rubins et al., 2002) 
o Decreased healthcare and pharmaceutical burden, potentially resulting in cost 
savings for the healthcare system, including fewer specialist visits for diabetes 
complications, fewer primary care visits for diabetes monitoring, reduced 
medication costs, and lower expenses for injection and glucose monitoring supplies 
(pens, test strips, educational materials, etc.) 
o Improved patient quality of life, enabling simpler treatment with a positive impact 
on well-being and mood 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The intervention proposed in CREDOenAp involves a very low exposure to potential risks for 
patients. It is a non-invasive intervention that does not include the use of experimental drugs and 
is conducted under continuous clinical supervision and follow-up. 
Moreover, CREDOenAP is justified by the potential clinical benefit to patients of achieving partial 
or total reversal (remission) of a chronic disease with high prevalence in the population. 
Demonstrating the effectiveness of this intervention would provide crucial evidence for the 
healthcare system, enabling the implementation of cost-effective interventions in Primary Care. 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To quantify the 
percentage of type 2 
diabetes (T2DM) reversal 
among participants 
without signs of absolute 
insulinopenia enrolled in 
the CREDOenAP 
lifestyle intervention 
program at the end of the 
program (6 months). 
 
Percentage of participants achieving 
type 2 diabetes (T2DM) remission at 
6 months, defined as HbA1c <6.5% 
after 6 months of intervention and at 
least 3 months without antidiabetic 
medication. HbA1c will be 
measured from fasting venous blood 
samples (minimum 8 hours fasting). 
 
Percentage of participants achieving 
T2DM remission at 6 months, 
defined as fasting venous plasma 
glucose <126 mg/dL after 6 months 
of intervention and at least 3 months 
without antidiabetic medication. 
Fasting plasma glucose will be 
measured from venous blood 
samples after a minimum 8-hour 
fast. 
 
 
These measures allow 
evaluation of the 
intervention’s efficacy, as 
they are widely accepted 
indicators of type 2 diabetes 
(T2DM) remission. These 
criteria have been 
consensually established 
and accepted by 
international organizations 
such as the American 
Diabetes Association 
(ADA) and the European 
Association for the Study of 
Diabetes (EASD). 
 
 

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Secondary 
 
 
1. To quantify the 
percentage of type 2 
diabetes (T2DM) remission 
among participants in the 
CREDOenAP lifestyle 
intervention program one 
year after completing the 
program (18 months). 
 
 
 
 
 
 
 
 
 
 
2. To assess dietary 
patterns, physical activity, 
and health-related quality 
of life of participants in the 
CREDOenAP program at 
the end of the intervention 
and one year later. 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  To assess 
anthropometric, metabolic, 
and imaging markers for 
cardiovascular risk 
evaluation in participants 
of the CREDOenAP 
Percentage of participants 
maintaining type 2 diabetes 
(T2DM) remission at 18 months, 
defined as HbA1c <6.5% after 12 
months following the intervention 
and at least 9 months without 
antidiabetic medication. 
 
Percentage of participants 
maintaining T2DM remission at 18 
months, defined as fasting venous 
plasma glucose <126 mg/dL after 
12 months following the 
intervention and at least 9 months 
without antidiabetic medication 
 
 
 
Change in dietary patterns at 6 and 
18 months, assessed using a 
validated 24-hour recall 
questionnaire, to evaluate 
adherence to the nutritional 
component of the intervention. 
 
Change in physical activity levels 
at 6 and 18 months, measured 
using the International Physical 
Activity Questionnaire (IPAQ). 
 
Change in health-related quality of 
life at 6 and 18 months, assessed 
using validated instruments such as 
the SF-36 or EQ-5D 
questionnaires. 
 
 
 
Change in cardiovascular risk 
factors at 6 and 18 months, 
including blood pressure, total 
cholesterol, HDL cholesterol, LDL 
cholesterol, Apo B100, 
triglycerides, and the presence and 
These measures allow 
evaluation of the efficacy 
and long-term sustainability 
of the intervention, as they 
are widely accepted 
indicators of type 2 diabetes 
(T2DM) remission. These 
criteria have been 
consensually established 
and accepted by 
international organizations 
such as the American 
Diabetes Association 
(ADA) and the European 
Association for the Study of 
Diabetes (EASD). 
 
 
 
 
Changes in the scores of the 
aforementioned 
questionnaires will allow 
evaluation of changes in 
dietary patterns, physical 
activity, and health-related 
quality of life. 
 
 
 
 
 
 
 
 
 
 
 
These measures will allow 
evaluation of key 
underlying mechanisms 
contributing to type 2 
diabetes (T2DM) remission. 

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program at the end of the 
intervention (6 months) 
and one year later (18 
months). 
size of carotid atherosclerotic 
plaques. 
 
Change in metabolic indicators at 6 
and 18 months, assessed through 
weight, body mass index (BMI), 
waist circumference, insulin 
resistance (HOMA-IR), pancreatic 
beta-cell function (HOMA-B), and 
fasting insulin levels. 
Tertiary/Exploratory 
 
 
To assess secondary 
metabolic markers for 
cardiovascular risk 
evaluation in participants 
of the CREDOenAP 
program at the end of the 
intervention (6 months) 
and one year later (18 
months). 
 
 
To assess healthy lifestyle 
habits and health-related 
quality of life patterns in 
participants of the 
CREDOenAP program at 
the end of the intervention 
and one year later. 
Change in metabolic indicators at 6 
and 18 months, assessed through 
the diagnosis of Metabolic 
Syndrome, NAFLD Fatty Liver 
Index, and NAFLD Fibrosis Score. 
 
 
 
 
 
 
Change in healthy lifestyle habits 
at 6 and 18 months, assessed 
through smoking habits (custom 
questionnaire), alcohol 
consumption (questionnaire and 
conversion calculator for standard 
drink units), and circadian habits 
(custom questionnaire). 
 
Change in quality of life at 6 and 
18 months, assessed through 
medication use measured as 
Defined Daily Dose (DDD) of the 
active ingredient. 
These measures will allow 
evaluation of secondary 
underlying mechanisms for 
T2DM remission. 
 
 
 
 
 
 
 
 
 
Changes in the scores of the 
aforementioned 
questionnaires and 
indicators will allow 
evaluation of changes in 
healthy lifestyle habits and 
quality of life. 
 
4 
STUDY DESIGN 
4.1 OVERALL DESIGN 
The study is designed as an open-label, randomized clinical trial. The strategy includes Group A 
– Intervention, which will undergo the CREDOenAP program, and a parallel control group, Group 
B – Control, which will receive standard T2DM care from a primary care team (family physicians 

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and nurses) without any intervention from the research team, except for data collection at baseline 
and at the end of each study phase. 
The study has been designed to evaluate the effectiveness of a lifestyle-focused intervention 
(CREDOenAP) on T2DM reversal in primary care patients. It is a multicenter study involving two 
primary 
care 
centers 
in 
Barcelona 
(CAP 
Larrad 
and 
CAP 
Barceloneta). 
 
The main hypothesis is that the proposed intervention, based on a structured and culturally adapted 
program, is effective in achieving biochemical and functional remission of T2DM. The study 
design corresponds to a randomized clinical trial aimed at establishing the initial efficacy of the 
intervention under real-world clinical practice conditions. 
Each center will recruit participants who will be randomly assigned in a 1:1 ratio to each study 
arm. Recruitment is planned as follows: 
 
Center 1 (CAP Barceloneta): Group A – Intervention (20 participants) and Group B – 
Control (20 participants). 
 
Center 2 (CAP Larrard): Group A – Intervention (40 participants) and Group B – Control 
(40 participants). 
Group A – Intervention, comprising a total of 60 participants (20 from Center 1 and 40 from Center 
2), will receive standard care plus the CREDOenAP intervention. 
Group B – Control, comprising a total of 60 participants (20 from Center 1 and 40 from Center 2), 
will receive standard care alone. 
Both Group A – Intervention and Group B – Control will include patients meeting the inclusion 
and exclusion criteria, with assignment conducted via stratified randomization. Potential 
participants will be validated by a healthcare professional not involved in the intervention to 
exclude false positives due to registration errors. 
For stratification, performed through statistical programming, relevant characteristics that may act 
as potential confounding variables will be considered. In this study, stratification will be based on: 
 
Healthcare center (Center 1: CAP Barceloneta / Center 2: CAP Larrard) 
 
Sex (Male / Female) 
 
Age (18–50 years / ≥50 years) 
 
Years since T2DM diagnosis (<5 years / ≥5 years) 
The randomization sequence will be generated by an independent statistician. 
The intervention has been designed to last 6 months. During this period, participants in the 
intervention group will receive individualized follow-up, both in-person and via telephone, aimed 
at achieving lifestyle changes (dietary modifications, increased physical activity, improved 
emotional management, etc.). 

