Effect of Dapagliflozin on Nighttime Blood Pressure in Type 2 Diabetes
Phase: PHASE4
Conditions: Type2 Diabetes
Sponsor: LM Diagnósticos S.L.

 
 
 
 
 
 
RESEARCH PROJECT 
 
EFFECT OF DAPAGLIFLOZIN  
ON NIGHTTIME BLOOD  
PRESSURE IN TYPE 2 DIABETES 
 
 
 
 
 
PROTOCOL NUMBER: DAPA-ESR-16-12460 
EudraCT number:2017-002125-38 
Version 1.1.-October 2018 
 
 
Promotor: LM Diagnósticos, S.L. 
Address:  
c/ Castelló, 117, 6ª planta, despacho 628 
28006 Madrid 
 
 
 
 
 
 
 

Principal Investigator: 
 
 
 
• 
Julián Segura de la Morena 
Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Madrid.  
 
Coordinator: 
 
• 
Luis Miguel Ruilope Urioste (IP) 
Grupo de Hipertensión Arterial y Riesgo Cardiovascular, Hospital Universitario 12 de 
Octubre, Instituto de Investigación i+12,Madrid 
Departamento de Salud Pública y Medicina Preventiva, Universidad Autónoma Madrid  
Escuela de Estudios Postdoctorales y de Investigación, Universidad Europea de Madrid  
 
Collaborators: 
 
• 
Aquilino Sánchez 
Unidad de Hipertensión, Departamento de Medicina Interna, Hospital La Paz.  
• 
José Antonio García Donaire 
Unidad de Hipertensión, Departamento de Medicina Interna, Hospital Clínico San Carlos.  
• 
Tomás Gómez Gascón 
Director de la Fundación para la investigación e innovación biomédica de atención 
primaria de la Comunidad de Madrid. 
• 
Gema Ruiz Hurtado. 
Laboratorio de Hipertensión y Riesgo Cardiovascular del Instituto de Investigación 
IMAS12, Hospital Universitario 12 de Octubre. 
 
Promotor: 
 
 
 
• 
LM Diagnósticos S L. 
 

SUMMARY 
 
0. SUMMARY 
5 
1. INTRODUCTION 
7 
2. OBJECTIVES 
10 
3. METHODS 
 
3.1.  Study design 
11 
3.2.  Patients 
11 
3.3. Description of the intervention 
12 
3.4. Randomization 
13 
3.5. Drug under evaluation 
14 
3.6. Drugs not permitted during the clinical trial 
16 
3.7. Interactions with other medicinal products and other forms of interaction  
17 
3.8. End points 
20 
3.9.  Visits, variables and measurements 
20 
3.10. Withdrawal of patients from the study 
21 
3.11.  Sample size considerations 
22 
3.12.  Data management 
23 
3.13.  Plan of analysis 
23 
3.14. End of the trial 
24 
3.15.  Ethical issues 
24 
3.16. Potential risks and benefits of the study 
26 
3.17.  Quality control 
26 
3.18. Safety and monitoring of adverse reactions 
26 

3.19. Publication policy 
32 
3.20. Conduct of the study 
33 
3.21. Planned chronogram of the study 
34 
3.22. Budget 
34 
3.23. Addendum 
34 
4. REFERENCES 
35 
 
 
 

0. SUMMARY 
 
Title 
Effect of dapagliflozin on nighttime blood pressure in type 2 diabetes 
Protocol number 
DAPA-ESR-16-12460 
EudraCT number 
2017-002125-38 
Promotor 
 
LM Diagnósticos S.L. 
C/ Castelló 117, 6ª planta, despacho 628.- 28006 Madrid 
Principal 
Investigator 
 
Coordinator 
Julián Segura de la Morena 
Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Madrid.  
 
Luis Miguel Ruilope Urioste 
Grupo de Hipertensión Arterial y Riesgo Cardiovascular, Hospital 
Universitario 12 de Octubre. 
Project office 
[CRO]: 
 
ODDS SL 
C/ Wenceslao Fernández Flórez, 1  piso 2 •15005 A Coruña 
Centres 
Three university hospitals and the primary care centres in their area 
in Madrid (Clínico San Carlos, La Paz, 12 de Octubre) 
Type of study 
Randomized, multicentric, placebo-controlled, single-blind pilot study 
Main outcome 
Nighttime blood pressure in type 2 diabetic patients 
Objective 
To investigate the effect of the addition of 10 mg daily of dapagliflozin 
to the treatment of diabetic patients compared to the addition of 
placebo on the change in nighttime blood pressure (measured by 
ABPM) over 12 weeks among patients withalbuminuria levels ≥ 30 
and < 3000 mg/g creatinine and estimated glomerular filtration rate ≥ 
60 mL/min/1.73 m2.. 

