Clinical trial NCT03476460
Conditions: Kidney Failure, Chronic Kidney Failure, Acute Heart Failure Diabetes
Keywords: Acute kidney failure CT scan Iodine contrast Sodium chloride
Sponsor: Hospital Universitario Ramon y Cajal
Start date: 2014-04-01; Completion date: 2019-11-29
Enrollment: 271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II, open, non-inferiority, randomized and controlled clinical trial is aimed to ascertain the incidence of contrast nephropathy in outpatients undergoing CT scan with contrast.

Patients will be randomized to receive oral prophylaxis with capsules of sodium chloride and free water ingestion or prophylaxis with sodium chloride 0.9% intravenous solution.

The total dose (mmol) of sodium chloride will be the same regardless administration via. The contrast will be iodixanol.

Patients \>65 years, of both sexes, with at least one of the following criteria: diabetes, stable heart failure or chronic kidney disease (estimated glomerular filtration rate between 30 and 60 ml/min), undergoing CT scan with contrast, and who give written informed consent, will be included in the study. Patients with estimated glomerular filtration rate \<30 ml/min, serum potassium \<3.5 mEq/L, infusion of iodine contrast in the previous 15 days, administration of nephrotoxic drugs in the previous 72 hours or expected in the following hours after contrast infusion, decompensated chronic conditions (heart failure, chronic obstructive pulmonary disease, hypertension), allergy to iodine contrast, or the presence of hyperchloremia or hypernatremia, will be excluded from the study.

Contrast nephropathy will be defined as the increase of serum creatinine \>0.3 mg/dL from baseline, or the reduction of estimated glomerular filtration rate (MDRD-4) \>25% from baseline, in the first 48 hours after contrast administration.

Detailed description:
This phase II, open, non-inferiority, randomized and controlled clinical trial is aimed to ascertain the incidence of contrast nephropathy in outpatients undergoing CT scan with contrast.

Patients will be randomized to receive oral prophylaxis with capsules of sodium chloride and free water ingestion or prophylaxis with sodium chloride 0.9% intravenous solution.

In those patients randomly allocated to oral prophylaxis (n=133), patients will receive capsules of sodium chloride and free water ingestion (for each capsule of sodium chloride, patients will take 250 ml of water, assuring a minimum ingestion of 750 ml of water) in the 48 hours prior contrast injection. Patients will take capsules of sodium chloride at a dose of 100 mg/kg during 48 hours previous the injection of contrast (48, 40, 32, 24, 16, and 8 hours), at the moment of contrast injection and 12 hours after the injection of contrast. In those patients randomly allocated to receive sodium chloride 0.9% intravenous solution (n=133), patients will receive at hospital 3 ml/Kg of sodium chloride 0.9%, one hour previous contrast injection and 2 ml/kg during the 4 hours after contrast injection. The total dose (mmol) of sodium chloride will be the same regardless administration via. The contrast will be iodixanol (320 mg of iodine/ml, in 100 ml, at an infusion rate of 2-5 ml/sec).

Patients \>65 years, of both sexes, with at least one of the following criteria: diabetes, stable heart failure or chronic kidney disease (estimated glomerular filtration rate between 30 and 60 ml/min), undergoing CT scan with contrast, and who give written informed consent, will be included in the study. Patients with estimated glomerular filtration rate \<30 ml/min, serum potassium \<3.5 mEq/L, infusion of iodine contrast in the previous 15 days, administration of nephrotoxic drugs in the previous 72 hours or expected in the following hours after contrast infusion, decompensated chronic conditions (heart failure, chronic obstructive pulmonary disease, hypertension), allergy to iodine contrast, or the presence of hyperchloremia or hypernatremia, will be excluded from the study.

Contrast nephropathy will be defined as the increase of serum creatinine \>0.3 mg/dL from baseline, or the reduction of estimated glomerular filtration rate (MDRD-4) \>25% from baseline, in the first 48 hours after contrast administration.

Arms: arm 1: Patients will receive capsules of sodium chloride and free water ingestion (for each capsule of sodium chloride, patients will take 250 ml of water, assuring a minimum ingestion of 750 ml of water) in the 48 hours prior contrast injection. Patients will take capsules of sodium chloride at a dose of 100 mg/kg during 48 hours previous the injection of contrast (48, 40, 32, 24, 16, and 8 hours), at the moment of contrast injection and 12 hours after the injection of contrast. arm 2: Patients will receive at hospital 3 ml/Kg of sodium chloride 0.9%, one hour previous contrast injection and 2 ml/kg during the 4 hours after contrast injection.
Interventions: intervention 1: Oral sodium chloride intervention 2: Intravenous sodium chloride
Intervention descriptions: intervention 1: Patients will receive capsules of sodium chloride and free water ingestion (for each capsule of sodium chloride, with 250 ml of water, assuring a minimum ingestion of 750 ml of water) in the 48 hours prior contrast injection. Patients will take capsules of sodium chloride at a dose of 100 mg/kg during 48 hours previous the injection of contrast (48, 40, 32, 24, 16, and 8 hours), at the moment of contrast injection and 12 hours after the injection of contrast. intervention 2: Patients will receive at hospital 3 ml/Kg of sodium chloride 0.9%, one hour previous contrast injection and 2 ml/kg during the 4 hours after contrast injection.

Protocol documents:
Prot_SAP_000.pdf: 
PNIC-Na Protocol 
Date & Version No: 02-Aug-2013 V2.0 (ENG) 
 
1 
 
 
Hospital Universitario 
Ramón y Cajal 
 
 
 
 
 
 
 
Study Title: Efficacy of oral and intravenous sodium chloride administration in the 
prophylaxis of post-contrast acute kidney injury in outpatients. 
Short Title: PNIC-Na 
Study phase: 2 
Ethics Ref: 124-13 
Project ID: EC11-132; 2012/0019. 
EudraCT Number: 2013-001229-15 
NCT03476460 
Date and Version No.: 02-Aug-2013 V2.0 (ENG) 
Principal Investigator: Luis Manzano Espinosa, Internal Medicine Dept., Hospital 
Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.  
Sponsor: The Foundation for Biomedical Research of the Hospital Universitario Ramón 
y Cajal (FIBioHRC) 
Funder: The Spanish Health Ministry through the Fondo de Investigaciones Sanitarias 
(FIS) of the Instituto de Salud Carlos III, Madrid. 
 
 
 
 
 
 
 
 
 
 
 
 
 


PNIC-Na Protocol 
Date & Version No: 02-Aug-2013 V2.0 (ENG) 
 
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Contents 
1. 
INVESTIGATOR COMMITMENT STATEMENT 
5 
2. 
SUMMARY 
6 
3. 
KEY CONTACTS AND GENERAL INFORMATION 
8 
4. 
RATIONALE AND OBJECTIVES 
9 
4.1. 
Background and current status 
9 
4.2. 
Benefits and risks for humans 
10 
4.3. 
Justification of the route of administration, dose, regimen and treatment period 
10 
4.4. 
References 
10 
4.5. 
Description of the study groups 
12 
4.6. 
Description of the study population 
12 
4.7. 
Main objective 
12 
4.8. 
Secondary objectives 
12 
5. 
TRIAL TYPE AND DESIGN 
13 
5.1. 
Clinical trial phase 
13 
5.2. 
Main and secondary variables 
13 
5.3. 
Study design 
14 
5.4. 
Recruitment and randomization 
14 
5.5. 
Treatment 
14 
5.6. 
Schedule 
15 
5.7. 
Completion criteria 
15 
5.8. 
Study medication accounting 
15 
5.9. 
Randomization 
16 
5.10. 
Data source 
16 
5.11. 
End of clinical trial 
16 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
16 
6.1. 
Inclusion criteria 
16 
6.2. 
Exclusion criteria 
17 
6.3. 
Sample size and justification 
17 
6.4. 
Withdrawal criteria and analysis 
17 
6.5. 
Estimated duration of the recruitment period 
17 
7. 
DESCRIPTION OF TREATMENT 
17 
7.1. 
Treatment definition 
18 
7.2. 
Compliance 
18 
8. 
EFFICACY ASSESSMENT 
18 