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The control group will receive standard care for T2DM, with follow-up according to routine 
primary care practices. They will participate in periodic assessments but will not receive any 
components of the intervention program. 
The study design includes a follow-up assessment 12 months after the end of the intervention (18 
months from the start of the intervention) to evaluate the sustainability and long-term effects of 
the intervention. 
Finally, no interim analyses or additional sub-studies are planned within this protocol. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Evidence regarding the possibility of T2DM remission through patient-centered lifestyle 
interventions has generated increasing interest in replicating these results outside highly controlled 
settings. However, most available studies have been conducted in hospital or experimental 
environments, with resources that are difficult to implement or scale in primary care and at a large 
scale. 
This protocol addresses this gap by focusing on the creation of an intervention adapted to primary 
care resources, where routine follow-up of T2DM patients is performed. This intervention will 
allow evaluation of both the effectiveness and feasibility of a program under real-world clinical 
practice conditions and which is using sustainable real food nutrition recommendations. 
Additionally, the use of a control group receiving standard care will facilitate comparison with 
currently available care, without introducing biases associated with placebo or other external 
factors. 
The chosen intervention design—a block-randomized study stratified by key variables (center, 
age, sex, duration of diagnosis)—aims to ensure comparability between groups and minimize 
potential biases. The study is open-label, as blinding of participants and investigators is not feasible 
due to the behavioral nature of the intervention. (Friedman et al., 2015) 
4.3 JUSTIFICATION FOR INTERVENTION 
 
The intervention has been specifically designed for implementation in the primary care setting in 
Spain, based on the available scientific evidence on effective interventions for T2DM remission. 
This program combines individual sessions, biweekly telephone follow-up, and individualized 
clinical support. 
 
The 6-month duration is based on previous studies demonstrating that this period is sufficient to 
achieve significant metabolic remission in patients with T2DM without insulinopenia. Biweekly 
follow-up aims to reinforce adherence, identify incidents, provide guidance and support, and 
monitor participants’ health status. 
 

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A participant is considered sufficiently exposed to the intervention when at least 70% of the 
program has been completed. A minimum of 70% adherence to scheduled sessions and activities 
has been established in several studies as a reasonable threshold to ensure the effectiveness of 
lifestyle interventions. Completing at least 70% of the program allows participants to achieve 
significant clinical benefits, as reflected in systematic reviews on physical activity and dietary 
interventions. (Burke et al., 2011; Zabaleta-Del-Olmo et al., n.d.)  
Furthermore, the World Health Organization highlights the importance of maintaining high 
adherence levels in long-term therapies to ensure optimal clinical outcomes (WHO, 2003). 
Therefore, in this study, participants who complete at least 70% of the planned intervention will 
be considered adherent, as this threshold is supported by scientific evidence to be sufficient for 
producing meaningful clinical changes. 
4.4 END-OF-STUDY DEFINITION 
For study completion, all participants must have attended all follow-up visits, with the final visit 
occurring 18 months after the start of the intervention. A participant will be considered to have 
completed the intervention if they have undergone the initial assessments, attended at least four 
biweekly telephone follow-up sessions, and completed the assessments at 6 months and 18 months 
from the start of the intervention. These stages are detailed in Section 1.3 (Activity Schedule). 
5 
STUDY POPULATION 
The study population comprises adults over 18 years of age diagnosed with T2DM, without signs 
of insulinopenia. These individuals must be assigned to one of the primary care centers, CAP 
Barceloneta or CAP Larrad, which belong to the Catalan public health system in the city of 
Barcelona. 
In 2024, according to the latest updated data, CAP Barceloneta had an assigned population of 
15,426 individuals and CAP Larrad had 38,819 individuals. Of the total 54,245 people served 
across these two primary care areas, approximately 2,800 individuals (5.3% of the population) 
have an active diagnosis of T2DM. By sex, the estimated prevalence of T2DM is 6.0% in men and 
4.6% in women. 
The population selected for this study represents a clinical group characterized by overweight or 
obesity and poor glycemic control. However, one of the most relevant exclusion criteria is the 
absence of indications of potential insulin dependence. These characteristics are expected to form 
a sample representative of individuals with T2DM associated predominantly with obesity. This 
population group represents the patients most likely to benefit from the intervention. 
Patient recruitment will be conducted through screening using health records, based on the 
inclusion and exclusion criteria detailed in this study. Compliance with these criteria will be 
evaluated by a physician external to the research team. 

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5.1 INCLUSION CRITERIA 
The inclusion criteria for patient recruitment in this study are as follows: 
1. Signed informed consent. 
2. Men and women aged 18–80 years, inclusive. 
3. Confirmed diagnosis of T2DM according to recognized diagnostic criteria (Association, 
2021) 
4. Most recent recorded hemoglobin A1c (HbA1c) > 6.5%. 
5. Body Mass Index (BMI) greater than 27 kg/m². 
Individuals considered eligible for recruitment must meet all of the above inclusion criteria and 
be able to comply with the activities described in the intervention process. 
5.2 EXCLUSION CRITERIA 
The exclusion criteria for this study are as follows (meeting any of these criteria precludes 
participation): 
1. Failure to meet the diagnostic criteria for T2DM in the screening laboratory tests. 
2. Being dependent for basic activities of daily living (Barthel score ≤ 90 points). 
3. Lack of willingness to cooperate with the follow-up of the lifestyle intervention plan. 
4. Presence of serious or terminal comorbidities significantly worsening short- to medium-
term prognosis (active cancer, terminal chronic diseases, myocardial infarction within the 
last 6 months, acute heart failure or NYHA stage ≥ III, etc.). 
5. History of ketoacidosis. 
6. Presence of criteria or potential autoimmune insulinopenia (abnormal C-peptide, anti-
GAD+ antibodies, pattern of basal and/or glucose-stimulated hypoinsulinemia). 
7. Cognitive impairment. 
8. Weight loss exceeding 5 kg in the past 6 months. 
9. Significant changes in physical activity and/or dietary patterns in the past 6 months. 
10. History of eating disorders. 
11. History of substance abuse. 
12. History of severe psychiatric disorders. 
13. Pregnancy or intention to become pregnant within the study period. 
5.3 LIFESTYLE CONSIDERATIONS 
Since this study involves a behavioral intervention aimed at changing patients’ lifestyle, 
participants must commit to following the recommendations upon which the intervention protocol 
is based. The restrictions and recommendations (detailed in Appendix 1) are as follows: 
 
Adherence to a low-carbohydrate Mediterranean diet. Participants should reduce or avoid 
the following: 

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o Processed and ultra-processed foods 
o Added sugars and sweeteners (e.g., sugar, honey, syrups) 
o Starchy foods (e.g., bread, pasta, rice, potatoes, legumes, cereals) 
o High-fructose fruits (e.g., bananas, grapes, dates, tropical fruits) 
o Fruit juices and sugar-sweetened beverages (including “zero-calorie” drinks) 
o Fried foods (frying is discouraged; the only recommended oil is extra virgin olive 
oil, consumed raw) 
 
Avoid alcohol consumption 
 
Avoid tobacco use 
 
Daily physical activity: 
o Recommended 10,000 steps per day 
o Strength training (progressive and individualized): During the first two weeks, at 
least one hour of walking per day is recommended. Strength exercises will then be 
gradually introduced (e.g., two sets of 5–10 squats). Weightlifting routines may be 
added according to individual tolerance. 
 
Healthy circadian habits: 
o Maintain regular sleep schedules 
o Wake up between 6:00 and 8:00 a.m. 
o Sun exposure for 15 minutes (preferably between 7:00 and 9:00 a.m.) 
o Go to bed before 11:00 p.m. 
o Sleep approximately 8–9 hours per night 
 
No use of pharmacological treatments or supplements for weight or appetite control is 
allowed during the study. 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are 
subsequently not assigned to the intervention or included in the study. 
Participants who do not meet the eligibility criteria will continue to receive standard healthcare 
from their primary care team. Failure to participate in this study will not affect the patient’s usual 
treatment or follow-up in any way. 
This protocol does not include provisions for re-screening participants if their circumstances 
change and they subsequently meet the eligibility criteria. 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
The recruitment strategy includes: 
1. Initial identification from patients’ medical records to search for potential participants who 
meet the inclusion criteria. 
2. Manual clinical confirmation by a physician external to the project, using the Shared 
Clinical History, to verify that selected candidates do not meet any exclusion criteria. 

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3. Contact with potential participants via telephone call, followed by an in-person visit to 
obtain signed informed consent. 
Participation in the intervention is voluntary, and no material or financial incentives are provided. 
No specific patient retention plan is included. Follow-up visits will be conducted as scheduled in 
the protocol. Appointment reminders will be provided, and during the visits, participants will 
receive positive reinforcement regarding the benefits of the intervention and their participation. 
This protocol does not specifically include vulnerable populations. However, if during the course 
of the study a participant becomes part of a vulnerable group, their continued participation will 
be evaluated, prioritizing the participant’s health and safety. 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
ADMINISTRATION 
6.1.1 STUDY 
INTERVENTION 
OR 
EXPERIMENTAL 
MANIPULATION 
DESCRIPTION 
This protocol describes an intervention focused on lifestyle changes, with the primary objective of 
achieving remission of T2DM. This goal is intended to be accomplished through modifications in 
patients’ lifestyle factors, such as dietary patterns and regular physical activity. 
Remission is considered achieved when HbA1c is < 6.5% for at least 6 months, including a 
minimum of 3 months without antidiabetic pharmacological treatment. 
The control group will receive standard care for T2DM in the primary care setting. 
 