Patients 
225 patients with a previous diagnosis of type 2 diabetes and eGFR> 
30mL/min x1,73m2, office BP above 140/70 mmHg, HbA1C 7.5-10%, 
albuminuria levels between 30 mg/g creatinine and 3000 mg/g 
creatinine and estimated glomerular filtration rate ≥ 60 mL/min/1.73 
m2. 
Intervention 
10 mg once daily of dapagliflozin or placebo resembling dapagliflozin. 
Chronogram 
Administrative issues: 3 months (September-November2018) 
AEMPS/Ethical committee approval to first subject in: 1 month 
First subject in: December2018 
50% enrollment: April 2019 
Last subject in: June 2019 
Last subject last visit: September2019 
Recruitment of patients: 7 months (December2018-June 2019) 
Data cleaning and closing of the database: 3 months (october2019-
December2019) 
Data analysis: 4 months (January 2020- April 2020) 
Final report and drafting of the manuscript: May 2020 
 
 
 
 

 
1. INTRODUCTION 
 
Cardiovascular (CV) disease is the leading cause of death worldwide, accounting for 30% of 
all deaths(1). High blood pressure (BP) is the most important individual factor contributing to 
global burden of disease worldwile (2),and as a consequence BP is the most important 
modifiable risk factor for CV disease. Prospective cohort studies have established a graded 
positive association between BP and the risk of CV disease, starting at 115 mmHg for systolic 
BP measured in the morning(3). The effectiveness of antihypertensive therapy was initially 
demonstrated in patients with systolic BP above 160 mmHg and the results of early 
prospective trials were reviewed two decades ago(4). More recently, the possibility of 
measuring BP out of the office has opened the investigation about the caveats of office BP 
measurements mainly consisting of white coat hypertension, masked hypertension, short-
term BP variability, and nighttime BP, all these situations are characterized by an increase in 
CV and renal risk when compare to well controlled arterial hypertension(5, 6). The most 
relevant differences according to the accompanying risks is the one observed when daytime 
and nighttime BP levels are compared. Nighttime BP has shown to be the one accompanied 
by the highest level of risk when it is elevated(5).Data from the Spanish ABPM Registry(7) 
have shown that nighttime BP in albuminuric type 2diabetics shows a significant difference 
when compared to values obtained in non-albuminuric type 2 diabetics. The same is true in 
non-diabetic patients with higher nighttime BP levels when albuminuria is present albeit not 
as much as in type 2 diabetics (7). According to our data, the differences in nighttime BP 
oscillates on average between 9-12 mmHg (7). Such a difference can account for the 
development of albuminuria as shown by Lurbe et al. type 1 diabetics(8).Both albuminuria 
and elevated nighttime BP are significant predictors of cardiovascular (CV) events and 

deathas well as of progression of chronic kidney disease (CKD)(5, 9), hence the control of 
nighttime BP could translate into a better CV protection and in a significant diminution of 
albuminuria if present.  
The newest class of drugs for type 2 are the sodium glucose co-transporter 2 receptor (SGLT-
2) inhibitors. These reduce the reabsorption of renal-filtered glucose back into the 
bloodstream, thereby leading to loss glucose in the urine. The Figure 1 obtained from 
Rajasekeran et al. (10)shows the main mechanisms of action of these drugs mediated mainly 
through glycosuria and natriuresis.  
 
 
Figure 1.Cardiorenal protection of SGLT2 inhibitors mediated by glycosuria and 
natriuresis.Obtained from Rajasekeran et al.(10) 
 
 

 
Other protective effect directly related to the heart improving left ventricular function and 
diminishing left ventricular mass have been described for these drugs(11, 12). Recently, the 
Empagliflozin Cardiovascular Outcome and Mortality in Type 2 Diabetes (EMPA-REG) 
trial(13) demonstrated the capacity of empagliflozin to significantly reduce the relative risk 
for both CV mortality and all-cause mortality as well as hospitalizations due to heart failure 
in type 2 diabetic patients. The study also demonstrated the capacity of the drug to slow the 
progression of kidney disease in type 2 diabetic patients together with the finding of a 
significantly lower risk of clinically relevant renal events(14).   
SGLT2 antagonists are drugs with the capacity to lower BP above the level obtained by 
commonly used antihypertensive drugs(15).The decrease in BP contributes importantly to 
the good effects observed in EMPA-REG study(13).Dapagliflozin also improves significantly 
BP and does it during 24 hours(16). 
We have hypothesized that the capacity of dapagliflozin to lower BP could be particularly 
intense during nighttime. This in turn could participate in the observed decay in albuminuria. 
Should this hypothesis be confirmed, it could contribute importantly to the potential positive 
influence of all SLGT2 in preventing mortality and hospitalization due to heart failure as 
shown by the EMPA-REG study(13).  
 