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8.1. 
Efficacy assessment criteria 
18 
8.2. 
Development of the study 
19 
8.3. 
Methods for efficacy assessment 
20 
9. 
SAFETY 
20 
9.1. 
Definitions 
20 
9.2. 
Causality assessment 
21 
9.3. 
Safety assessment 
21 
9.4. 
Intensity assessment 
21 
9.5. 
Severity assessment 
22 
9.6. 
Expectancy assessment 
22 
9.7. 
Safety recording procedure 
22 
9.8. 
Safety reporting procedure 
22 
9.9. 
Follow-up plan 
23 
9.10. 
Notification of other safety information 
23 
9.11. 
Annual safety reports 
23 
9.12. 
Notification to investigators 
23 
9.13. 
Access to the randomization code during the trial 
23 
10. 
STATISTICAL CONSIDERATIONS 
24 
10.1. 
Sample size calculation 
24 
10.2. 
Randomization and treatment assignment 
24 
10.3. 
Statistical methods 
24 
10.4. 
Missing data 
24 
10.5. 
Deviations from the statistical plan 
24 
10.6. 
Selection of subjects for analysis 
25 
11. 
ACCESS TO SOURCE DATA AND DOCUMENTS 
25 
12. 
QUALITY CONTROL AND ASSURANCE 
25 
13. 
ETHICAL ASPECTS 
25 
13.1. 
General and specific rules for the investigators 
25 
13.2. 
Informed consent 
26 
13.3. 
Security and confidentiality arrangements 
26 
13.4. 
Content of the trial budget 
26 
13.5. 
Insurance 
26 
14. 
PRACTICAL CONSIDERATIONS 
26 
14.1. 
Responsibilities of the participants of the clinical trial 
26 
14.2. 
Deviations from the protocol 
27 


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14.3. 
Storage of the study file 
27 
14.4. 
Sample identification 
27 
14.5. 
Amendments to the protocol 
27 
14.6. 
Acceptance by the investigator 
27 
14.7. 
Conditions for publication 
28 
15. 
APPENDICES 
28 
APPENDIX A. WMA DECLARATION OF HELSINKI 
28 
APPENDIX B. ADVERSE REACTION REPORTING 
31 
APPENDIX C. SODIUM CHLORIDE ADMINISTRATION SCHEDULE ACCORDING TO 
WEIGHT 
35 
 
 
 


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1. INVESTIGATOR COMMITMENT STATEMENT 
 
 
I assume the responsibility for the proper conduct of the study at this site. 
 
I agree to conduct the study in accordance with this protocol Version 2, August 2, 2013. 
 
I will not make any changes to the protocol without the prior consent of the sponsor and the written 
authorization of the Clinical Research Ethics Committee (CEIC), except as necessary to counteract any 
imminent danger to patients or as it relates to the administrative aspects of the study (and when permitted 
by current legal regulations to this effect). 
 
I am aware of and will comply with Good Clinical Practice (GCP) and other relevant legal requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed: MD PhD Luis Manzano Espinosa. Principal investigator of the study.  
 
 
Date: 2nd August of 2013.  
 
 


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2. SUMMARY  
 
Type of request 
Phase II clinical trial of oral sodium chloride in a new indication. 
Sponsor 
The Foundation for Biomedical Research of the Hospital Universitario Ramón y Cajal (FIBioHRC) 
Funder 
The Spanish Health Ministry through the Fondo de Investigaciones Sanitarias (FIS) of the Instituto de Salud 
Carlos III, Madrid. 
Clinical trial title 
Efficacy of oral and intravenous sodium chloride administration in the prophylaxis of post-contrast acute 
kidney injury in outpatients (PNIC-Na).  
Protocol code  
EudraCT: 2013-001229-15 
Principal Investigator 
Luis Manzano Espinosa.  
Internal Medicine Department, Hospital Universitario Ramón y Cajal.  
Ctra. de Colmenar Km 9.100 28034 Madrid. Tel: +34913368921; Fax: +34913368922. e-mail: 
luis.manzano@uah.es  
Sites where the trial is planned to be carried out 
Hospital Universitario Ramón y Cajal  
Clinical Research Ethics Committee that evaluates the trial 
Clinical Research Ethics Committee from Hospital Universitario Ramón y Cajal  
Monitoring  
Unit of Clinical Research and Clinical Trials (UICEC) of Hospital Universitario Ramón y Cajal, ISCIII 
National Network (SCReN). Tel/Fax +34 91 336 8825. e-mail: marisa.monitoracaiber@gmail.com 
Experimental and control group  
Experimental group: 500 mg capsules of sodium chloride (NaCl), supplied by the Pharmacy Department 
of the Hospital Universitario Ramón y Cajal. The total dose administered will be 100 mg/kg of body weight 
distributed in 60 hours, 48 hours before and 12 hours after the procedure. Appendix C describes the specific 
regimen according to weight.  
Control group: 0.9% NaCl solution, supplied by the Pharmacy Department of the Hospital Universitario 
Ramón y Cajal. Dose: 3 ml/kg in the hour prior to the procedure and 2 ml/kg/hour in the following 4 hours. 
Clinical trial phase 
Phase II.  
Main objective  
To compare the incidence of post-contrast acute kidney injury (PC-AKI) in high-risk ambulatory patients 
after oral versus intravenous administration of sodium chloride prophylaxis. 


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Design  
Phase 2, monocenter, randomized, open-label, controlled clinical trial for non-inferiority. 
Disease or condition studied  
Post-contrast acute kidney injury. 
Main outcome 
The main efficacy criteria for PC-AKI is defined as an increase in serum creatinine > 0.3 mg/dL or a 
reduction >25% in estimated glomerular filtration rate (MDRD-4), within 48 hours from baseline.  
Study population 
Patients at high risk of developing PC-AKI. The total number of patients will be 266, 133 for each treatment 
group. 
Study duration 
Three years. 
Schedule and expected completion date  
After approval by the Ethics Committee and other regulatory bodies: 
Patient inclusion: 30 months. 
Duration of treatment and follow-up: 72 hours. 
Overall estimated completion of the study 36 months after approval. 
 
 
 


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3. KEY CONTACTS AND GENERAL INFORMATION 
 
Sponsor’s Contact Person 
Itziar de Pablo López de Abechuco.  
Hospital Universitario Ramón y Cajal Ctra. de Colmenar Km 9,100 28034 Madrid.  
Tel: +34 91 336 8825; Fax: +34 91 336 8825. e-mail: ipablo.hrc@salud.madrid.org 
Principal Investigator 
Luis Manzano Espinosa MD PhD.  
Internal Medicine Department. Hospital Universitario Ramón y Cajal Ctra. de Colmenar Km 9.100, Madrid 
(28034). 
Tel: +34913368921; Fax: +34913368922. e-mail: luis.manzano@uah.es 
Collaborating Investigators 
Fernando Liaño García MD. Nephrology Department. Hospital Universitario Ramón y Cajal Ctra. de 
Colmenar Km 9.100, Madrid (28034). e-mail: lianof@yahoo.es 
Javier Blázquez Sánchez MD. Radiology Department. Hospital Universitario Ramón y Cajal Ctra. de 
Colmenar Km 9.100, Madrid (28034). e-mail: javier.blazquez@salud.madrid.org 
Research Site 
Hospital Universitario Ramón y Cajal Ctra. de Colmenar Km 9,100 28034 Madrid. Tel: +34913368000 
Clinical Laboratories 
Heart Failure and Vascular Risk Unit. Internal Medicine Department. Hospital Universitario Ramón y 
Cajal. 
Nephrology Department. Hospital Universitario Ramón y Cajal. 
Radiology Department. Hospital Universitario Ramón y Cajal. 
Biochemistry Department. Hospital Universitario Ramón y Cajal. 
 
 
 