6.1.2 ADMINISTRATION AND/OR DOSING 
The intervention program will be conducted over a period of 6 months, with a final follow-up 12 
months after the end of the intervention. Participants assigned to the intervention group will 
receive: 
 
Low-carbohydrate dietary plan, adapted to the Mediterranean diet. 
 
Promotion of physical activity, including light and progressive strength exercise plans. 
 
Dietary monitoring and logging. 
 
Follow-up of progress and relevant parameters measured during the intervention. 

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The intervention will be delivered by a family physician and the evaluations of the adherence to 
the programm will be monitored by the intervention team, consisting of a phamily physician, nurce 
and nutritionist. Sessions will take place at the primary care centers (CAP Barceloneta and CAP 
Larrard). 
6.2 FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
This protocol includes internal training for the intervention staff to ensure proper implementation 
of the program and fidelity to the outlined activities. Training will be provided prior to the start of 
the intervention and will include: 
 
Education on low-carbohydrate diets and their clinical application. 
 
Protocols and guidelines for conducting the intervention sessions. 
 
Procedures for maintaining intervention records. 
 
Training on the procedures for aortic imaging tests. 
Any changes to the procedures described above will be officially documented and agreed upon 
with the intervention team. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
The process of randomization and group assignment will be carried out through a randomization 
system with a 1:1 allocation ratio. However, due to the nature of the present study, no blinding of 
participants or professionals is planned, as this is a behavioral intervention and blinding would be 
counterproductive to the development of the research. 
On the other hand, in order to minimize potential biases: 
 
An external analysis will be conducted by professionals who are not involved in the 
screening or in the implementation of the intervention activities. 
 
Patient screening and randomization will be performed by a team of professionals 
independent from the intervention group. 
6.4 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
To monitor and promote participant adherence to the intervention activities, biweekly telephone 
contacts will be conducted. During these contacts, the following will be performed: 
 
24-hour dietary recall survey: using photographs of the participant’s food intake over one 
day, their diet will be recorded. 
 
Overall health check of the participant. 
 
Review and adjustment of daily exercise plan. 

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A participant will be considered adherent to the intervention if they complete the initial session 
and at least 70% of the follow-up sessions. All adherence information will be recorded in the 
official intervention log. 
6.5 CONCOMITANT THERAPY 
During the study, participants will be allowed to continue their usual treatment for concomitant 
conditions. However, the use or initiation of weight-loss medications (such as GLP-1 receptor 
agonists) or diets other than those specified in this protocol will be prohibited, as this constitutes 
an exclusion criterion for the intervention. Use of concomitant medications will be recorded at 
each study visit. 
6.5.1 RESCUE THERAPY 
In the event of a significant glycemic decompensation in any participant (HbA1c > 9% or presence 
of symptoms), the study team may initiate pharmacological treatment based on clinical judgment 
or refer the participant to their usual physician for further evaluation. The date, type, and dose of 
any medication initiated will be recorded. 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION 
OF 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
Participation in the study is voluntary, and participants may withdraw from the intervention at any 
time. Additionally, the study team may decide to discontinue a participant’s involvement if any of 
the following conditions occur: 
 
Non-compliance with the intervention activities. 
 
Emergence of new comorbidities incompatible with the intervention. 
 
Deterioration of health status since the start of the intervention (e.g., significant involuntary 
weight loss). 
 
Experiencing discomfort related to the intervention, whether physical or psychological. 
In the event of intervention discontinuation, the following information will be recorded: 
 
Date of discontinuation. 
 
Reason for discontinuation. 
 
Health status at the time of discontinuation. 
 
Plan to continue with the scheduled follow-up visits, provided the participant consents. 

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7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Any participant may permanently withdraw from the intervention at any time without providing 
justification and without affecting their routine medical care. Additionally, the study team may 
permanently discontinue a participant’s involvement in the intervention if any of the following 
occur: 
 
Loss of any contact with the participant (see Section 7.3). 
 
Occurrence of significant medical changes (e.g., hospitalization, new pathologies 
incompatible with the intervention). 
 
Identification of exclusion criteria that were not previously detected. 
 
Pregnancy or explicit intention to become pregnant. 
 
Initiation of therapies incompatible with the intervention. 
 
Evidence that the participant no longer wishes to continue the intervention activities. 
Replacement of participants may be considered only if the individual was assigned to the 
intervention group but did not start the activities. Participants who begin the intervention and 
subsequently cannot continue will not be replaced. 
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if they fail to attend scheduled visits and cannot 
be contacted after three attempts (via telephone at different times of day). 
To minimize loss to follow-up, the following measures will be implemented: 
 
Sending reminders prior to each scheduled visit. 
 
Rescheduling missed visits. 
 
Recording all contact attempts. 
If these measures are unsuccessful and contact with the participant cannot be established, the 
participant will be classified as “lost to follow-up” and will be excluded from the intervention. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
To evaluate the effectiveness of the CREDOenAP intervention on the different health indicators 
defined in the objectives, various variables will be collected. 
Sociodemographic Variables 
 
Sex: dichotomous variable according to biological sex (Male/Female). 

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 
Age: age at study entry. 
 
Living situation: current living arrangement (Lives alone / Lives with others). 
 
Socioeconomic level: determined using the individual health insurance card (TSI) based 
on the pharmaceutical copayment level. Copayment is calculated according to each 
individual’s income and employment status. Based on the copayment contribution, 
individuals are categorized into four socioeconomic levels: 
o Very low: TSI 001, exempt from copayment. Includes individuals receiving 
minimum insertion income, active insertion income, guaranteed citizen income, 
exhausted unemployment benefits, or non-contributory pensions. 
o Low: TSI 002 (10% copayment) and TSI 003 (40% copayment). Population with 
annual income < €18,000. 
o Medium: TSI 004 (50% copayment) and TSI 006. Population with annual income 
€18,000–€100,000 or individuals in administrative mutual schemes. 
o High: TSI 005 (60% copayment). Population with annual income > €100,000. 
Clinical Variables 
 
Year of T2DM diagnosis: year of T2DM registration in eCAP. 
 
Main comorbidities: the primary active diagnoses recorded in eCAP will be obtained and 
corroborated with the participant. 
Primary Outcome Variables 
All primary outcome variables will be measured, calculated, and recorded at study baseline, at the 
end of the intervention, and 12 months after the intervention. 
 
Presence of T2DM remission (according to ADA consensus definition, (Riddle et al., 
2021)): 
o Glycated hemoglobin (HbA1c): T2DM remission will be considered if HbA1c is 
< 6.5% after 6 months of intervention and at least 3 months without antidiabetic 
medication. HbA1c will be determined by blood analysis after a minimum of 8 
hours of fasting (Association, 2021)  
o Fasting plasma glucose: T2DM remission will be considered if fasting venous 
plasma glucose is < 126 mg/dL after 6 months of intervention and at least 3 months 
without antidiabetic medication. Fasting plasma glucose will be measured by 
venous blood analysis after a minimum of 8 hours of fasting (Association, 2021) 
Secondary Outcome Variables 
All secondary outcome variables will be measured, calculated, and recorded at study baseline, at 
the end of the intervention, and 12 months after the intervention. 
a) Cardiovascular Risk Factors 

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 
Blood pressure: Blood pressure will be measured three times after the participant has been 
seated at rest for 10 minutes with uncrossed legs. The mean of the last two measurements 
will be used for statistical analysis. Systolic and diastolic blood pressure will be reported 
in mmHg using a brachial cuff sphygmomanometer. 
 
Total cholesterol: Measured in mg/dL via blood analysis. 
 
HDL cholesterol: High-density lipoprotein (HDL) cholesterol measured in mg/dL via 
blood analysis. 
 
LDL cholesterol: Low-density lipoprotein (LDL) cholesterol measured in mg/dL via 
blood analysis. 
 
Apolipoprotein B100 (ApoB100): A protein involved in cholesterol transport and relevant 
for evaluating elevated cholesterol causes, measured in mg/dL via blood analysis. 
 
Triglycerides: Measured in mg/dL via blood analysis. 
 
Presence and size of atherosclerotic plaques in carotid arteries: Assessed via Carotid 
ultrasonography. If plaques are present, the total plaque area will be measured in cm², and 
changes in plaque area will be tracked throughout the study. 
 
b) Metabolic Indicators 
 Weight: Measured in kilograms using a calibrated scale. 
 Body Mass Index (BMI): Calculated from weight and height using the formula: BMI 
= weight (kg) / [height (m)]². 
 Abdominal circumference: Measured at the midpoint between the lowest rib and the 
iliac crest during maximal inspiration and expiration, in centimeters. 
 Insulin resistance: Evaluated using the HOMA-IR index (Homeostasis Model 
Assessment of Insulin Resistance), which estimates insulin resistance and beta-cell 
function. Determined via blood analysis after a minimum 8-hour fast. Values above 2.5 
may indicate T2DM. Calculated as: [fasting insulin (μU/mL) x glucemia basal 
(mmol/L)] / 22.5 = [fasting insulin (μU/mL) x (Glucemia basal (mg/dL) x 0,0555)] / 
22.5 (HOMA Calculator — Radcliffe Department of Medicine, n.d.) 
 Pancreatic activity: Assessed using the HOMA-B index, which evaluates the function 
and activity of pancreatic beta cells. HOMA-B, together with HOMA-IR, helps in the 
diagnosis of T2DM. Values between 167 and 175 are considered normal and not 
indicative of T2DM. Values below this range suggest impaired beta-cell function, 
resulting in insufficient insulin production (insulinopenia). (HOMA Calculator — 
Radcliffe Department of Medicine, n.d.) 
 Fasting insulin: Measures the amount of insulin in a blood sample. Insulin is a 
hormone produced by the pancreas. Normal values range between 5–25 U/mL. It will 
be measured via blood analysis after a minimum 8-hour fast. 
 Metabolic Syndrome Diagnosis: Refers to a cluster of metabolic abnormalities 
considered a high-risk factor for cardiovascular disease and other health complications. 
It will be assessed according to the criteria of the International Diabetes Federation 
(IDF) new classification.(International Diabetis federation (IDF), 2006) y National 
Cholesterol Education Program’s Adult Treatment Panel III (NCEP ATP 
III)(Alexander et al., 2003).  