 

2. OBJECTIVES 
 
Primary Objective:  
To investigate the effect of the addition of 10 mg daily of dapagliflozin to the treatment of 
diabetic patients compared to the addition of placebo on the change in nighttime blood 
pressure (measured by ABPM) over 12 weeks among patients with albuminuria levels ≥ 30 
and < 3000 mg/g creatinine and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2. 
Secondary objectives:  
1) To investigate the effect of the addition of 10 mg daily of dapagliflozin to the 
treatment of diabetic patients compared to the addition of placebo on the change in 
nighttime blood pressure (measured by ABPM) over 12 weeks in the subgroup of 
patients with high (30-300 mg/g creatinine) albuminuria levels.  
2) To investigate the effect of the addition of 10 mg daily of dapagliflozin to the 
treatment of diabetic patients compared to the addition of placebo on the change in 
nighttime blood pressure (measured by ABPM) over 12 weeks in the subgroup of 
patients with very high (>300 mg/g creatinine) albuminuria levels.  
3) Changes in albuminuria, office BP and HBA1C in the two subgroups of patients 
investigated 
 
 

3. METHODS 
 
This clinical trial will be conducted according to this Protocol, under the Regulation (EU) No 
536/2014 and all regulatory requirements applicable to clinical trials and following the 
principles of Good Clinical Practice. 
 
3.1. STUDY DESIGN 
Type of study: Randomized, multicentric, placebo-controlled, single-blind pilot study.  
 
3.2. PATIENTS 
Type 2 diabetic patients recruited in the primary care setting in the area of three 
university hospitals in Madrid, irrespectively of the time since diagnosis and type of 
treatment received for their diabetes.   
Entry criteria 
• Patients with a previous diagnosis of type 2 diabetes and 
o Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min x1.73m2and 
o Diagnosis of essential hypertension established at least one year before 
inclusion visit and suboptimal BP control (office BP above 140/70 mmHg) 
o HbA1C 7.5-10% 
o Albuminuria levels ≥ 30 mg/g of creatinine 
Exclusion criteria 
• Age < 18 years old or ≥ 75 years old. 
• Women of childbearing potential. A woman is considered of childbearing potential 
(WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 

salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.  
• Type 1 diabetes 
• Albuminuria above 3000 mg/g of creatinine 
• Established cardiovascular disease (stable heart failure, peripheral arterial disease or 
myocardial infarction or stroke within the previous 6 months) 
• Intolerance to dapagliflozin 
• On treatment with loop diuretic 
• On treatment with SGLT2 inhibitors. 
• On treatment with pioglitazone. 
•  Patients diagnosed of hereditary problems of galactose intolerance, Lapp lactase 
deficiency or glucose-galactose malabsorption.  
• Patients who routinely work during nightime (period between 11.00 p.m. and 7.00 
a.m.) 
 
3.3. DESCRIPTION OF THE INTERVENTION 
The drug under evaluation, dapagliflozin, is approved to be used in adults who are 18 or 
older with type 2 diabetes mellitus for improving glycemic control and can be used in 
monotherapy when diet and exercise alone do not achieve good glycemic control and 
metformin use is not indicated due to intolerance, or in combination with other 
hypoglycemic agents, including insulin, when these, added to diet and exercise do not 
achieve good glycemic control. In this study it will be used in agreement with the terms 
in which its use is authorized.  

The participants in the study, in addition to the treatment for their diabetes that were 
receiving from their attending physician, will receive 10 mg once daily of dapagliflozin or 
placebo resembling dapagliflozinin. The randomization scheme follows below.  
 
3.4. RANDOMIZATION 
Two strata will be considered based on albuminuria levels: 
• High albuminuria (30-300 mg/g creatinine) 
• Very high (>300 mg/g creatinine)  
Patients will be randomized to either dapagliflozin or placebo in a 2:1 ratio. 
 