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4. RATIONALE AND OBJECTIVES 
 
4.1. 
Background and current status 
 
Post-contrast acute kidney injury (PC-AKI) is defined by an increase in plasma creatinine greater than 0.3 
mg/dL, or greater than 25-50% of the baseline value, 24-48 hours after administration in the absence of 
other causes (surgery, arteriothrombotic disease, nephrotoxic, hemodynamically compromised or 
hypovolemia).1 Despite it is usually transitory, it is a relevant complication. This is the third most frequent 
cause of acute renal failure in hospitalized patients, with an incidence of around 12%.2 It may require 
permanent dialysis and is associated with an increased risk of other non-renal complications. It also 
increases hospitalization time and mortality.3-5 Up to 30% of subjects who suffer PC-AKI will remain with 
some degree of renal failure.6  
The existence of previous renal failure, diabetes, heart failure and the type and volume of contrast used 
have been recognized as risk factors.4 The incidence of PC-AKI in general population is low (0.6-2.3%), 
increases in elderly and diabetic patients (5-29%), and is very striking in the presence of renal failure 
(incidence 15-55%).6,7 Predictive scales have been developed for early identification of those at risk in 
whom preventive measures are especially indicated.8 The European Society of Urogenital Radiology 
established a Contrast Safety Committee in 1996, which recommends the measurement of renal function 
prior to the test, and after it within a maximum of 7 days, as well as preventing measures in patients 
considered to be at risk.9 Regarding the assessment of renal function, it is advisable to estimate the 
glomerular filtration rate using formula such as  the Modification of Diet in Renal Disease (MDRD).10 
However, the MDRD formula may underestimate glomerular filtration rate in healthy subjects and 
overestimate it in diabetic patients with normal plasma creatinine.11 Cystatin C is a low molecular weight 
protein freely filtered and metabolized after its reabsorption in the proximal tubule and its values show less 
variability than those of creatinin.12  
Different in vitro and animal studies suggest that PC-AKI is a consequence of the existence of both direct 
and indirect tubular damage triggered by ischemia secondary to reactive oxygen species that induce local 
vasoconstriction.13  On the other hand, the presence of contrast in the renal tubular lumen constitutes an 
osmotic force that induces natriuresis and stimulates tubule-glomerular feedback with reduction of renal 
perfusion.14 These evidences constitute the pathophysiological basis for the benefit of hydration in patients 
submitted to contrast administration.  
Numerous studies on PC-AKI prophylaxis have been performed but there is still not enough evidence to 
establish a clear recommendation. In addition to the use of hypo or isomolar contrast agents, experts advise 
the administration of intravenous isotonic solutions, with a wide variability between the type of solution 
and its administration schedule. Current recommendations are intravenous volume expansion, which is 
inapplicable in most outpatients undergoing radiological procedures. 
Most of the preventive guidelines evaluated have used intravenous saline or sodium bicarbonate solutions.15 
It has been postulated that sodium bicarbonate offers greater protection than sodium chloride probably 
because of its urinary alkalinizing effect.16,17  However, clinical trials and several recent meta-analyses have 
not demonstrated a greater efficacy of sodium bicarbonate vs sodium chloride (NaCl) in the prevention of 
PC-AKI.18-20 A clinical trial is currently underway to conclusively clarify the efficacy of bicarbonate versus 
sodium chloride infusion (ClinicalTrials.gov NCT00930436). 
N-acetyl-cysteine has been used in PC-AKI prophylaxis with heterogeneous results. Recently, a clinical 
trial with a large number of patients has shown no benefit associated with the use of N-acetyl-cysteine, so 
its administration should probably be abandoned.21  
Regarding oral volume expansion, studies are scarce, with non-comparable designs, limited statistical 
power and heterogeneous results.22-24 The findings of a recent study with NaCl suggest that oral 
administration is non-inferior to intravenous administration in the prevention of PC-AKI in high-risk 
subjects.23 Nevertheless, due to the small number of patients in each group no conclusions can be drawn. 


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An important aspect of PC-AKI is the early detection, before the loss of renal function occurs.25 In this 
sense, creatinine is not a good marker, since its elevation occurs when there is an established renal failure. 
Sensitive biomarkers of renal damage would allow not only to an early detection of renal injury, but also 
the identification of those patients at risk of suffering it.25-27 Among the new candidate predictors of early 
kidney injury is the measurement in urine of neutrophil gelatinase-associated lipocalin (NGAL), an enzyme 
released after renal tissue injury, which is one of the most accurate, sensitive and specific methods.28,29 
Other state-of-the-art urinary markers related to the early diagnosis of renal damage are renal damage 
molecule 130, N-acetyl glucosaminidase31, and other molecules patented by Spanish researchers: t-gelsolin 
(a proteolytic fragment of gelsolin) and ganglioside M2 activating protein (GM2AP).32,33 
On the basis of the above, and taking into account the prevalence and clinical relevance of this complication, 
the possibility of introducing an effective oral regimen for the prevention of PC-AKI would have a 
considerable impact, both in terms of patient benefit and health care cost. Otherwise, the patient would have 
to be hospitalized. We consider the project to be sufficiently justified due to the high incidence of PC-AKI. 
The selected population group presents a high risk, so the expected benefit of this study will be especially 
relevant in this population. On the other hand, the incorporation of biomarkers of early diagnostic and/or 
prognostic utility would be of great help in identifying those patients at greater risk of suffering a severe 
nephropathy.  
 
4.2. 
Benefits and risks for humans 
 
The intended benefit is the demonstration that oral NaCl is non-inferior to an intravenous administration. 
This would allow the widespread application of a preventive treatment for contrast nephropathy, easy to 
administer to all patients. Likewise, the study could help us to identify patients at risk of PC-AK analyzing 
the molecules mentioned.  
The administration of saline compounds can increase blood volume and increase congestive symptoms such 
as edema. However, at the doses used and taking into account the criteria required for participation, patients 
are not expected to suffer any complication from the study. In any case, oral treatment, which is the subject 
of the study, should not produce more volume overload at the proposed doses than conventional intravenous 
treatment.  
 
4.3. 
Justification of the route of administration, dose, regimen and 
treatment period 
 
The proposed intravenous regimen of 11 mL/kg body weight of 0.9% NaCl, over the course of 6 hours is 
within the accepted recommendations. The oral regimen is intended to provide volume support with NaCl 
for a reasonable period of 60 hours. 
 
4.4. 
References 
 
1 
Kellum JA. Section 4: Contrast-induced AKI. Kidney Intern Suppl 2012;2:69-88 
2 
Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930-
6. 
3 
Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ,et al. Incidence and prognostic 
importance of acute renal failure after percutaneous coronar intervention. Circulation 2002; 
105:2259-64. 
4 
McCullough PA, Stacul F, Becker CR, Adam A, Lameire N, Tumiin JA, Davidson CJ. Contrast- 
lnduced Nephropathy (CIN) Consensus /Working Panel. RevCardiovasc Med 2006;7:177-97. 


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5 
Gupta R, Gurm HS, Bhatt DL, Chew DP, Ellis SG: Renal failure after percutaneus cornary 
intervention is associated with high mortality. Catheter Cardiovasc Interv 2005, 64:442-448. 
6 
Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology and patients at 
risk. Kid Int Suppl 2006: 100; 511-5.. 
7 
Aspelin P, Aubry P, Fransson SG, et al. Nephrotoxíc effects in high-risk patients undergoing 
angiography. N Engl J Med 2003;348:491-9. 
8 
Merhan R, Aymong E, Nikolsky E et al. A simple risk score for prediction of contrast induced 
nephropathy after percutaneus coronary intervention. J Am Coll Cardiol 2004; 44 : 1393-1399. 
9 
Thomsen HS. How to avoid CIN: guidelines from the European Society of Urogenital Radiology. 
Nephrol Dial Transplant 2005; 20: 118-122. 
10 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estímate 
glomerular filtartion rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 
130:461-70. 
11 
Ibrahim H, Mondress M, Tello A. Et al. An alternative formula to the Cockroft-Gaultand the 
modification of diet in renal disease formulas in predicting GFR in individuáis with Type 1 
diabetes. J Am Soc Nephrol 2005; 16:1051-1060. 
12 
Rule AD, Bergstralh EJ, Slezak JM, Bergert J, Larson TS. Glomerular filtration rate estimated by 
cystatin C among different clinical presentations. Kidney Int 2006; 69:399-405. 
13 
Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney 
Int 2005;68:14-22. 
14 
Heinrich MC, Kuhlmann MK, Grgic A et al. Cytotoxic effects of ionio high-osmolar, nonionic 
monomeric, and nonionic iso-osmolardimeric iodinated contrast media on renal tubular cells in 
vitro. Radiology 2005;3:843-9. 
15 
Asif F, Prevention of radiocontrast induced nephropathy. Am J Kid Dis 2004; 44: 12-24. 
16 
Merten GJ, Burgess WP, Gray LV et al. Prevention of contrast-induced nephropathy with sodium 
bicarbonate: a radomized controlled trial. JAMA 2004;291:2328-34. 
17 
Hoshino A, Enomoto S, Kawahito H, Kurata H, Nakahara Y, Nakamura T. Prevention of contrast-
induced nephropathy using cardiaccatheterization combined with hydration, oral N-
acetylcysteine, sodium bicarbonate and iso-osmolar contrast agents. J Cardiol 2007;50:119-26. 
18 
Ozcan EE, Guneri S, Akdeniz B, Akyildiz IZ, Senaslan O, Baris N, Asían O, Badak O. Sodium 
bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A 
comparison of 3 regímens for protecting contrast-induced nephropathy inpatients undergoing 
coronary procedures. A single-center prospective controlled trial. Am Heart J. 2007; 154:539-44. 
19 
Briguori C, Airoldi F, D'Andrea D, Bonizzoni E, Morid N, Focaccio A, Michev I, Montorfano M, 
Carlino M, Cosgrave J, Ricciardelli B Colombo A. Renal Insufficiency Following Contrast Media 
Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. 
Circulation. 2007;115:1211-7. 35. 
20 
Kunadian V, Zaman A, Spyridopoulos I, Qiu W. Sodium bicarbonate for the prevention of contrast 
induced nephropathy: a meta-analysis of published clinical trials. Eur J Radiol 2011;79:48-55 
21 
ACT investigators. Acetylcisteine for Prevention of Renal Outcomes in Patients Undergoing 
Coronary and Perpheral Vascular Angiography. Circulation 2011;124:1250-9 
22 
Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P, Hewett J A randomized 
prospective trial to assess the role of saline hydration on the development of contrast 
nephrotoxicíty. Nephron Clin Pract. 2003 Jan;93(1):C29-34. 
23 
Dussol B, Morange S, Loundoun A et al. A randomized trial of saline hydration to prevent contrast 
nephropathy in chronic renal failure patients. Nephrol Dial Transplant 2006: 21(8): 2120-2126. 
24 
Taylor AJ, Hotchkiss D, Morse RW, McCabe J. PREPARED: Preparation for Angiography in 
renal Dysfunction: a randomized trial on inpatient vs outpatient hydratation protocols for cardiac 
catheterization in mild-to-moderate renal dysfunctions. Ches 1998; 114: 570-4. 
25 
Waikar SS, Bonventre JV. Biomarkers for the diagnosis of acute kidney injury. Nephron Clin 
Practice 2008; 109: 192-197. 
26 
Keyes R, Bagshaw SM. Early diagnosis of acute kidney injury in critically ill patients. Expert Rev 
Mol Diagn 2008: 8: 455-68. 
27 
Ferguson MA, Vaidya VS, Bonventre JV. Biomarkers of nephrotoxic acute kidney injury. 
Toxicology 2008; 245: 182-193. 