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Metabolic Syndrome Diagnosis is established if at least three of the following five 
criteria are present: 
- 
Abdominal circumference: Men of European descent > 94 cm; Women of 
European descent > 80 cm. For other ethnicities, cut-off points are defined 
according to the International Diabetes Federation (IDF). (López De La Torre et 
al., 2010) 
- 
Fasting glucose: > 100 mg/dL or receiving pharmacological treatment for 
hyperglycemia. 
- 
Triglycerides: > 150 mg/dL or receiving lipid-lowering therapy. 
- 
HDL cholesterol: < 40 mg/dL in men; < 50 mg/dL in women, or receiving lipid-
lowering therapy. 
- 
Blood pressure: Systolic > 130 mmHg or Diastolic > 85 mmHg, or receiving 
antihypertensive treatment. 
 NAFLD Liver Fat Score: Non-alcoholic fatty liver disease (NAFLD) is a condition 
characterized by excessive fat accumulation in the liver. Its severity can vary according 
to the score: < –1.455 low risk, –1.455 to 0.675 intermediate risk, > 0.675 high risk 
(Angulo et al., 2007; Kotronen et al., 2009). 
 
The calculation is determined using the following formula: 
–2.89 + 1.18 × Metabolic Syndrome (Yes = 1 / No = 0) + 0.45 × T2DM (Yes = 2 / No 
= 0) + 0.15 × Fasting Insulin (mU/L) + 0.04 × Fasting Serum AST (U/L) – 0.94 × 
AST/ALT ratio 
 NAFLD Fibrosis Score: The identification and quantification of fibrosis are clinically 
relevant since fibrosis is associated with an unfavorable clinical prognosis. An NFS > 
0.676 indicates the presence of advanced fibrosis (Angulo et al., 2007; Kotronen et al., 
2009). The calculation is determined using the following formula: 
–1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m²) + 1.13 × IFG/diabetes (Yes = 1 / 
No = 0) + 0.99 × AST/ALT ratio – 0.013 × Platelets (×10⁹/L) – 0.66 × Albumin (g/dL) 
 
c) Healthy lifestyle habits 
 Physical activity: Physical activity will be assessed using the International Physical 
Activity Questionnaire (IPAQ). It consists of seven questions regarding the frequency, 
duration, and intensity of physical activity (moderate and vigorous) performed during 
the previous seven days, as well as walking and sitting time on a typical workday. The 
questionnaire may be administered through face-to-face interview, telephone interview, 
or self-administered survey (Mantilla Toloza & Gómez-Conesa, 2007). 
 Nutritional and energy composition: The 24-hour dietary recall questionnaire will 
be administered at each biweekly visit. This questionnaire is a reference tool in most 

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nutritional studies (Block, 1982; Fanelli & Stevenhagen, 1986; Gersovitz et al., 1978; 
Madden et al., 1976), and will be used to determine the daily intake of each type of 
food (Freedman et al., 2017). 
 Smoking habits: Using a study-specific questionnaire, participants will be directly 
asked: Do you smoke? (Yes/No). If the response is affirmative, participants will be 
asked: How many cigarettes do you smoke per day? 
 Alcohol consumption: Alcohol intake will be quantified using a questionnaire 
combined with a standardized alcohol unit conversion calculator. Participants will be 
asked about their consumption of different alcoholic beverages during the previous 
seven days. Using the conversion calculator, the total alcohol content (in ml of pure 
alcohol) will be estimated to obtain the average daily alcohol intake (Cálculo: 
Cuantificación Del Consumo de Alcohol - Fisterra, n.d.; Valencia-Martín et al., 2014). 
 Circadian habits: Using a study-specific questionnaire, participants will be directly 
asked: What time did you go to bed yesterday? and How many hours did you sleep 
today? 
d) Quality of life 
 SF-36: This is a generic scale that provides a health status profile and is applicable both 
to patients and to the general population. The 36 items of the instrument cover the 
following domains: Physical Functioning, Role Physical, Bodily Pain, General Health, 
Vitality, Social Functioning, Role Emotional, and Mental Health. For each domain, 
items are coded, aggregated, and transformed into a scale ranging from 0 (worst health 
status for that dimension) to 100 (best health status) (Alonso et al., 1995). 
 
 
e) Medication consumption 
 
 Defined Daily Dose (DDD) by active substance: DDDs of the active substances 
consumed will be classified according to ATC7. Each ATC classification has a defined 
daily dose based on international standards, which determine the recommended 
maximum daily amount for the approved indication of the active substance (WHOCC, 
n.d.). 
 
Control variables and management of T2DM 
 
Patients will be assessed during each follow-up telephone visit throughout the intervention, at the 
end of the intervention, and one year after its completion. For the control group (Group B), 
episodes will be identified through records in the electronic health record system (eCAP). 
 
 Number of hypoglycemia episodes: Episodes of hypoglycemia detected by patients 
through capillary blood glucose levels and/or recorded in eCAP during the intervention 
(plasma glucose <60 mg/dl). 
  Number of symptomatic hyperglycemia episodes: Episodes of hyperglycemia 
recorded in eCAP during the intervention (plasma glucose >350 mg/dl accompanied by 
compatible symptoms such as general malaise, nausea, asthenia, among others). 

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 Total number of healthcare visits: Annual contacts with the healthcare system 
including Primary Care (physicians and nursing), Specialized Care, and Emergency 
Care. 
 Number of diabetes-related emergency episodes: Emergency visits related to 
diabetes during the intervention period. 
Recruitment 
Through the internal registry of the Primary Care Clinical Station (eCAP), patients with a diagnosis 
of Type 2 Diabetes Mellitus (T2DM) from each primary care center (CAP) will be identified. 
Potential participants will be validated by a physician not involved in the intervention, in order to 
exclude false positives due to registry errors and to confirm inclusion and exclusion criteria. 
Randomization will be performed by stratifying according to the characteristics defined in section 
6.2. Study Design. 
Potential participants will receive an invitation to take part in the study during their last medical 
consultation (in person or by telephone) by their physician, nurse, or the principal investigator. 
They will then be scheduled for a screening visit with a member of the research team, following 
completion of the screening blood test. Patients will be informed of the necessary requirements for 
the laboratory tests (fasting status and first morning urine sample) as well as the location where 
they will be carried out (extraction and laboratory areas of each primary care center). 
Screening and Study Inclusion Visit 
During this visit, eligibility criteria will be assessed to determine whether patients meet the study 
selection requirements. Participants who fulfill the criteria will receive a detailed explanation of 
the study objectives and the implications of participation. They will be provided with the study 
information sheet and, if they agree to participate, will sign an informed consent form for data 
collection throughout the study. If consent is obtained, a physical examination (anthropometric 
measurements) will be performed, sociodemographic variables will be recorded, and participants 
will complete the questionnaires assessing quality of life, physical activity, nutritional status, and 
lifestyle habits (including substance use). Additionally, appointments will be scheduled for all 
participants to undergo the imaging test (Carotid ultrasonography). 
Laboratory Tests 
Blood and urine analyses will be performed at three different time points during the study: at 
baseline, at the end of the intervention, and 12 months after completion of the intervention. These 
analyses do not involve any additional procedures, as they are part of the routine clinical practice 
for monitoring and follow-up of all patients with type 2 diabetes mellitus (T2DM) in primary care. 
No requests, extractions, or analyses will be conducted outside of standard clinical care. The 
laboratory tests will include: Complete blood count, HbA1c, Creatinine, Glomerular filtration rate, 
GOT (AST), GPT (ALT), GGT, Ionogram, Lipid profile (Total cholesterol, HDL, LDL, 

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Triglycerides, Apo B100), Fasting insulin, Anti-GAD antibodies (only at baseline), Urine: 
sediment and albumin/creatinine ratio. 
Imaging Diagnosis: Carotid ultrasonography 
As part of the cardiovascular risk factor assessment, three ultrasound examinations of the carotides 
will be performed during the study: at baseline, at the end of the intervention, and 12 months after 
the completion of the intervention. 
 