Figura 2.-Randomization scheme 
 
 
 
Total number of patients: 225; distributed as:  
• 150 diabetic patients treated with dapagliflozin (10mg/day in a single dose), half of 
them with high albuminuria levels (albuminuria 30-300 mg/g of creatinine) and half 
with very high albuminuria levels (albuminuria > 300 mg/g of creatinine) 

• 75 diabetic patients treated with placebo, half of them with high albuminuria levels 
(albuminuria 30-300 mg/g of creatinine) and half with very high albuminuria levels 
(albuminuria > 300 mg/g of creatinine) 
Randomization will be stratified by albuminuria strata and participating hospital (three 
hospitals); center specific randomization lists (active treatment or placebo) will be 
prepared centrally at the project office with a treatment code assigned to each patient. 
Allocation will be concealed by means of sequentially numbered, opaque, sealed envelopes 
that contain the medication code assigned. The envelopes have to be opened sequentially and 
only after the participant’s name is written on the appropriate envelope.  
 
3.5. DRUG UNDER EVALUATION. BLINDING AND RELABELLING OF THE MEDICATION 
The investigational medicinal product (IMP) is dapagliflozin10 mg given once daily (film 
coated tablets, oral use). 
The comparator will be placebo matching dapagliflozin 10 mg.  
Either dapagliflozin or placebo will be administered through out the planned 
intervention period of the study (12 weeks).  
AstraZeneca will donate both dapagliflozin 10 mg and placebo resembling dapagliflozin 
10 mg for the study.  
Identity of investigational product(s) 
Investigational 
product 
Dosage form and strength 
Manufacturer 
Dapagliflozin 
10 mg, Green, plain, diamond 
shaped, film coated tablet (orally)  
AstraZeneca 
 
Matching 
placebo for 
dapagliflozin 
Green, plain, diamond shaped, film 
coated tablet (orally). Does not 
contain active ingredient 
AstraZeneca 
 
 

Primary packaging of the Investigational Medicinal product (IMP) will be carried out by 
AstraZeneca or their designee in accordance with Good Manufacturing Practice (GMP).  
Unlabeled bottles (identical) containing 35 tablets of each IMP will be provided by 
AstraZeneca. 
The tablets contain lactose, which may cause discomfort in lactose-intolerant 
individuals. 
Label, storage and distribution are a promotor’s responsibility. 
Preparation and labelling of Investigational Medicinal Product 
To allow for adequate treatment for the diabetes, only participants will be blinded to 
the treatment they receive. Attending physicians will know the group in which every 
patient is. To preserve blinding for the patient, the study medication (active and 
placebo) will be sent from AstraZeneca to a certified company (LogistaPharma), where, 
in coordination with the CRO of the study [ODDS, S.L.], it will be counted, labeled and 
distributed to the participating centers. The IMPs will be labelled in accordance with 
Good Manufacturing Practice (GMP) and local regulatory guidelines for labeling. The 
labels will fulfill GMP Annex 13 requirements for labelling. 
LogistaPharma will send labeled medication with the corresponding randomization 
codified list to Hospital 12 de Octubre (Pharmacy Service). The investigator coordinator 
of the trial will distribute the medication to the primary care investigators. The study is 
single blinded, every investigator in each of the sites will have the randomization list 
with the individual treatment codes for each individual patient. The unblinding for the 
patient must not be done unless in medical emergencies. If the codes are broken for 
an individual patient, the promotor must be notified and decision if the data should be 
excluded from the analysis must be done by the promotor 

The patient will receive the labelled medication, and counting of the pills will be done 
in the following visits: week 4, week 8 and week 12. Patients will also receive the 
medication leaflet of dapagliflozin, as stated in the form “Information for the patient” 
Storage 
All study drugs will be kept in a secure place under appropriate storage conditions. The 
IMP label on the bottle specifies the appropriate storage. 
At the end of the study, all the study medication that has not been used will be 
collected from the patients by the investigators to be properly destroyed. 
 
3.6. DRUGS NOT PERMITTED DURING THE CLINICAL TRIAL  
While in the clinical trial, this protocol does not permit the use of the following drugs 
and/or changes in medication: 
• 
Loop diuretics. 
• 
SGLT2 inhibitors. 
• 
Pioglitazone  
If the attending physician considers that for the best care of the patient the use of any 
of the above mentioned drugs or changes in treatment is absolutely essential, the 
patient will be withdrawn from the study, the blinding for the patient will be broken 
and the promotor informed.  
Any other change in medication which does not lead to withdrawal from the study will 
be recorded in the CRD. 
 