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28 
Ling W, Zhaohui N, Ben H, Leyi G, Jianping L, Huili D, Jiaqi Q. Urinary IL-18 and NGAL as 
Early Predictive Biomarkers in Contrast-lnduced Nephropathy after Coronary Angiography. 
Nephron Clin Pract 2008;108:176-c181. 
29 
Hirsch R, Dent C, Pfriem H, et al. NGAL is an early predictive biomarker of contrast-induced 
nephropathy in children. Pediatric Nephrology 2007: 22:2089-2095. 
30 
Han WK, Bailly V, Abichandani R, et al. Kidney Injury Molecule-1 (KIM-1): a novel biomarker 
for human renal proximal tubule injury. Kidney Int 2002;62:237-44. 
31 
Liangos O, Perianayagam MC, Vaidya VS, et al. Urinary N-acetyl-beta-(D)-glucosaminidase 
activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal 
failure. J Am Soc Nephrol 2007;18(3):904-12. 
32 
Ferreira L, Quiros Y, Sancho-Martínez SM, et al. Urinary levels of regenerating islet-derived 
protein III β and gelsolin differentiate gentamicin from cisplatin-induced acute kidney injury in 
rats. Kidney Int 2011;79:518-28. 
33 
Quiros Y, Ferreira L, Sancho-Martínez SM, et al. Sub-nephrotoxic doses of gentamicin predispose 
animals to developing acute kidney injury and to excrete ganglioside M2 activator protein. Kidney 
Int 2010;78:1006-15. 
 
4.5. 
Description of the study groups 
 
Experimental group 
Sodium chloride capsules of 500 mg, supplied by the Pharmacy Department of the hospital. The total dose 
administered will be 100 mg/kg distributed in 60 hours, 48 hours before and 12 hours after the procedure. 
Water (250 mL) will be administered with each oral dose, ensuring a minimum daily water intake of 750 
mL. 
Control group 
Sodium chloride solution 0.9% will be supplied by the Pharmacy Department of the hospital at a dose of 3 
mL/kg in the hour before to the procedure and 2 mL/kg/hour in the 4 hours after. 
 
4.6. 
Description of the study population 
 
The study will be performed in 266 outpatients aged over 65 years, with prior consent, at high risk of 
developing PC-AKI undergoing a contrast-enhanced CT scan (CE-CT). The following risk factors where 
considered: diabetes mellitus, stable heart failure and renal insufficiency (estimated glomerular filtration 
rate calculated by the MDRD-4 formula between 30 and 59 mL/min).  
In order to ensure that the amount, volume and type of contrast infusion is similar in all subjects, only 
patients who underwent CE-CT were selected. 
 
4.7. 
Main objective 
 
To compare the incidence of PC-AKI after oral vs. intravenous administration of NaCl in high-risk 
outpatients. 
 
4.8. 
Secondary objectives 
 


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To study and evaluate the clinical usefulness of various biomarkers of damage in PC-AKI, both 
for early diagnosis of renal damage and for prior stratification of the risk of PC-AKI.  
- 
To elaborate a recommendation applicable to elderly outpatients at high risk of developing PC-
AKI. 
 
5. TRIAL TYPE AND DESIGN 
 
5.1. 
Clinical trial phase 
 
Clinical trial phase 2. 
 
5.2. 
Main and secondary variables 
 
Primary endpoint  
PC-AKI is defined by the presence any of the following criteria in the first 48 hours after contrast 
administration. 
 
Increase in serum creatinine greater than 0.3 mg/dL from baseline. 
 
Reduction in glomerular filtration rate estimated by the MDRD* formula greater than 25% from 
baseline.  
 
*MDRD: 186 x (Cr)-(1.154) x (Age)-(0.203) x 0.742 (if female) x 21 (if African American).  
 
Clinical variables  
The following variables will be collected between 7 days and 24 hours before contrast administration: 
- 
General data: patient code and date of inclusion. 
- 
Demographic data: date of birth and gender. 
- 
Personal history: smoking, hypertension, diabetes mellitus, heart failure, dyslipidemia, ischemic 
heart disease, atrial fibrillation, chronic kidney disease, peripheral arterial disease, cerebrovascular 
disease, anemia, COPD, hypoventilation (pCO2>50 mmHg). 
- 
Anamnesis and physical examination: NYHA functional class orthopnea, edema in extremities, 
ischemic chest pain, height, weight, BMI, HR, blood pressure. Pulmonary auscultation, 
hepatojugular reflux, hepatomegaly. 
- 
Other analytical determinations: hemoglobin, basal glycemia, glycosylated hemoglobin, oxygen 
saturation by pulse oximetry, BNP. 
- 
Imaging tests: electrocardiogram. 
- 
Concomitant medication.  
- 
Procedure data: volume of contrast administered. 
 
Biological variables 
Apart from creatinine measurement and glomerular filtration rate according to MDRD, which constitutes 
the primary response variable of the study, the following parameters will be measured immediately before 
the procedure, and at 24 and 48 hours after contrast administration: plasma cystatin C, serum biochemistry 
with ions, venous gasometry, urinary concentrations of: NGAL, KIM-1*, NAG*, t-gelsolin*, GM2AP*, 
sodium, microalbuminuria and protein. 


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* The biomarkers identified with an asterisk will be stored at -80 ºC until processing in the Laboratory of 
the Heart Failure and Vascular Risk Unit of the Internal Medicine Department of Hospital Universitario 
Ramón y Cajal. This Unit guarantee traceability, quality and safety in computer management, storage 
control and processing samples. 
 
5.3. 
Study design 
 
PNIC-Na is a phase 2, monocenter, randomized, open-label, non-inferiority trial. Two types of preventive 
treatment will be compared in patients undergoing a CE-CT scan: 
- 
Oral prophylaxis with NaCl capsules and free water intake (250 mL of water with each capsule, 
ensuring a water intake of 750 mL/day) in the 48 hours prior to contrast exposure (n=133). It will 
be performed on an outpatient basis at a dose of 100 mg/kg body weight distributed in 60 hours, 
48 hours prior to the procedure and 12 hours after. Appendix C describes the specific dose 
according to weight.  
- 
Intravenous prophylaxis with 0.9% NaCl before and after contrast exposure (n=133). It will consist 
of in-hospital administration of 3 mL/kg in the hour before and 2 mL/kg in the 4 hours after the 
procedure. 
The contrast used will be iodixanol (320 mg iodine/mL, infusion rate 2-5 mL/sec).  
The corresponding treatment will be administered after medical prescription, validation by the pharmacist 
and confirmation. The nurse in charge of the patient will administer the treatment. The intravenous 
prophylaxis schedule for the study will begin in the Radiology Department of the Hospital, and will 
conclude in the Clinical Trials Unit of the same center.  
The study will consist on the schedule of visits described in section 9.2.  
 
 
5.4. 
Recruitment and randomization 
 
Patients will be recruited from the Heart Failure and Vascular Risk Unit (UICARV) of the Internal Medicine 
Department of the Hospital Universitario Ramón y Cajal. Eligible patients will be informed at the time of 
requesting the contrast-enhanced CT scan and, after signing the consent, they will be selected. They may 
also be identified from the requests made to the Radiology department. In this case, the patient will be 
contacted prior to get the informed consent. After their definitive inclusion they will be randomized to one 
of the two arms. A 1:1 randomization will be performed. The randomization sequence will be generated by 
computer in variable blocks, ranging from 4 to 6. An automated allocation system will be used, so that the 
allocation sequence will be unknown to the researchers participating in the study. The patient will be 
considered as randomized as soon as a randomization number is assigned. 
 