 
1st 
Examination 
and Sample 
Collection 
T0 (Baseline 
/ Start of 
Intervention) 
Follow-up 
Visits 
2nd 
Examination 
and Sample 
Collection 
T-6 months 
(End of 
Intervention) 
3rd 
Examination 
and Sample 
Collection 
T-18 months 
(12 months 
after End of 
Intervention) 
Questionnaires and Assessment Scales 
24-Hour Recall 
x 
x 
x 
x 
SF36 
x 
 
x 
x 
IPAQ 
x 
 
x 
x 
Tobacco 
consumption 
x 
x 
x 
x 
Alcohol consumption 
x 
x 
x 
x 
Circadian cycle 
X 
X 
X 
x 
Physical Examination (Anthropometric Measurements) 
Weight 
x 
x 
x 
x 
Height 
x 
 
 
 
Abdominal 
circumference 
x 
x 
x 
x 
Blood Analysis 
Complete blood 
countα (CBCα) 
x 
 
x 
x 
C-Reactive proteinα 
(CRPα) 
X 
 
X 
X 
HbA1c 
X 
 
X 
X 
Creatinineα 
X 
 
X 
X 
Glomerular filtration 
rateα (GFRα) 
X 
 
X 
X 
Aspartate 
Aminotransferase 
(AST) 
X 
 
X 
X 

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Alanine 
Aminotransferase 
(ALT) 
X 
 
X 
X 
Gamma-Glutamyl 
Transferase (GGT) 
X 
 
X 
X 
Alkaline 
Phosphataseα (ALP α) 
X 
 
X 
X 
Amylase α 
X 
 
X 
X 
Total Blood Protein α 
X 
 
X 
X 
Electrolyte Panel α 
X 
 
X 
X 
Calcium α 
X 
 
X 
X 
Phosphate α 
X 
 
X 
X 
Lipid Profile (Total 
Cholesterol, HDL, 
LDL, Triglycerides, 
Apo B100) 
X 
 
X 
X 
Basal C-Peptide α 
X 
 
X 
X 
Anti-GAD 
Antibodies (GAD 
Ab) 
X 
 
 
 
TSHα 
X 
 
X 
X 
Free T4 α (Free 
Thyroxine α) 
X 
 
X 
X 
CA 19.9. α 
X 
 
X 
X 
Urine Analysis 
Urine Sediment α 
X 
 
X 
X 
Albumin/Creatinine 
Ratio α 
X 
 
X 
X 
Imaging Test (Ultrasound) 
Carotid 
ultrasonography 
X 
 
X 
X 
Type 2 Diabetes Management and Monitoring 
Hypoglycemia 
episode(s) 
 
X 
x 
 
Hyperglycemia 
episode(s) 
 
X 
x 
 
α Parameters to assess the participant’s general health status. These parameters are included in the 
routine monitoring of a person with type 2 diabetes (T2DM). 
β Only in cases of a discordant relationship between HbA1c values and plasma glucose. 
Examinations, laboratory tests, imaging studies, and questionnaires will be conducted at the 
patient’s primary care center (CAP Barceloneta or CAP Larrard) by healthcare personnel 
(physician/nurse according to the test and training) during regular working hours. Blinding will be 
implemented for the evaluators, as all tests and questionnaires will be carried out by personnel not 

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involved in the research team and not responsible for delivering the intervention, with no 
knowledge of the participant’s assignment to group A or B in the study. 
 
8.2 SAFETY ASSESSMENTS 
The CREDOenAP program intervention is considered a low-risk intervention due to its behavioral 
nature. It does not involve the use of any drugs or invasive procedures. However, several measures 
have been planned to assess and ensure the safety of participants in the intervention: 
 Adverse event monitoring: During the scheduled follow-up sessions within the 
intervention, the professional responsible for conducting the sessions will also be in 
charge of identifying and reporting any adverse events. Any signs of physical or 
emotional discomfort or change will be recorded. Subsequently, the event will be 
evaluated to determine its severity and the appropriate response protocol. 
In the event of an adverse event, it will be assessed to determine its severity and whether it requires 
additional medical attention or poses a risk to the participant’s safety. If necessary, the participant 
will be referred to receive specific treatment. Finally, their continuation in the intervention will be 
evaluated. 
All identified adverse events will be documented in the study’s official registry. 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
This protocol uses the definition of Adverse Event established in 21 CFR 312.32(a): 
"Any unintended medical occurrence in a clinical study participant, associated with the use of the 
investigational intervention, regardless of whether it is causally related to it." 
In this specific case, the Adverse Events that may be observed include: 
 
Physical symptoms. 
 
Hypoglycemia/Hyperglycemia. 
 
Physical discomfort. 
 
Metabolic disturbances. 
Although this study is not expected to have a high incidence of Adverse Events due to its nature, 
any notable event will be documented and evaluated by the research team. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 

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In this protocol, a Serious Adverse Event (SAE) is defined as any occurrence that involves: 
 
Patient death. 
 
Risk to the patient’s health or physical integrity. 
 
Hospitalization. 
 
Any other medical event resulting from the intervention. 
Given the nature of the intervention, the occurrence of Serious Adverse Events is not expected 
during the course of the study. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the grading system defined in the protocol, the following 
guidelines will be used to describe severity: 
 
Mild: Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
 
Moderate: Events result in a low level of inconvenience or concern with therapeutic 
measures. Moderate events may cause some interference with functioning. 
 
Severe: Events disrupt the participant’s usual daily activities and may require systemic 
pharmacological treatment or other interventions. Severe events are often potentially life-
threatening or disabling. It should be noted that the term “severe” does not necessarily 
equate to “serious.” 
8.3.3.2 RELATIONSHIP 
TO 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
All adverse events (AEs) will have their relationship to study procedures, including the 
intervention, assessed by a qualified clinical professional, based on temporal association and 
clinical judgment. The degree of certainty regarding causality will be classified using the following 
categories: 
 
Related – The AE is known to occur with study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the 
study procedures and the event. “Reasonable possibility” means there is evidence 
suggesting a causal relationship between the study procedures and the AE. 
 
Not Related – There is no reasonable possibility that the study procedures caused the 
event, there is no temporal relationship between the study procedures and the onset of the 
event, or an alternative etiology has been established. 
8.3.3.3 EXPECTEDNESS  

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A clinical professional with appropriate experience in type 2 diabetes (T2DM) from the 
Endocrinology Department of Hospital de Mar, Barcelona, and external to the intervention, will 
be responsible for determining whether an adverse event (AE) is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the previously described risk information for the study procedures. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
All procedures and events occurring in the patients will be recorded. These records will be made 
every 15 days, coinciding with the scheduled follow-up visits of the intervention. The classification 
of the type of event will be carried out by a clinician external to the intervention, who can 
independently assess the severity of the event. 
 
All adverse events occurring at any time after obtaining informed consent will be recorded, up to 
7 days after the study completion for mild adverse events, or up to 30 days for serious adverse 
events. At each study visit, the investigator will inquire about the occurrence of adverse or serious 
adverse events since the last visit. Events will be followed up to obtain information on outcomes 
until resolution or stabilization. 
 
For each identified event, the symptoms, onset date, duration of symptoms (if applicable), and any 
required treatment will be documented. Any deterioration or change in the patient’s baseline 
conditions, both related to T2DM and other comorbidities, will also be recorded as an adverse 
event. 
8.3.5 ADVERSE EVENT REPORTING  
 
All information related to an adverse event will be recorded both in the patient’s shared medical 
record and in the study’s official registry. 
 
The person responsible for recording will be the investigator conducting the follow-up calls or the 
professional performing the examinations scheduled in the protocol. 
 
Once an adverse event has been identified, it will be reported to the principal investigator of the 
intervention to assess the feasibility of the patient continuing in the study. In addition, the patient’s 
primary care physician will be contacted to evaluate the necessary treatment. This assessment will 
be carried out within a maximum of 5 days. 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Serious adverse events (SAEs) will be recorded both in the patient’s shared medical record and in 
the study’s official registry. The person responsible for recording will be the investigator 

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conducting the follow-up calls or the professional performing the examinations scheduled in the 
protocol. 
 
Once a serious adverse event has been identified, it will be reported to the principal investigator 
of the intervention, who will assess the feasibility of the patient continuing in the study. 
 
Additionally, the patient’s primary care physician will be contacted to evaluate the patient’s health 
status and determine the appropriate treatment. In cases of severe urgency, an emergency physician 
will be contacted. This referral will be made within 24 hours of reporting the event. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
All adverse events and unexpected findings regarding the patients’ health status will be 
communicated. This information will be conveyed privately and individually to each patient, either 
via telephone contact or during the scheduled follow-up visits with their primary care physician. 
8.3.8 EVENTS OF SPECIAL INTEREST  
No events of special interest, other than those previously described in the protocol, have been 
identified. 
8.3.9 REPORTING OF PREGNANCY  
 
In the event that a pregnancy is identified in any participant, the situation will be appropriately 
communicated to the patient. Subsequently, the participant’s health status will be documented in 
the study’s official registry. As previously indicated, pregnancy constitutes an exclusion criterion 
in this study, and participation in the intervention will be immediately discontinued. 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as established by the Office for Human 
Research Protections (OHRP). The OHRP considers unanticipated problems involving risks to 
participants or others to generally include any incident, experience, or outcome that meets all of 
the following criteria: 
 
Unexpected in terms of its nature, severity, or frequency, taking into account: 
(a) the study procedures described in protocol-related documents, such as the protocol 
approved by the Research Ethics Committee and the informed consent document; and 
(b) the characteristics of the participant population being studied; 
 
Related or possibly related to participation in the research (where “possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome was caused by 

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the study procedures); and suggests that the research places participants or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
previously known or recognized. 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
The principal investigator will be responsible for reporting any unanticipated problem to the 
responsible entity, Parc Sanitari Pere i Virgili. The report of the problem will include: 
 
Study identification information 
 
Detailed description of the incident 
 
Justification for why it is considered an unanticipated problem 
 
Description of the proposed protocol changes or corrective measures adopted in response 
The deadlines for reporting incidents are as follows: 
 
Unanticipated problems that constitute serious adverse events (SAEs) will be reported to 
Parc Sanitari Pere i Virgili within a maximum of 10 days from the investigator becoming 
aware of the event. 
 