 

 
3.7. INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF 
INTERACTION  
The summary of the product characteristics details the interactions of dapagliflozin as 
follows: 
Pharmacodynamic interactions 
Diuretics 
Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may 
increase the risk of dehydration and hypotension. 
Insulin and insulin secretagogues 
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. 
Therefore, a lower dose of insulin or an insulin secretagogue may be required to 
reduce the risk of hypoglycaemia when used in combination with dapagliflozin. 
Pharmacokinetic interactions 
The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by 
UDP glucuronosyltransferase 1A9 (UGT1A9). 
In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or 
CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of 
coadministered medicinal products that are metabolised by these enzymes. 
Effect of other medicinal products on dapagliflozin 
Interaction studies conducted in healthy subjects, using mainly a single dose design, 
suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, 

pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, 
valsartan, or simvastatin. 
Following coadministration of dapagliflozin with rifampicin (an inducer of various 
active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin 
systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-
hour urinary glucose excretion. No dose adjustment is recommended. A clinically 
relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is 
not expected. 
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of 
UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no 
clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment 
is recommended. 
 
Effect of dapagliflozin on other medicinal products 
In interaction studies conducted in healthy subjects, using mainly a single-dose design, 
dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, 
glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or 
warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as 
measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin 
(a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% 
increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid 
exposures are not considered clinically relevant. 
 
 
 

Other interactions 
The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics 
of dapagliflozinhave not been studied. 
Paediatric population 
Interaction studies have only been performed in adults. 
Population of advanced age (65-75 years old) 
Population older than 65 years of age are more likely to have a mildly reduced 
glomerular filtration rate (eGFR 60-90 mL/min x1.73m2) and/or being on treatment 
with drugs that may affect renal function (as ACE inhibitors or Angiotensin-2 receptor 
blockers). In these patients, as in the usual clinical practice, administration of 
dapagliflozin should be done with extra caution (education of the patient and self 
monitoring of symptoms).  
Specific drug alert 
Severe cases of diabetic ketoacidosis associated with treatment with canagliflozin, 
dapagliflozin and empagliflozin have been reported. It is recommended to health 
professionals: 
- 
Perform monitoring of ketone bodies in patients who develop symptoms suggestive 
of diabetic ketoacidosis during treatment even when blood glucose levels do not 
suggest diagnosis. 
- 
Inform patients in treatment about the symptoms of diabetic ketoacidosis and the 
need to see the doctor if they occur. 
 
 

3.8. END POINTS 
Primary: Changes in mean nocturnal BP from baseline (week 0) to last visit (week 12).  
Secondary:  
• 
Changes in office BP from baseline (week 0) to last visit (week 12). 
• 
Changes in HBA1C from baseline (week 0) to last visit (week 12). 
• 
Changes in albuminuria from baseline (week 0) to last visit (week 12). 
• 
Natural variability of mean nocturnal BP on separate visits (placebo group).  
 
 
3.9.  VISITS, VARIABLES AND MEASUREMENTS 
Four clinical visits are planned in every patient at 0 (recruitment and randomization), 4, 
8 and 12 weeks. Information on personal and family history of disease, clinical 
examination (including office BP determination), ABPM and blood and urine samples 
will be obtained on visits 0. The variables measured in the blood and urine samples 
depend on the criterium of the attending physician. For this trial, only HbA1c, serum 
creatinine, estimated glomerular filtration rate (eGFR) and albuminuria are mandatory.  
All this information, except personal and family history of disease, will also be 
collected at week 12 (see “3.20. Conduct of the study”). Thirty days after the end of 
the medication (visit of week 12) all participants will be contacted by telephone to 
assess safety. For the initial laboratory data required in the CRF, data obtained in 
primary care in the previous 3 months could be valid. These data will be repeated at 
the end of the study. Informed consents for the study will be signed by the patients 
before coming to the hospital. Blood samples extractions included in this protocol will 
be done, handled and analyzed at each clinical setting according to usual clinical 

practice. No blood sample storage will be needed in this study. Extra blood samples 
drawn will be handled as described in “3.23. Addendum”. 
The relationship of the procedures performed at every clinical visit is presented below 
(see “3.20. Conduct of the study”). Case report forms (CRFs)are presented in Annex I. 
Albuminuria will be measured according to generally used and previously described 
methodologies(18-23). 
ABPM will be measured using Mobil-o-Graph that will give us 24 hours brachial and 
central BP as well as pulse wave velocity and heart rate(24). As diary of activity of the 
patient will not be recorded, in this study, nocturnal (or nighttime) blood pressure 
refers to measurements within the period from 12.00 p.m. to 6.00 a.m. 
 