5.5. 
Treatment 
 
Treatment under study 
Oral prophylaxis with NaCl capsules and free water intake (250 mL of water with each capsule, ensuring a 
water intake of 750 mL/day) in the 48 hours prior to contrast exposure (n=133). It will be performed on an 
outpatient basis at a dose of 100 mg/kg body weight distributed in 60 hours, 48 hours prior to the procedure 
and 12 hours after. Appendix C describes the specific dose according to weight. Common salt will be used 


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in the experimental group. It will be encapsulated in the Pharmacy Department to ensure the exact dose 
administered to each subject in the trial. 
Control treatment 
Intravenous prophylaxis with 0.9% NaCl before and after contrast exposure (n=133). It will consist of in-
hospital administration of 3 mL/kg in the hour before and 2 mL/kg in the 4 hours after the procedure. The 
NaCl solution used as a control drug is commercialized in our country and will be acquired by the promoter 
through the Hospital Pharmacy department, which will be responsible for its labeling and distribution.  
Contrast used  
The contrast used will be iodixanol (320 mg iodine/mL). A volume of 100 mL, at infusion rate 2-5 mL/s 
will be administered.  
 
5.6. 
Schedule 
 
Estimated duration of the clinical trial is 3 years.  
 
Trial schedule 
 
- 
Preparation of the study (3 months): Planning work for adequate information to patients, acquire 
the necessary material and schedule the laboratory determinations and the application of protocols. 
- 
Development of the study: progressive inclusion and follow-up of patients, as well as sample 
collection (estimated at 8 patients per month). It is estimated that 30 months will be needed to 
include the 266 patients. This phase could be prolonged due to limitations in the recruitment. The 
protocol for the collection of samples will be applied to process and conserve the samples. 
- 
Determinations of serum and urinary markers will be performed at the same time in an estimated 
period of 3 months. NAG, NGAL, KIM-1, GM2AP, t-gelsolin will be measured.  
- 
Elaboration of the database for the inclusion of clinical and analytical variables. Collection and 
computerization of clinical data and analytical results (6 months). 
- 
Statistical study of the results and their interpretation. Writing of the work and publications (5 
months). 
 
5.7. 
Completion criteria 
 
Patients will terminate their participation in the study for the following reasons: 
 
- 
Completion of treatment according to the study protocol. 
- 
Medical safety reasons, at the discretion of the responsible Investigator. 
- 
Serious adverse effect or adverse effect that the Researcher considers unacceptable. 
- 
Voluntary abandonment by the patient. 
- 
Death. 
- 
Demonstration during follow-up that the patient did not meet the criteria for inclusion in the 
clinical trial. 
 
5.8. 
Study medication accounting 
 
Study medication should be used in accordance with the study protocol. The Principal Investigator, or the 
person he/she delegates, will be responsible for administering the study medication. The Principal 
Investigator will record used and unused medication for each trial patient on a Medication Record Sheet. 
This Record Sheet will be available for monitoring visits. To ensure traceability of intravenous NaCl the 


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following will be noted: trade name, quantity and lot number dispensed at each visit. This information will 
also appear in the electronic data capture system. 
In the case of common salt (capsules), a record will be kept of those given to the patient and of the blisters 
returned by the patient at the 24h visit after the procedure. Accordingly, patient's adherence to the treatment 
will be assessed. 
 
5.9. 
Randomization 
 
The Clinical Biostatistics Unit of Hospital Universitario Ramon y Cajal will generate (by computer) a 
randomization list to assign each treatment. The ratio will be 1:1. This list will be sent to the Pharmacy 
Department of the hospital, which will be responsible for supplying the study researchers with the treatment 
corresponding to the patient number in the trial. 
 
5.10. 
Data source 
 
All procedures and variables related to this work will be collected in an electronic data capture system 
(EDC). There will be an EDC for each subject included, independently of the group he/she belongs, and all 
the variables related to the study will be recorded in this EDC. During the study, no personal data will be 
collected from patients as study participants that would allow identification of the subject. The data obtained 
will be kept under strict confidentiality (Organic Law 15/1999, on personal data protection) and only the 
research team of the project will have access to them. Radiological images and other complementary tests 
related to the study, as well as the EDC will be numbered with a code to guarantee the confidentiality of 
the sample and the data. During the study period EDC will be kept under lock, which will be held 
exclusively by the researcher responsible for the project. The coordinators of this study are committed to 
maintain absolute confidentiality and to protect the information provided to them. 
All the information contained in the Clinical History and certified copies of the tests performed, necessary 
for the evaluation of the clinical trial. 
Original documents, data and tests (e.g., medical history, medical charts, nursing charts, pharmacy records, 
laboratory tests, or radiological studies). 
 
5.11. 
End of clinical trial 
 
The end of the clinical trial will be the last visit of the last subject enrolled in the study. 
 
6. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
6.1. 
Inclusion criteria 
 
Patients are eligible to be included if they meet the following inclusion criteria: outpatients, aged over 65 
years old, undergoing a contrast-enhanced CT scan, who are at high risk of developing PC-AKI, defined as 
having at least one of the following risk factors: diabetes mellitus, stable heart failure, chronic kidney 
disease (MDRD-4 between 30 and 59 mL/min), and capable of giving signed informed consent. 
 


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6.2. 
Exclusion criteria 
 
- 
Glomerular filtration rate less than 30 mL/min. 
- 
Presence of hypokalemia (serum potassium less than 3.5 mEq/L). 
- 
Performance of other procedures with intravenous contrast in the previous fifteen days. 
- 
Administration of nephrotoxic drugs (NSAIDs, aminoglycosides and/or potentially nephrotoxic 
chemotherapy) in the last 72 hours, or anticipation of receiving them in the following hours. 
- 
Chronic decompensated pathology: acute heart failure, decompensated COPD or poorly controlled 
arterial hypertension. 
- 
Allergy to iodinated contrasts. 
- 
Patients diagnosed with hyperchloremia or hypernatremia. 
- 
When assessing the inclusion of a patient in the study, all the specifications of the technical data 
sheet in relation to "special warnings and precautions for use" will be taken into account. 
 
 
6.3. 
Sample size and justification 
 
The study will be conducted in 266 individuals on an outpatient basis. Taking into account the non-
inferiority design, for the determination of the sample size it has been considered acceptable to establish a 
priori a difference of no more than 5% in the incidence of PC-AKI of oral prophylaxis with respect to 
intravenous. Considering our high-risk population, we estimated an incidence of PC-AKI in the intravenous 
group of 7% and 12% in the oral group. With this expected response, a non-inferiority margin of 5%, a 
power of 80% and a degree of significance of 2.5%, the sample size will be 266 patients, 133 per group. 
 
6.4. 
Withdrawal criteria and analysis 
 
The patient may discontinue participation in the study at any time he/she wishes. The investigator/physician 
may also decide to withdraw a patient from the trial if the patient does not meet the protocol standards. 
Patients will terminate their participation in the study for the following reasons: 
 
- 
Completion of treatment according to the study protocol. 
- 
Medical safety reasons. 
- 
Serious adverse effect or adverse effect that the Investigator considers unacceptable. 
- 
Voluntary withdrawal by the patient. 
- 
Death. 
- 
Acknowledgement during the follow-up that the patient did not meet the selection criteria for the 
clinical trial. 
 
 
6.5. 
Estimated duration of the recruitment period 
 
The recruitment period is estimated to extend over 30 months. 
 
 
7. DESCRIPTION OF TREATMENT 
 


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7.1. 
Treatment definition 
 
Treatment A:  
Sodium chloride, capsules of 500 mg. 
- 
Dose per subject: 100 mg/kg total administered in several daily intakes during the 48 hours prior 
to the procedure and 12 hours after. 
- 
Route of administration: oral. 
 
Treatment B:  
Sodium chloride, 0.9%. 
- 
Dose per subject: 3 mL/kg of 0.9% sodium chloride in the hour before and 2 mL/kg in the 4 hours 
after the procedure. 
- 
Route of administration: intravenous. 
 
Concomitant treatments 
Permitted: Diuretic and hypotensive medication will be maintained, as long as there have been 
no changes in the previous 10 days. No changes in these medications will be allowed, except in 
special cases, during the 48 hours following the CE-CT. Those patients in treatment with 
metformin, will suspend this medication from 48 hours before to 24 hours after the administration 
of the contrast, and it can be replaced by the introduction or temporary increase of insulin. During 
the 48 hours before and 24 hours after the procedure, free water and salt intake will be allowed. 
Prohibited: Any nephrotoxic agent will be prohibited (NSAIDs, chemotherapy or 
immunosuppressants, nephrotoxic antibiotics) during the 10 days before and 48 hours after the 
procedure. 
 