Any other unanticipated problem will be reported within no more than 15 days. 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Patients will be informed if an unanticipated problem occurs and poses any risk to them. They will 
be notified individually if the unanticipated problem affects a specific patient; otherwise, they will 
be informed collectively if the problem affects the entire group. Notification will be made via 
telephone contact, by letter, or, if necessary, through a meeting with all participants in the 
intervention. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 STATISTICAL HYPOTHESES 
Primary Endpoint: 
The primary hypothesis is based on the null hypothesis (H0), which states that there is no 
difference in the percentage of type 2 diabetes (T2DM) remission between the intervention group 
and the control group. Conversely, the alternative hypothesis (H1) states that the percentage of 
T2DM remission will be significantly higher in the intervention group compared to the control 
group. An efficacy analysis is planned and will be evaluated right after the end of the intervention. 
 

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Secondary Endpoints: 
The null hypothesis (H0) states that there will be no significant differences in the proposed 
secondary variables (metabolic, behavioral, and quality-of-life variables) between the intervention 
group and the control group. Conversely, the alternative hypothesis (H1) states that there will be 
statistically significant differences in the proposed secondary variables (metabolic, behavioral, and 
quality-of-life variables), with more favorable outcomes for the intervention group compared to 
the control group. An efficacy analysis of the intervention is planned, and the evaluation will be 
carried out 12 months after the end of the intervention. 
9.2 SAMPLE SIZE DETERMINATION 
 
Based on the primary variable of the intervention, the percentage of T2DM remission, the required 
sample size has been calculated to observe statistically significant differences. This variable will 
be coded dichotomously. A total of 120 volunteers (60 per arm) will be recruited for the study. 
Accepting an alpha risk of 0.05 (5%) and a beta risk of less than 0.2 in a two-sided test, at least 52 
subjects in the control group and 52 subjects in the intervention group would be required to detect 
as statistically significant a 20% difference between two proportions (primary endpoint: T2DM 
remission). For the control group, the expected remission rate ranges from 0 to 5%, whereas in the 
intervention group, it is expected to be at least 25%. The remission rates have been benchmarked 
against previous studies (Lean et al., n.d.). An estimated loss to follow-up rate of 15% has been 
considered. 
 
Given the estimated 15% loss to follow-up, the sample size has been increased to 60 participants 
instead of 52. This ensures that the statistical power of the analysis will be preserved. 
 
9.3 POPULATIONS FOR ANALYSES 
 
The populations identified to be included in the study are as follows: 
 
Intention-to-Treat (ITT) Analysis: All randomized participants who have completed the minimum 
required follow-up and for whom clinical data and questionnaires are available at baseline (T0), 6 
months post-intervention (T-6 months), and 18 months post-intervention (T-18 months). 
 
Per-Protocol Analysis: Participants who have completed at least the main intervention session and 
for whom clinical data and questionnaires are available at a minimum of baseline (T0) and 6 
months post-intervention (T-6 months). 
 
Sensitivity Analysis: Sensitivity analyses will be performed in subgroups according to participant 
characteristics, including population with more than five years since T2DM diagnosis, sex, and 
age. 
 

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9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
The statistical analysis will consist of two sub-analyses. First, a descriptive analysis will be 
performed, followed by an analysis to determine differences between the intervention and control 
groups. These analyses will be conducted using STATA/MP statistical software. 
In the initial descriptive analysis, qualitative variables (e.g., sex, socioeconomic status) will be 
described using absolute and relative frequencies. Continuous variables (e.g., age, HbA1c, weight, 
BMI, blood pressure, cholesterol, HOMA-IR) will be described using mean and standard deviation 
for normally distributed variables, or median and interquartile range for variables with non-normal 
distributions. Normality of quantitative variables will first be assessed using the Kolmogorov-
Smirnov test. Group comparability will be assessed using standardized mean differences (SMD), 
with SMD < 0.10 indicating negligible imbalance and SMD ≥ 0.20 indicating meaningful 
imbalance. Formal hypothesis testing at baseline will not be routinely performed; if included, such 
p-values will be reported as descriptive only. 
The primary efficacy analysis will use analysis of covariance (ANCOVA), with the 6-month value 
of the primary outcome as the dependent variable and the baseline value as a covariate. The model 
will include prespecified covariates: baseline outcome, age, sex, site (if applicable), and 
block/stratum used in randomization. The primary result will be the adjusted mean difference 
between intervention and control. Absolute risk reduction, relative risk reduction, and number 
needed to treat will also be calculated. 
The secondary efficacy analysis will be a longitudinal analysis. The effect of the intervention in 
terms of T2DM reversal or remission (dichotomous variable) will be estimated using a mixed-
effects model for repeated measures (MMRM) with a random intercept for participant and fixed 
effects for time, group, and group × time interaction. 
All statistical tests will be two-sided, with a significance level of α = 0.05 considered statistically 
significant. 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
The primary endpoint is the change in glycated hemoglobin (HbA1c, %) from baseline to 6 
months. HbA1c is measured as a continuous variable on an interval scale. The endpoint will be 
calculated as the absolute difference between baseline HbA1c and the value obtained at 6 months. 
The primary analysis will be performed using analysis of covariance (ANCOVA) with treatment 
group (intervention vs. control) as the fixed factor, and baseline HbA1c as a covariate to improve 
precision. Additional prespecified covariates will include age, sex, study site, and randomization 
block, based on their potential clinical relevance and to ensure adjustment for any residual 
imbalance despite randomization. A secondary, confirmatory analysis will be conducted using a 

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mixed-effects model for repeated measures (MMRM), which includes all available timepoints 
(baseline, 3 months, and 6 months). This model accounts for within-subject correlation by 
specifying an unstructured covariance matrix. 
Results will be presented as adjusted mean differences between groups with 95% confidence 
intervals and corresponding two-sided p-values. Least-squares means (LSMEANS) will be used 
to report group means adjusted for covariates. 
The Intention-to-Treat (ITT) population will be the primary analytic set, including all randomized 
participants according to their allocated group. A Per-Protocol (PP) population, defined as 
participants with at least 70% adherence to the intervention, will be analyzed as a sensitivity 
approach. 
Handling of Missing Data; for ANCOVA, missing data at 6 months will be addressed using 
multiple imputation under the missing-at-random (MAR) assumption. In MMRM, missing data 
are implicitly handled under MAR. Additional sensitivity analyses will explore the robustness of 
results to different missing-data mechanisms. 
For ANCOVA, residuals will be checked for normality and homoscedasticity. If these assumptions 
are substantially violated, transformations or nonparametric methods will be considered. For 
MMRM, model fit will be evaluated and alternative covariance structures tested. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoint is diabetes remission at 18 months, defined as achieving HbA1c <6.5% 
without glucose-lowering medications. It will be analyzed using a generalized linear mixed-effects 
model (GLMM) with a logit link, including treatment group, time, and group × time interaction as 
fixed effects, and a random intercept for participants to account for repeated measurements. 
Prespecified covariates include baseline HbA1c, age, sex, site, and randomization block. Results 
will be reported as adjusted odds ratios with 95% confidence intervals and two-sided p-values. 
The analysis will follow the Intention-to-Treat (ITT) principle; a Per-Protocol (PP) analysis 
(adherence ≥70%) will be performed as sensitivity. Missing data will be handled under the 
missing-at-random assumption, with multiple imputation applied if necessary. Trajectories of 
remission probabilities over time will also be presented. 
Others secondary endpoints include: 
 Change in body weight (kg) from baseline to 6 months (continuous, interval scale). 
 Change in blood pressure (systolic and diastolic, mmHg) from baseline to 6 months 
(continuous, interval scale). 
 Change in lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides, mg/dL) from 
baseline to 6 months (continuous, interval scale). 
 Change in circadian rhythm regularity (measured via validated questionnaire scores; 
ordinal/interval scale). 