 
3.10. WITHDRAWAL OF PATIENTS FROM THE STUDY AND UNBLINDING 
Any patient can be withdrawn from the study at anytime during follow-up based on 
medical criteria of attending physician. The latter will detail the reasons of the 
withdrawal and communicate it urgently to the coordinating office of the trial if 
needed. If the reason for withdrawal is an adverse event (AE), the patient will be 
followed according to the procedures described for AEs (3.16). 
Any patient can decide to abandon the study at any time during the study.  
Withdrawal from the trial for any reason is definitive. When leaving the study, the 
main reason will be recorded and, if possible, the patient should have a final exam with 
the content of the visit of week 12. Patients that abandon the study will not be 
substituted. 
All the above mentioned situations cause unblinding of the study. The primary care 
physician is always aware of the medication that receives the patient (single blind) and 

will be the contact person and responsible to break the blind. Contact details are 
available in the patient information form. After unblinding, the responsible primary 
care physician will report it to the coordinating office of the project (ODDS, S.L., 
proyectos@odds.es).   
 
3.11.  SAMPLE SIZE CONSIDERATIONS 
For the main objective of the study, changes in mean nocturnal systolic blood pressure 
will be compared between the active treatment and placebo groups.  
The use of SGLT2 inhibitors has been reported to be associated with reductions in 
office blood pressure of 4–8 mmHg, reductions that could be even higher with the use 
of ambulatory BP monitoring.15 
Accepting an alpha error of 0.05 in a two-sided test, 150 patients are needed in the 
active treatment group and 75 in the placebo group (2:1 randomization) to have an 
80% power (beta error=0.2) to detect as statistically significant a difference greater 
than or equal to 5 mmHg in mean nocturnal BP between placebo and active treatment 
(conservative estimate of the expected effect). The standard deviation is assumed to 
be 12 mmHg and it is expected a drop-out rate of 9%.  
In the prespecifiedsubgroup analysis by albuminuria levels, this sample size (75 in 
active treatment and 37 in placebo) allows to detect as statistically significant, within 
each albuminuria stratum and with the same asumptions and alfa and beta errors, a 
difference greater than or equal to 7,1 mmHg in the reduction of mean nocturnal BP 
between both groups (active treatment and placebo), an effect still within what can be 
expected. 
 

3.12.  DATA MANAGEMENT 
Data will be collected in an electronic CRF by participating doctors and nurses both at 
the hypertension units and at primary care centers. A range of acceptable values and 
logical rules among variables will be implemented to improve quality of data and 
reduce the need of queries.  
The processing, communication and transfer of data will be in accordance with the 
provisions of the Organic Law 15/1999, December 13th, on the protection of personal 
data. 
Trial documentation will be kept and storaged in each site for 25 years after 
completion of the study. 
 
3.13.  PLAN OF ANALYSIS  
The main analysiswill compare baseline and final visit values of nocturnal blood 
pressure and all the rest of quantitative variables of interest within each stratum of 
albuminuria by means of paired t-test. Changes of nighttime blood pressure from 
baseline to final visit among patients with high and very high albuminuria levels will be 
compared to placebo with t-test.  
Variables will be described by means of mean (and standard deviation) or proportion 
depending on the type of variable considered. Whenever the test of hypothesis may 
involve discrete variables, chi-squared testwill be used.  
Comparability of treatment and placebo groups will be tested (t-student or chi-squared 
test, depending on the variable) to assess randomization, and linear regression will be 
used to adjust for potential confounders, if needed; stratum of albuminuria at 
randomization will be forced in the model. 

To respond to secondary objectives, the same analyses will be done for each stratum 
of albuminuria at randomization.  
Only patients that complete the 3-month follow-up will be analyzed. Patients who do 
not complete the follow-up will be compared to those who adhere to the protocol. 
No interim analysis is planned. A p value<0.05 will be considered as statistically 
significant. 
 
3.14.  END OF THE TRIAL 
The trial will end with the last visit of the last patient recruited. Details of the planned 
chronogram can be seen in 3.21 
As no interim analysis are planned (see 3.13), no formal stopping rules of the trial are 
considered in this regard. 
The study may be terminated if the study procedures are not being performed 
according to Good Clinical Practice (GCP). The promotor also may terminate the entire 
study prematurely if concerns for safety arise within this study or in any other study 
with dapagliflozin. 
 
3.15.  ETHICAL ISSUES  
At the recruitment visit, all patients meeting criteria and invited to participate will 
receive adequate written information on the study (Annex II) and will have the 
opportunity to ask the investigator any question regarding their participation and will 
be given enough time to make a decision. Following all this, they will sign and date 
their acceptance to participate in it (Annex III) prior to randomization. This is a trial 