7.2. 
Compliance 
 
Study medication should be used in accordance to the study protocol. The Principal Investigator, or a 
member of the team, will be responsible for administering the study medication. The researcher team will 
record used and unused medication for each trial patient on a Medication Record Sheet. This Record Sheet 
will be available for monitoring visits in accordance with RD 223/2004. To ensure traceability of the study, 
for NaCl intravenous, the following will be noted: trade name, quantity and lot number dispensed at each 
visit. This information will also appear in the EDC. In the case of common salt (capsules), a record will be 
kept of those given to the patient and of the blisters returned by the patient at the 24h visit after the contrast. 
In this way, the patient's adherence to the treatment will be assessed. 
 
 
8. EFFICACY ASSESSMENT 
 
8.1. 
Efficacy assessment criteria 
 
- 
Increase in serum creatinine from baseline greater than 0.3 mg/dL. 
- 
Reduction of the estimated glomerular filtration rate greater than 25% from baseline value. 
 
 


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8.2. 
Development of the study 
 
Patients will undergo the following procedures:  
Screening visit (from two months to 48 hours before the procedure): verification of inclusion and exclusion 
criteria. Signature of the informed consent. A laboratory blood test will be recorded within two months 
from the CE-CT scan. The screening visit may take place on the same day as randomization (visit 1). 
Visit 1 (from two months to 48 hours before the procedure): review of inclusion and exclusion criteria. 
Serum creatinine, eGFR and ions will be checked. Registration of demographic and clinical data. The 
patient will be randomized and will receive therapeutic information to the assigned group. In the case of 
the oral sodium chloride arm, capsules will be provided.  
Visit 2 (day of the procedure): Before the contrast administration, the investigator will ensure the patient 
has taken study medication. A physical examination will be performed.  Furthermore, blood and urine 
samples will be collected for the specific analytical determinations and biomarkers. After that, contrast will 
be administered as well as the intravenous sodium chloride (intravenous arm). Adverse events will be 
reported. 
Visit 3 (24 hours after contrast): The investigator will perform a physical examination, will ensure the 
compliance of study medication (oral NaCl arm), and will report the adverse events. Moreover, blood and 
urine samples will be collected.  
Visit 4 (48 hours after contrast): same evaluation as visit 3, excluding compliance assessment. 
 
 Study Flowchart 
 
SCREENING 
(From 
two 
months to 48 
hours 
before 
the procedure) 
VISIT 1† 
(From 
two 
months to 48 
hours 
before 
the procedure) 
VISIT 2 
(Day of the 
procedure; 
0 hours) 
VISIT 3  
(24 hours 
after 
contrast) 
VISIT 4 
(48 hours 
after 
contrast) 
Inclusion and exclusion criteria 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Medical history 
 
X 
 
 
 
Clinical variables 
 
X 
X 
X 
X 
Contrast administration 
 
 
X 
 
 
Study treatment administration 
 
X* 
X 
 
 
Evaluation of treatment compliance 
 
 
X 
X* 
 
Clinical laboratory assessments 
X 
 
X 
X 
X 
Biomarkers 
 
 
X 
X 
X 
Adverse events evaluation 
 
X 
X 
X 
X 
* Patients in oral NaCl arm. 
† The screening visit may take place on the same day as randomization (visit 1). 


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8.3. 
Methods for efficacy assessment 
 
The determinations of the study will be performed prior to contrast administration, and at 24 and 48 hours 
after the CE-CT scan. 
 
- 
Plasma creatinine, ions, cystatin C, blood count and venous gasometry will be assessed. 
- 
NGAL*, KIM-1*, NAG*, t-gelsolin*, GM2AP*, and urinary creatinine will be determined to 
homogenize the values of the different biomarkers. Sodium, pH, microalbuminuria and proteinuria 
will also be measured in urine. 
- 
 
These analyses will be performed in the laboratories of the Hospital Universitario Ramón y Cajal, as part 
of the clinical routine, except for the biomarkers identified with an asterisk. This samples will be stored at 
-80ºC in the Laboratory of the Heart Failure and Vascular Risk Unit of the Internal Medicine Dept. Working 
conditions guarantee traceability, quality and safety storage control and processing.  
 
The methods for the different determinations are presented below: 
 
- 
Creatinine in blood and urine: using the alkaline picrate colorimetric technique (kinetic Jaffé) on 
the Architect 16000 analyzer (Abbott Diagnostics). 
- 
Cystatin C in blood: by turbidimetric technique on the Architect 16000 analyzer (Abbott 
Diagnostics). 
- 
NAG: by commercial kit (Roche Diagnostics) based on spectrophotometric detection of the 
reaction product catalyzed by NAG. 
- 
NGAL: by chemiluminescence detection techniques on the Architect 2000 immunoassay analyzer 
(Abbott Diagnostics). 
- 
T- Gelsolin: by Western blot. 
- 
KIM 1: by commercial ELISA kit (CUSABIO). 
- 
Ganglioside M2 activating protein (GM2AP): by Western blot. 
 
 
9. SAFETY 
 
Safety assessments will be carried out in accordance with the Standards of Good Clinical Practice (GCP) 
and current legislation. 
 
9.1. 
Definitions 
 
Adverse Event (AE) 
Any untoward health occurrence in a patient or clinical trial subject treated with a drug, even if not 
necessarily causally related to that treatment. An AE can be any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of an investigational product, whether or not related to the 
investigational product.  
 
Adverse Reaction (AR)  
An unintended, harmful reaction to an investigational product, regardless of the dose administered. In this 
case there is a suspected causal relationship between the investigational product and the AR.  
 
Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR) 


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Any adverse event or adverse reaction that, at any dose, results in death, threatens the life of the subject, 
requires hospitalization of the patient, or prolongs an existing hospitalization, causes permanent or 
significant disability or incapacity, results in a congenital anomaly or malformation.  
 
Suspected AA or AR that are considered medically significant, even if they do not meet the above criteria, 
will also be treated as serious, including major medical events that require intervention to prevent the 
occurrence of one of the consequences described above. Likewise, all suspected transmission of an 
infectious agent should be reported as serious.  
 
Unexpected Adverse Reaction (UAR) 
Any AR whose nature, intensity or consequences do not correspond to the reference information for the 
medicinal product. 
 
Minimum information to be specified 
The researcher team will follow up on the possible adverse events that could arise throughout the study. 
Thus, analytical safety parameters will be determined periodically and the patient will be asked at each visit 
if he/she has experienced any type of symptomatology since the previous visit. If it exists, it will be reflected 
in the clinical history and in the data collection sheet. The information regarding the time of appearance, 
duration, intensity, course and outcome will be recorded. In addition, all patients in the study will be given 
a diary to record anything they consider of interest, including possible AEs. The reporting of serious or 
unexpected adverse events will be done according to Spanish legislation. All adverse events should be 
documented in the patient's medical record.  
 
9.2. 
Causality assessment 
 
Researches will take into account all aspects related to adverse reactions, contraindications, warnings and 
precautions for use, and possibilities of interactions with other drugs, as specified in the data sheets of the 
investigational drugs. Safety parameters to be measured are described in the section 6.2. 
 
9.3. 
Safety assessment 
 
Adverse events in this study will be classified on the basis of their causal relationship with the drug as: 
 
- 
Possibly/probably related: if there is reasonable suspicion of a possible or probable relationship 
(reasonable temporal sequence between the administration of the investigational product and the 
occurrence of the adverse event and the AE cannot reasonably be attributed to any alternative 
cause). 
- 
Unrelated: there is a reasonable time sequence between the administration of the investigational 
product and the occurrence of the adverse event, but the adverse event can be explained by 
alternative causes; or there is no reasonable time sequence between the administration of the drug 
and the occurrence of the adverse event. 
- 
 
The investigator should evaluate the causality of all serious adverse events. In the event that the investigator 
does not know causality, for reporting purposes the adverse event should be considered to be related to the 
investigational product. 
 
 
9.4. 
Intensity assessment 
 
For all AR observed the investigator will use the following definitions to rate the intensity of any AR 
collected during the study in the EDC:  


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- 
Mild: that which does not cause limitation in daily activities.  
- 
Moderate: that which causes some limitation in the performance of daily activities.  
- 
Severe: that which prevents the performance of daily activities. 
 
9.5. 
Severity assessment 
 
AR should also be classified on the basis of their severity. In general, if they meet any of the following 
criteria should be considered serious adverse reactions: 
 
- 
Life-threatening.  
- 
Requiring hospitalization or prolongation of an existing hospitalization.  
- 
Causing permanent or significant disability or incapacity.  
- 
Result in congenital anomaly or malformation.  
- 
Considered medically important, understood as that which requires urgent intensive treatment to 
avoid one of the outcomes. 
 
9.6. 
Expectancy assessment 
 
An AE not listed in the drug label.  
 