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 Change in health-related quality of life (measured via validated scale, e.g., SF-12 or 
equivalent; interval scale). 
 Intervention adherence (measured as percentage of scheduled sessions completed; 
continuous, but categorized as adherent ≥70% vs. non-adherent for analysis). 
The analysis models for continuous outcomes (e.g., weight, blood pressure, lipid levels, quality of 
life scores) will be analyzed using ANCOVA with treatment group as a fixed factor and baseline 
values as covariates. Repeated measures across timepoints (baseline, 3 months, 6 months) will be 
analyzed with MMRM to account for within-participant correlations. 
For binary/categorical outcomes (e.g., adherence ≥70%, achievement of HbA1c <6.5%) will be 
analyzed using logistic regression, adjusted for prespecified covariates. 
For ordinal outcomes (e.g., circadian rhythm scores if treated as ordinal), ordinal logistic 
regression will be considered. 
All analyses will adjust for baseline values of each outcome, plus prespecified covariates such as 
age, sex, and site. Covariate selection will be guided by clinical relevance and baseline 
comparability, aiming for a parsimonious model.  
Results will be reported as adjusted mean changes with standard errors (for continuous outcomes), 
odds ratios with 95% confidence intervals (for binary/ordinal outcomes), and associated p-values. 
For binary endpoints, absolute risk differences and numbers-needed-to-treat (NNT) will also be 
reported when applicable. 
The same approach as for the primary endpoint will be applied: MMRM for repeated measures 
(implicitly handling missing values under MAR) and multiple imputation for single-timepoint 
ANCOVA analyses. Sensitivity analyses will evaluate the robustness of results. 
Normality and homoscedasticity will be checked for continuous outcomes. Logistic regression 
models will be checked for linearity in the logit and absence of multicollinearity. Ordinal models 
will be checked for proportional odds assumption. 
9.4.4 SAFETY ANALYSES 
“N/A” 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline descriptive analysis of the study population will include the following: qualitative 
variables (sex, socioeconomic status, etc.) will be described using absolute and relative 
frequencies. Continuous variables (age, HbA1c, weight, BMI, blood pressure, cholesterol, 
HOMA-IR, etc.) will be described as mean and standard deviation for normally distributed data, 
or as median and interquartile range for non-normally distributed data. Normality of quantitative 
variables will be assessed using the Kolmogorov-Smirnov test. 

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Group comparability will be assessed using standardized mean differences (SMD), with SMD < 
0.10 indicating negligible imbalance and SMD ≥ 0.20 indicating meaningful imbalance. Formal 
hypothesis testing at baseline will not be routinely performed; if included, such p-values will be 
reported as descriptive only. 
 
9.4.6 PLANNED INTERIM ANALYSES  
“N/A” 
9.4.7 SUB-GROUP ANALYSES 
 
Pre-specified subgroup analyses will be conducted to explore potential heterogeneity of the 
intervention effect. Subgroups include: age, sex, and duration of DM2.  
 
For each subgroup, the primary and relevant secondary endpoints will be analyzed using the same 
statistical models as in the main analyses, including the corresponding interaction term between 
treatment group and subgroup factor. Results will be presented as adjusted effect estimates with 
95% confidence intervals and two-sided p-values. 
 
Subgroup analyses are exploratory; no formal adjustment for multiplicity will be applied. Findings 
will be interpreted cautiously, primarily to generate hypotheses about differential treatment effects 
across subgroups. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed in tabular form by measure and time point in the study 
database and for reporting purposes. Each participant’s measurements for primary and secondary 
endpoints, as well as adherence and safety outcomes, will be recorded at all scheduled visits. These 
tables will be used for internal review, data verification, and regulatory reporting, but will not be 
published with identifiable participant information. 
9.4.9 EXPLORATORY ANALYSES 
 
See 9.4.7 Sub-Group Analyses. 
 
 
 
 
 
 
 
 

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10 SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Informed consent and required documentation will be obtained from participants prior to the 
initiation of the intervention. Potential participants to be included in the study will be informed 
about its objectives, implications, schedule, and duration. If they agree to participate, they will be 
provided with the information sheet and the informed consent form to be signed. At any time, 
participants may consult with a member of the research team for any questions or clarifications. 
Once informed consent has been obtained, they may be included in the study. 
The information sheet and informed consent form to be provided to all participants are attached, 
available in Catalan and Spanish (the official languages of the study region). 
No external recruitment materials will be used, as invitations will be extended directly by the 
primary care professionals responsible for the patients. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The CAP Larard, CAP Vila Olímpica and CAP Barceloneta, belonging to the Parc Sanitari Pere 
Virgili (Carrer d'Esteve Terradas, 30, Gràcia, 08023 Barcelona), are responsible for the appropriate 
management of the data and commit to adhering to the principles of the Declaration of Helsinki 
(Fortaleza, Brazil, October 2013), Good Clinical Practice, and applicable data protection 
regulations, including EU Regulation 2016/679 of the European Parliament and of the Council of 
27 April 2016 on Data Protection (General Data Protection Regulation – GDPR), Organic Law 
3/2018, as well as all applicable Spanish and European regulations on privacy and personal data 
protection. 
The study will be conducted in accordance with the protocol reviewed by the Research Ethics 
Committee on Medicinal Products (CEIm) of Parc de Salut Mar, Barcelona, with registration 
number 2025/12023/I. (The final assessment report from CEIm Parc Salut Mar, Barcelona is 
attached). 
If participants agree to take part in the study, they will be provided with the information sheet and 
the informed consent form to be signed (see Attached Documents 1 and 2). Participants will have 
a period of time to reflect on their decision and may consult members of the research team at any 
time to resolve any questions before signing the informed consent form. Study materials will be 
provided in Catalan and Spanish. 

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This study does not include consent by a legal representative, as no minors or individuals with 
cognitive impairment or who are legally incapacitated will be enrolled. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if reasonable grounds justify 
such a decision. Written notification, documenting the reasons for the suspension or termination, 
will be provided by the responsible party to the participants and to Parc Sanitari Pere Virgili. 
In the event of suspension or early termination, the principal investigator will immediately inform 
the study participants and Parc Sanitari Pere Virgili of the reasons for the decision. Participants 
will be contacted to communicate any changes in visit scheduling or other implications related to 
their participation. 
Circumstances that may justify temporary suspension or early termination of the study include, 
but are not limited to: 
 
Identification of unexpected, significant, or unacceptable risks to participants. 
 
Early evidence of efficacy warranting study interruption. 
 
Major protocol deviations by the research team. 
 
Incomplete or non-evaluable data preventing the validity of results. 
 
Determination that the study’s primary endpoint has been achieved. 
 
Determination of futility of the study. 
The study may be resumed once concerns regarding safety, protocol compliance, and data quality 
have been adequately addressed and resolved, and provided that approval is granted by Parc 
Sanitari Pere Virgili. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
This study will be conducted in strict compliance with 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 (General Data Protection Regulation – GDPR), as well as with 
Organic Law 3/2018 of 5 December on the Protection of Personal Data and Guarantee of Digital 
Rights. 
Pseudo-anonymization of data will be implemented to ensure the confidentiality of participants’ 
personal information. Each participant will be assigned an identification number to associate all 
data collected throughout the study. The link between the identification number and the personal 
data will be kept exclusively by the principal investigator. 
Data storage will ensure integrity, traceability, and appropriate preservation for the established 
period (maximum 5 years after the study). Under no circumstances will the data be partially or 
fully removed. 

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Data will be stored on the internal network units of Parc Sanitari Pere i Virgili with restricted 
access for the research team, and in the Data Protection Officer (DPO) unit of Parc Sanitari Pere i 
Virgili with password-protected access. 
All data collected during the study will be anonymized and stored in REDCap (Research Electronic 
Data Capture). The REDCap platform provides a secure environment for data storage and supports 
all stages of the study, from administering questionnaires and scales to participants to storage and 
subsequent analysis. 
No data will be removed or disclosed at any point during the study. If it becomes necessary to 
share information with third parties (e.g., for external statistical analysis), the data will be fully 
anonymized. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Biological samples will be obtained as part of routine clinical care, and the resulting data will be 
used for the study. 
For each participant, the biological samples collected throughout the study will include: 
 
Number and type of samples: Three blood samples and three urine samples will be 
collected. 
 
Timing of collection: Samples will be obtained at the start of the intervention, 6 months 
post-intervention, and 18 months post-intervention. 
 
Processing and analysis methods: Blood samples will be collected by venipuncture using 
standard clinical practice procedures in primary care, obtaining the minimum volume 
necessary, and stored in sealed tubes. Urine samples will be collected by providing the 
participant with a sterile container to collect the first morning urine, which will then be 
retrieved by healthcare personnel. Both blood and urine samples will be processed in an 
external laboratory. 
 
Analysis location: Sample collection will take place at the participant’s reference CAP 
(CAP Larrard or CAP Barceloneta). 
 
Sample disposition: Once the project analyses are completed, all samples will be destroyed 
according to the standard protocols of the analysis laboratory. 
 