proposed as “low level of intervention trial” [“RD 1090/2015 de 4 de diciembre”] and 
every participant will be covered by an insurance for this instances. 
This study will be done conforming to the principles of the Declaration of Helsinki and 
posterior amendments, Good Clinical Practice and the applicable legislation including 
the requirements of the Spanish law of data protection (“Reglamento General de 
Protección de Datos (Reglamento (UE) 2016/679 del Parlamento Europeo y del 
Consejo, de 27 de abril de 2016”, "Ley Orgánica 15/1999 de 13 de diciembre, de 
protección de datos de carácter personal”, and “RD1720/2007”), as described in the 
“Information for the patient sheet” (Annex II). Data will be entered online and stored 
securely in a centralized database in a devoted server. To access the eCRF, an user 
name and password with limited access to allow the development of the study will be 
assigned to every investigator in the trial (including coordinators and CRO). All 
personal identification data of the patients will be dissociated from the rest of the data 
and only the attending physicians will have access to that information to allow the 
follow-up. All data will be treated anonymously in the analysis and no report from the 
study will contain any information that allows to identify the patients. 
The clinical study will be reviewed by health authorities and an ethic committee and 
the study will only be started when the approval from the regulatory authorities and 
the ethic committee is obtained. 
At the end of follow-up, every patient will be informed of the treatment group in 
which he remained during the study and continue the standard care for his/her 
condition by his/her attending physician. 
 
 

3.16. POTENTIAL RISKS AND BENEFITS OF THE STUDY 
The drug under investigation is accepted and of common use in Spain for the 
treatment of the type of patients that will be included. It will be administered as 
approved in its specifications. Its use is evidence based and its safety and efficacy are 
well documented. 
All tests and procedures included in the study are normal clinical practice in the 
diabetic patient with the exception of ABPM that poses no risk for the patient and is 
basic for the main outcome of the study.  
 
3.17.  QUALITY CONTROL  
Filters and logic rules will be implemented in the electronic CRF to minimize data entry 
errors. Throughout the study, 10% of the clinical sites will be randomly selected and 
visited by CRO (ODDS, S.L.) staff to monitor quality of data. 
 
3.18. SAFETY AND MONITORING OF ADVERSE REACTIONS 
The Principal Investigator is responsible for ensuring that all staff involved in the study 
is familiar with the content of this section. 
Adverse events will be monitored and registered during the study and communicated 
both to the promotor and to the “Agencia Española de Medicamentos y Productos 
Sanitarios” as by law (RD 1090/2015, December 4th). 
 
3.18.1. Definition of adverse event 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 

pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram). In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if 
no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
 
3.18.2. Definitions of serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., 
screening, treatment, follow-up), at any dose of the study drugs that fulfils one or 
more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital abnormality or birth defect. 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
 
3.18.3. Definition of suspected unexpected serious adverse reaction (SUSAR) 
As described in “REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human 
use, and repealing Directive 2001/20/EC” the following definitions on suspected 

unexpected serious adverse reaction (SUSAR) will apply in this protocol: A serious 
adverse reaction, the nature, severity or outcome of which is not consistent with the 
reference safety information. 
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to the promotor/CRO. 
 
3.18.4 Recording of adverse events 
Time period for collection of adverse events 
Adverse Events will be collected from time of signature of informed consent 
throughout the treatment period up to and including the 30-day follow-up period. All 
ongoing and any new AEs/SAEs identified during the 30 calendar days follow-up period 
after the last dose of study medication must be followed to resolution. After study 
treatment completion (i.e. after any scheduled post treatment follow-up period has 
ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in study patients. If an Investigator learns of any SAEs, including death, at 
any time after a patient has completed 30 days post treatment follow-up period, and 
he/she considers there is a reasonable possibility that the event is causally related to 
the study treatment, the investigator should notify the promotor by reporting the SAE. 
Follow-up of unresolved adverse events 
Any SAE or non-serious adverse event that is still ongoing during the 30-day follow-up 
visit must be followed up to resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow-up. AstraZeneca 
may request additional information for any patient with ongoing AE(s)/SAE(s) at the 
end of the study, if necessary. 

The following variables will be collected for each AE: 
• 
AE (verbatim). 
• 
The date when the AE started and stopped. 
• 
Whether the AE is serious or not. 
• 
Investigator causality rating against the Investigational Product (yes or no). 
• 
Action taken with regard to investigational product. 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE. 
• 
Date Investigator became aware of serious AE. 
• 
AE is serious due to. 
• 
Date of hospitalization. 
• 
Date of discharge. 
• 
Probable cause of death. 
• 
Date of death. 
• 
Autopsy performed. 
• 
Description of AE. 
• 
Causality assessment in relation to Study procedure(s). 
• 
Causality assessment in relation to Other medication. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 3.18.2. An AE of 
severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea, but not a SAE. On the 

other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be a SAE. 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are 
other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated: laboratory values, vital 
signs should therefore only be reported as AEs if they fulfill any of the SAE criteria or 
are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory term 
(eg, anemia versus low hemoglobin value). In the absence of clinical signs or 
symptoms, clinically relevant deteriorations in non-mandated parameters should be 
reported as AE(s s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, 
should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 

Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day 
post-study follow-up period after the administration of the last dose of study 
treatment, must be reported  
Reporting of serious adverse events 
The investigator will report immediately (first 24 h) any SAE by means of filling and 
sending the corresponding form [Annex IX] to the CRO (ODDS, S.L.) by fax [981 217539] 
or e-mail [proyectos@odds.es]. 
The promotor/CRO must inform the AEMPS of any Suspected unexpected serious 
adverse events (SUSAR) that occur in accordance with the reporting obligations, and 
will concurrently forward all such reports to AZ. A copy of the report must be sent by 
e-mail to AstraZeneca at the time the event is reported to the AEMPS. It is the 
responsibility of the promotor to compile all necessary information and ensure that 
the AEMPS receives a report according to the AEMPS reporting requirement timelines 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the SAE form indicating the following: 
• 
External Scientific Research (ESR) 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ESR reference number 
* Investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to 
disease progression, as determined by the principal investigator. 
* SAE report and accompanying cover pagewill be sentby way of Email to 
AEMailboxClinicalTrialTCS@astrazeneca.com. 

If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided to AstraZeneca and the AEMPS. 
Serious adverse eventsthat do not require expedited reporting to the AEMPS need to 
be reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events. This information should be reported under no circumstance less 
frequently than quarterly. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally 
related to the investigational product. All SAEs will be documented. The promotor is 
responsible for informing the Regulatory Authority of the SAE as per local 
requirements. 
 
3.19. PUBLICATION POLICY 
The investigators will submit the main results of the study to be published in a journal 
related to the topic of the trial. 
 

3.20. CONDUCT OF THE STUDY 
The table below shows the plan of visits for every patient participating in the study and 
the procedures to be done at every visit and where it takes place. 
 
Visit 0  
(recruitment&randomization) 
Visit 
Week 4 
(±3 days) 
Visit 
Week 8 
(±3 
days) 
Visit 
Week 12 
(final 
visit) 
Phone 
Call 
(30 days 
after the 
final visit) 
Primary 
care 
Hospital 
(within 7 days 
from primary 
care visit) 
Primary 
care 
Primary 
care 
Hospital 
Hospital 
Verification 
of 
inclusion 
and 
exclusion criteria and 
obtention 
of 
informed consent 
 
 
 
 
 
 
Randomization and 
drug distribution for 
the entire follow-up 
 
 
 
 
 
 
Personal and family 
history 
 
 
 
 
 
 
Office BP 
 
 
 
 
 
 
Pill counting 
 
 
 
 
 
 
Clinical exam 
 
 
 
 
 
 
Blood sample (to confirm 
entry criteria; recent [previous 
three months] analyses are 
aceptable) and urine 
 
(*) 
 
 
 
 
ABPM 
 
 
 
 
 
 
Adverse events 
monitoring 
 
 
 
 
 
 
 
(*) Only necessary if not all measurements in the blood sample drawn in primary are available 

3.21. PLANNED CHRONOGRAM OF THE STUDY 
Administrative issues: 3 months (September-November 2018) 
AEMPS/Ethical committee approval to first subject in: 1 month 
First subject in: December 2018 
50% enrollment: April 2019  
Last subject in: June 2019 
Last subject last visit: September 2019 
Recruitment of patients: 7 months (December 2018-June 2019) 
Data cleaning and closing of the database: 3 months (october 2019-December 2019) 
Data analysis: 4 months (January 2020- April 2020) 
Final report and drafting of the manuscript: May 2020 
 
3.22. BUDGET 
 
Astra-Zeneca will provide funding for the study.  
 
3.23. ADDENDUM 
Patients included in this study will be part of an ongoing project financed for the period 
2018-2020 by the “Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III), 
Referencia: PI17/01193” approved by the ethics committee of Hospital 12 de Octubre with 
the title “Papel de la presión arterial nocturna en la estratificación del riesgo cardiovascular: 
nuevas estrategias clínicas y experimentales” and aimed to evaluate oxidative stress, 
vascular remodeling and proteomic profiles in different clinical situations. To this end, 
coinciding with the blood extractions done in the hospital in this protocol (visits 0 and week-
12), extra blood samples will be obtained, prepared and stored. Four blood tubes (7 
ml/each) will be drawn, centrifuged and the plasm separated and stored in a private 
collection at Hospital 12 de Octubre (Dr. Ruiz Hurtado). This information is included in the 
information for the patient sheet.  
 

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