 
9.7. 
Safety recording procedure 
 
Researcher team should record all AR specifying the date of initiation, intensity, severity, action taken and 
outcome. If any treatment is given for the AR, it should be recorded in the EDC. All ARs should be recorded 
in each subject's EDC. 
 
 
9.8. 
Safety reporting procedure 
 
The investigator will immediately report all AR to the sponsor (always within 24 hours of knowledge) on 
the form designed for this purpose (Reporting Form). This form, after being completed and signed by a 
member of the researcher team, will be sent in paper format by fax to the Clinical Trials Unit of the Hospital 
Universitario Ramón y Cajal (Fax number: +34 917 291 890, Unidad de Ensayos Clínicos, Hospital 
Universitario Ramón y Cajal, 7ª planta Izquierda, Carretera de Colmenar Viejo Km 9.100, 28034, Madrid). 
The initial communication will be followed by detailed written communication. The investigator must 
follow up all the AR until resolution, return to baseline or stabilization in case of permanent involvement. 
Initial and follow-up communications should identify trial subjects by a specific code number. The sponsor 
will keep a detailed record of all AR reported by the researchers. These records should be submitted to the 
AEMPS and the IRB/IEC upon request. The notification period will be from the moment the patient signs 
the informed consent until 30 days after the administration of the last dose. After this period, only those 
serious AR related to the study medication of which the investigator is aware should be reported to the 
sponsor. 
 
Report of suspected serious AR and unexpected AR 
 
The sponsor will notify all the suspected serious and unexpected adverse reactions associated with the 
product to the AEMPS (Agencia Española de Medicamentos y Productos Sanitarios) Clinical Trials Area 
of the Department of Medicines for Human Use; the Ethics Committee involved and the Autonomous 
Communities delegates where the clinical trial is performed. Notification period will be 15 days, except 
when the suspected AR has caused the death of the subject, or endangered his life, which will be 
communicated within 7 days after its knowledge. 


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9.9. 
Follow-up plan 
 
When an AR occurs, it will be recorded as specified in this protocol and the patient will be followed-up 
until it is considered resolved. 
 
 
9.10. 
Notification of other safety information 
 
The sponsor should also report any information that could change the benefit of the research product or that 
could lead to changes in the schedule of administration of the trial, such as: 
 
- 
A qualitative change or an increase in the percentage of occurrence of unexpected and severe AR. 
- 
Unexpected and severe AR occurring after completion of the trial and reported by the investigator 
to the sponsor. 
- 
New events related to the conduct of the trial or the development of the research product and likely 
to affect patient safety such as: AR that may be associated with the trial procedures and may 
modify the conduct of the trial, lack of efficacy in a drug used for the treatment of a life-threatening 
disease, new safety findings from new animal studies (such as carcinogenicity), any premature 
termination or temporary halt of a clinical trial with the same research product for safety reasons, 
conducted in another country by the same sponsor, any recommendation from the Data Monitoring 
Committee that is relevant to patient safety. This information will be notified as soon as possible 
and no later than 15 days after the sponsor has become aware of it. Additional information will 
also be notified as soon as possible. 
 
 
9.11. 
Annual safety reports 
 
The annual safety reports, which will include the RAGIs collected in the study, will be sent by the sponsor 
to the AEMPS (Clinical Trials Area of the Sub-Directorate General for Medicinal Products for Human 
Use), the Autonomous Regions and the CEICs involved, within the deadlines established in the legislation 
in force. 
 
 
9.12. 
Notification to investigators 
 
The sponsor should notify the researcher of any information that could affect the safety of the trial subjects 
as soon as possible. The information on unexpected and severe AR will be sent annually in a list together 
with a brief analysis of the data provided. Researchers will also be informed of any safety issues impacting 
the conduct of the clinical trial or product development, including discontinuation of the development 
program or safety-related protocol modifications. 
 
 
9.13. 
Access to the randomization code during the trial 
 
In case of adverse events, the treatment assignment number from the randomization code list will be 
disclosed under special circumstances. If possible, the delegate should be contacted before the number is 
disclosed. Each patient will have a randomization code which contains the treatment assignment. It should 
be kept in a safe place throughout the clinical trial. The researcher is responsible for the integrity of the 


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randomization list. If a treatment assignment is unblinded, the researcher will record the date and reason in 
the EDC. Unblinding should not be a reason for withdrawal the product or the patient from the study. 
 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. 
Sample size calculation 
 
The sample size of the trial was calculated to be able to show the non-inferiority of oral sodium chloride to 
intravenous prophylaxis with regard to the primary study endpoint in outpatients undergoing a contrast-
enhanced CT scan. The calculation was based on an expected PC-AKI incidence of 7% in the intravenous 
arm and 12% in the oral arm. Accordingly, considering a non-inferiority margin of 5%, a power of 80% 
and a one-sided p-value of 0.025, the required sample size is 266 patients, 133 per arm.  
 
10.2. 
Randomization and treatment assignment 
 
The randomization process will be carried out by blocks of size six, in order to guarantee a balance in the 
study arms. Treatment assignment will be performed by opening numbered, sealed, opaque envelopes that 
describe inside whether the patient has been assigned to intravenous or oral NaCl prophylaxis 
10.3. 
Statistical methods 
 
A description of the study sample stratified by randomly assigned treatment will be made. Categorical 
variables will be described by absolute and relative frequencies. Quantitative variables will be described by 
the mean and standard deviation (or median and interquartile range in the case of highly asymmetric 
distributions). For the analysis of the primary endpoint of the study, the univariate comparison of the 
proportions of PC-AKI events within 48 hours after intravenous contrast administration in both arms will 
be carried out. The 95% confidence interval of the difference in proportions will be calculated and displayed 
graphically. All analyses will be intention-to-treat and per-protocol. For the main objective a p-value less 
than 0.025 (unilateral) will be considered as statistically significant. All other group comparisons will be 
of an exploratory nature. Subgroup analyses will be performed for the risk factors defined as inclusion 
criteria. For exploratory contrasts, a p-value less than 0.05 (two-sided) will be considered as statistically 
significant.  
 
10.4. 
Missing data 
 
The impact of missing data in the main outcome will be analyzed by sensitivity analysis. Participants whose 
main variable has not been collected will be assumed to have a PC-AKI event for both arms, only for the 
oral group, and only for the intravenous group. 
 
10.5. 
Deviations from the statistical plan 
 
Any deviation from the statistical plan will be communicated to the IRB and the AEMPS and its approval 
will be requested by means of an amendment. 


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10.6. 
Selection of subjects for analysis 
 
All analyses will be by intention to treat and by protocol. Since the study is a non-inferiority study, the main 
analysis will be per protocol. 
 
 
 
11. ACCESS TO SOURCE DATA AND DOCUMENTS 
 
All data collected for the study will be kept in the participating departments, in paper and electronic format. 
Clinical histories will be filed according to regulations or procedures established in the hospital. Data 
collected for the study will be identified by a code and only the principal researcher will be able to associate 
these data to the patient. Data will be included in a database that complies with Law 15/1999 on Personal 
Data Protection. Likewise, the transmission of data will be done with the appropriate security measures in 
compliance with that law and R.D. 1720/2007. Only the information from clinical history that is related to 
the study will be subject to verification. The research team is responsible for maintaining confidentiality. 
Only the sponsor, study physician/collaborators, health authorities (Spanish Agency of Medicines and 
Medical Devices), Clinical Research Ethics Committee and personnel authorized by the sponsor may check 
information always maintaining confidentiality in accordance to current legislation. Patients’ identity will 
not be revealed if the results of the study are published. 
 
12. QUALITY CONTROL AND ASSURANCE 
 
Monitoring visits 
At least 2 monitoring visits will be made during the study to ensure that all aspects of the protocol are 
followed. Source documents will be reviewed verify the information recorded in the EDC. Source 
documents are the original documents, data, and records. The investigator will ensure that the sponsor or 
the sponsor's representative have access to source documents. Documentation and aspects of the trial that 
can be reviewed: researcher's file, trial medication, medical records, informed consent, EDC and associated 
source documents. It is important that the researcher and study personnel are available during monitoring 
visits.  
Independent on-site monitoring will be performed by the Unit of Clinical Research and Clinical Trials 
(UICEC) of Hospital Universitario Ramón y Cajal, ISCIII National Network (SCReN). 
 
Health Authorities audits  
This study may be audited by the health authorities, AEMPS. If a health authority contacts the trial site for 
an inspection, the sponsor should be informed immediately. The researcher should guarantee the auditors 
access to all study documents for quality assurance. 
 