Sample coding: Samples will be labeled with barcodes and alphanumeric codes, each 
linked to the participant’s healthcare identification number. 
The storage of biological samples for future research after the study is not planned. 
Clinical data and questionnaires collected during the study will be anonymized and stored in the 
REDCap (Research Electronic Data Capture) platform, hosted on the secure servers of Parc 
Sanitari Pere Virgili (PSPV). Data will be retained for a maximum of 5 years after study 
completion and will not be shared with third parties. 
 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal investigator 
Alexandre Ternianov  
Physician specialist in Family and Community Care 
Parc Sanitari Pere Virgili, Barcelona 
Primary and Community Care Research Group in Barcelona (APICBA), Hospital del Mar 
Research Institute 
Tel: 932 21 37 85 
e-mail: aternianov@perevirgili.cat 
 
Collaborating investigators 
Neus Carrilero Carrió 
Primary and Community Care Research Coordinator, Parc Sanitari Pere Virgili 
Primary and Community Care Research Group in Barcelona (APICBA), Hospital del Mar 
Research Institute 
Tel: 659 77 29 79 
e-mail: ncarrilero@perevirgili.cat 
 
Sonia Moreno Escribà 
Physician specialist in Family and Community Care 
Parc Sanitari Pere Virgili, Barcelona 
Primary and Community Care Research Group in Barcelona (APICBA), Hospital del Mar 
Research Institute 
e-mail: smorenoe@perevirgili.cat 
 
Anna Parellada Roura 
Dietitian-Nutritionist 
Parc Sanitari Pere Virgili, Barcelona 
e-mail: aparellada@perevirgili.cat 
 
Vanina Andrés Troyas 
Physician  
Parc Sanitari Pere Virgili, Barcelona 
e-mail: vandrest@perevirgili.cat 
 
José Javier Vega Córdova 
Resident Physician specializing in Family and Community Care 
Parc Sanitari Pere Virgili, Barcelona 
e-mail: jvega@perevirgili.cat 

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Giulia Satu Faini 
Resident Physician specializing in Family and Community Care 
Parc Sanitari Pere Virgili, Barcelona 
e-mail: gfaini@perevirgili.cat 
 
Jesse Omar Anagua Melendres 
Resident Physician specializing in Family and Community Care 
Parc Sanitari Pere Virgili, Barcelona 
e-mail: janagua@perevirgili.cat 
 
Luis Adrian Soto Mota 
Internist (Specialist in Internal Medicine) 
Metabolic Diseases Research Unit, National Institute of Medical Sciences and Nutrition Salvador 
e-mail: adrian.soto@tec.mx 
The study is overseen by a Steering Committee responsible for the design, conduct, and reporting 
of the trial. Operational activities (data collection, monitoring, statistical analysis) are managed by 
the study team, including coordinators, data managers, and statisticians. Safety and ethical 
oversight is provided by the Ethics Committee (CEIm, Hospital del Mar, Barcelona). 
Key roles include Principal Investigator, Co-investigators, Study Coordinators, Data Management 
Team, and Statistical Team. Any suspected misconduct by staff can be reported to the institutional 
research office or Ethics Committee. Participants are informed in the consent form of their right 
to contact the Ethics Committee with concerns. 
10.1.6 SAFETY OVERSIGHT 
Due to the non-pharmacological nature of the intervention, it is considered low risk for 
participants. Therefore, safety oversight will be managed by the research team, who will be 
responsible for identifying and reporting any adverse events that occur. The internal safety 
monitoring plan outlined in this protocol consists of periodic meetings of the research team, during 
which any incidents arising from the intervention will be discussed, and adherence to the defined 
protocol and Good Clinical Practice will be evaluated. 
Any adverse event identified will be recorded and reported to the participant, the Principal 
Investigator, and Parc Sanitari Pere i Virgili. In the case of repeated serious adverse events, the 
situation will be urgently assessed, and if necessary, the intervention may be considered for 
temporary suspension. 
The creation of an independent Data Safety Monitoring Board (DSMB) is not planned, as the type 
of intervention and the risk profile of the study do not require it. 

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10.1.7 CLINICAL MONITORING 
Due to the low-risk nature of the intervention, independent external clinical monitoring is not 
planned. Compliance with this protocol, as well as oversight of the proper conduct of the study, 
will be the responsibility of the research team. They will ensure correct data collection, adherence 
to the protocol, participant safety, and compliance with Good Clinical Practice and other applicable 
regulations. 
Self-monitoring activities, as well as data quality control and quality assurance procedures, are 
described in section 10.1.8, Quality Assurance and Quality Control. A separate Clinical 
Monitoring Plan (CMP) is not required, and no independent external audits are anticipated. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Both quality assurance and quality control of the study will be the responsibility of the research 
team. The internal procedures to be followed are as follows: 
Quality Control: 
 Informed Consent: Verification of proper completion of the informed consent forms. The 
research team will ensure that all participants’ signed consent forms are properly 
collected and stored. 
 Clinical Data and Questionnaires: All data collected during the intervention sessions, 
validated questionnaires, and electronic records (in this case using the eCAP program, the 
shared electronic health record system used by healthcare professionals at primary care 
centers) will be entered into the REDCap database, which provides a secure environment 
for data storage. Random checks between source documents and the database will be 
performed to ensure accurate data entry. 
 Biological Samples: Both blood and urine samples will be obtained using standard 
clinical practice procedures in primary care and subsequently processed in an external 
laboratory. Samples will be coded using barcodes and alphanumeric codes, each linked to 
the participant’s healthcare identification number. To ensure proper handling, traceability 
checks will be performed, following the samples from collection through processing at 
the external laboratory. 
 
 
Additionally, the quality of the intervention will be ensured through:  
 Rigorous and specific training of intervention personnel: Staff will receive training on the 
protocol and proper data collection procedures. 
 Monitoring adherence to the intervention protocol: Compliance with the intervention 
procedures will be regularly assessed. Any incidents detected will be documented, 
reported, and evaluated. 

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10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the clinical and research staff at the participating 
centers, under the supervision of the Principal Investigator. The Principal Investigator will ensure 
the accuracy, completeness, legibility, and timeliness of all data recorded in the study. 
Data will be collected through a combination of paper source documents (such as self-administered 
questionnaires, clinical records, and sample collection forms) and the eCAP program, the shared 
electronic health record system used by healthcare professionals at primary care centers during 
patient visits. All data will be entered into the REDCap database, which provides a secure 
environment for data storage and requires user authentication with a username and password. 
Biological samples will be labeled with non-identifiable alphanumeric codes and managed by 
collaborating clinical laboratories. Analytical results will be entered into the REDCap database by 
the research team. 
All data will be handled in accordance with current personal data protection regulations 
(Regulation (EU) 2016/679 and Organic Law 3/2018) and will be retained for a minimum of 5 
years after study completion, in accordance with applicable law. 
10.1.9.2 STUDY RECORDS RETENTION  
All study documents (protocol, informed consent forms, etc.) will be retained for a minimum of 5 
years after study completion, in accordance with Good Clinical Practice (ICH-GCP) guidelines. 
Documents will not be destroyed without prior written consent from Parc Sanitari Pere i Virgili or 
the relevant regulatory authority. 
All documentation will be stored securely, protected against unauthorized access, and in 
compliance with current personal data protection regulations (Regulation (EU) 2016/679 and 
Organic Law 3/2018). 
 
10.1.10 
PROTOCOL DEVIATIONS   
This protocol defines a deviation as any non-compliance with the approved protocol or Good 
Clinical Practice (GCP) standards. Deviations may originate from participants, site staff, or the 
Principal Investigator and must be documented, reviewed, and reported in accordance with 
applicable ethical and regulatory requirements. 

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Protocol deviations are not permitted, except when necessary to eliminate an immediate risk to a 
participant. If a deviation occurs, it will be recorded in the official study record, evaluated by the 
research team, and reported to Parc Sanitari Pere i Virgili. 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
Publication and sharing policy wil be as follow: this trial will be registered on ClinicalTrials.gov, 
and information on the results will be submitted to this platform. In addition, every effort will be 
made to publish the results in peer-reviewed scientific journals. Data derived from this study may 
be requested by other researchers máximum 5 years after completion of the primary endpoint, by 
contacting Parc Sanitari Pere i Virgili. Considerations to ensure the confidentiality of these shared 
data are described in Section 10.1.3. 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any real or perceived influence, such as that of the 
pharmaceutical industry, is essential. Therefore, any actual conflict of interest of individuals 
involved in the design, conduct, analysis, publication, or any other aspect of this trial will be 
disclosed and managed. In addition, individuals with a perceived conflict of interest must undergo 
appropriate management in accordance with their participation in the study’s design and 
development. The study leadership, together with Parc Sanitari Pere i Virgili, has established 
policies and procedures to ensure that all members of the study team disclose any conflicts of 
interest and has implemented a mechanism to manage all reported dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
 
In this protocol, no additional considerations are anticipated beyond those already described above. 
 
 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
 
ADA 
American Diabetes Association 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
SMBP 
Self-Measured Blood Pressure 
PC 
Primary Care 
Apo B100 
Apolipoprotein B100 
AST 
Aspartate Aminotransferase 
CAP 
Centro Atención Primaria (Primary Care Center) 
DDD 
Defined Daily Dose 
T2DM 
Type 2 Diabetes Mellitus 

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GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
ITT 
Intention-To-Treat 
HbA1c 
Glycated Hemoglobin 
HDL 
High Density Lipoprotein 
AH 
Arterial Hypertension 
BMI 
Body Mass Index 
LDL 
Light Density Lipoprotein 
NAFLD 
Nonalcoholic fatty liver disease 
IHC 
Individual Health Card 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SA 
Schedule of Activities 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including 
a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
52 
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Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
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NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
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Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
54 
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Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
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Lifestyle Intervention Clinical Trial for the Remission of Type 2 Diabetes Mellitus in Primary Care  
(CREDOenAP) 
 
First version  
 
 
12 August 2025 
 
NIH Protocol Template for Behavioral and Social Sciences 
Research 
 
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