 
13. ETHICAL ASPECTS 
 
13.1. 
General and specific rules for the investigators 
 


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The investigators will strictly abide by the provisions of this protocol, filling out the data collection sheets, 
which will be sent in time to the sponsor or to the collaborating entity to analyze it. The trial will be carried 
out in accordance with the recommendations for clinical trials and evaluation of drugs in human, which 
appear in the Declaration of Helsinki (appendix A), revised in Tokyo, Venice, Hong Kong, South Africa, 
Edinburgh and Seoul (2008) and in the current Spanish legislation on clinical trials. 
 
 
13.2. 
Informed consent 
 
All participating subjects will be informed and give their written consent before starting the study.. The 
volunteer will be given a copy of this informed consent sheet. 
 
 
13.3. 
Security and confidentiality arrangements 
 
The information obtained by the implementation of the present study is considered confidential and should 
be treated as such at all times. The subjects of the study will be identified only with their subject code. In 
case of publication of the results of the study, the identity of the volunteers will not be revealed. 
 
 
13.4. 
Content of the trial budget 
 
The financial compensation to the trial researchers is specified in the financial report, which is included as 
an appendix. 
 
 
13.5. 
Insurance 
 
The Foundation for Biomedical Research of Hospital Universitario Ramón y Cajal has a civil liability 
insurance policy in accordance with Royal Decree 223/2004, which will provide compensation and 
indemnity to the participating subjects in case of damage to their health or injuries that may occur. In 
addition, this policy covers the responsibilities of the promoter, the research team and the Hospital 
Universitario Ramón y Cajal. 
 
 
14. PRACTICAL CONSIDERATIONS 
 
14.1. 
Responsibilities of the participants of the clinical trial 
 
The investigators will follow the Good Clinical Practice guidelines and Service's standard operating 
procedures. All information collected during the trial should be recorded directly in the eDC. When a 
correction is made, date and initials of the person making the correction should be noted. Auxiliary 
personnel will follow the instructions given by the researcher regarding the extraction of blood samples and 
other complementary explorations. Patients should receive oral and written information regarding the 
design, purpose of the study and possible risks that may arise from it before enrolling in the trial. To 
participate in the study, they must sign their consent, although they can revoke it at any time and for any 


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reason. Patients will receive instructions to strictly respect the instructions. They will be informed of the 
need to contact if any incident arises during the study. 
 
 
14.2. 
Deviations from the protocol 
 
The researcher present in such circumstances will fully document the deviation and the reason in the EDC. 
When the deviation is related to inclusion/exclusion criteria, researchers will contact the clinical monitor 
by telephone to inform of the deviation. 
 
 
14.3. 
Storage of the study file 
 
All data will be kept on paper and in electronic form during 15 years after the end of the study.  
 
This file should contain the following elements: 
1. IRB/IEC approval of the protocol and informed consent form. 
2. Copy of the written consent form and approved protocol with any amendments if 
applicable. 
3. Any correspondence regarding the study with the sponsor, during the course of the study. 
4. Any correspondence with the IRB/IEC. 
5. List of IRB/IEC members who approved the study protocol. 
6. Signed acceptance of the protocol. 
7. Curriculum vitae of the research team. 
8. Record of signatures of the members of the research team. 
9. Serious AR communications. 
10. Contract between the sponsor and the research team. 
11. List of patients. 
12. Copies of the EDC.  
 
The documentation will be filed following the standard procedures of the Internal Medicine Department. 
 
 
14.4. 
Sample identification 
 
The study medication will be provided by the sponsor, and will be labeled according to recommendations 
of Royal Decree 223/2004. 
 
 
14.5. 
Amendments to the protocol 
 
Neither the investigator nor the monitor or the sponsor will modify this protocol without first obtaining the 
consent of the other parties. The modification should be documented in writing. Any changes in the research 
activity, except those necessary to eliminate an immediate apparent risk to the patient, should be reviewed 
and approved by the IRB/IEC prior to implementation. Amendments to the protocol should be submitted 
by the sponsor to the health authorities, and modifications may require review and approval by the IRB/IEC. 
 
 
14.6. 
Acceptance by the investigator 
 
The investigator commitment statement is included in section 2. 


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14.7. 
Conditions for publication 
 
The results derived from the present study will be published; the approval of the investigators and the 
sponsor will be required. The monitor and the sponsor should have a copy of the manuscript to be published 
15 days before it is sent to the editor. Likewise, the confidentiality of the patient's identity will always be 
respected. The study sponsor undertakes to publish the results, whether positive or negative. 
 
 
15. APPENDICES 
 
APPENDIX A. WMA DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI - Ethical Principles for Medical 
Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th 
WMA General Assembly, Tokyo, Japan, October 1975. 35th WMA General Assembly, Venice, Italy, 
October 1983. 41st WMA General Assembly, Hong Kong, September 1989. 48th WMA General Assembly, 
Somerset West, Republic of South Africa, October 1996. 52nd WMA General Assembly, Edinburgh, 
Scotland, October 2000. 53rd WMA General Assembly, Washington 2002 (Note of Clarification on 
paragraph 29 added). 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 
added). 59th WMA General Assembly, Seoul, October 2008. 
 
INTRODUCTION 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human 
material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be 
applied without consideration of all other relevant paragraphs. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in 
medical research involving human subjects to adopt these principles. 
It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment of 
this duty. 
The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will 
be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall 
act in the patient's best interest when providing medical care." 
Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
In medical research involving human subjects, the well-being of the individual research subject must take 
precedence over all other interests. 


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The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human subjects and protect their 
health and rights. Some research populations are particularly vulnerable and need special protection. These 
include those who cannot give or refuse consent for themselves and those who may be vulnerable to 
coercion or undue influence. 
Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No national 
or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections 
for research subjects set forth in this Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, 
right to self-determination, privacy, and confidentiality of personal information of research subjects. 
Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research 
must be respected. 
Appropriate caution must be exercised in the conduct of medical research that may harm the environment. 
The design and performance of each research study involving human subjects must be clearly described in 
a research protocol. The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest, 
incentives for subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe arrangements for post-
study access by study subjects to interventions identified as beneficial in the study or access to other 
appropriate care or benefits. 
The research protocol must be submitted for consideration, comment, guidance and approval to a research 
ethics committee before the study begins. This committee must be independent of the researcher, the 
sponsor and any other undue influence. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research subjects 
set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the committee. 
Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the supervision of 
a competent and appropriately qualified physician or other health care professional. The responsibility for 
the protection of research subjects must always rest with the physician or other health care professional and 
never the research subjects, even though they have given consent. 
Medical research involving a disadvantaged or vulnerable population or community is only justified if the 
research is responsive to the health needs and priorities of this population or community and if there is a 
reasonable likelihood that this population or community stands to benefit from the results of the research. 
Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in comparison 


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with foreseeable benefits to them and to other individuals or communities affected by the condition under 
investigation. 
Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject. 
Physicians may not participate in a research study involving human subjects unless they are confident that 
the risks involved have been adequately assessed and can be satisfactorily managed. Physicians must 
immediately stop a study when the risks are found to outweigh the potential benefits or when there is 
conclusive proof of positive and beneficial results. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects. 
Participation by competent individuals as subjects in medical research must be voluntary. Although it may 
be appropriate to consult family members or community leaders, no competent individual may be enrolled 
in a research study unless he or she freely agrees. 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information and to minimize the impact of the study on their physical, mental and social integrity. 
In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it 
may entail, and any other relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the potential 
subject's freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be formally documented and witnessed. 
For medical research using identifiable human material or data, physicians must normally seek consent for 
the collection, analysis, storage and/or reuse. There may be situations where consent would be impossible 
or impractical to obtain for such research or would pose a threat to the validity of the research. In such 
situations the research may be done only after consideration and approval of a research ethics committee. 
When seeking informed consent for participation in a research study the physician should be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent should be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has no 
likelihood of benefit for them unless it is intended to promote the health of the population represented by 
the potential subject, the research cannot instead be performed with competent persons, and the research 
entails only minimal risk and minimal burden. 
When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject's dissent should be respected. 
Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research population. In such circumstances the physician should 
seek informed consent from the legally authorized representative. If no such representative is available and 
if the research cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research ethics committee. 


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Consent to remain in the research should be obtained as soon as possible from the subject or a legally 
authorized representative. 
Authors, editors and publishers all have ethical obligations with regard to the publication of the results of 
research. Authors have a duty to make publicly available the results of their research on human subjects 
and are accountable for the completeness and accuracy of their reports. They should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published 
or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to 
believe that participation in the research study will not adversely affect the health of the patients who serve 
as research subjects. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
current proven intervention, except in the following circumstances: 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; 
or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to 
determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment 
will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse 
of this option. 
At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome 
of the study and to share any benefits that result from it, for example, access to interventions identified as 
beneficial in the study or to other appropriate care or benefits. 
The physician must fully inform the patient which aspects of the care are related to the research. The refusal 
of a patient to participate in a study or the patient's decision to withdraw from the study must never interfere 
with the patient-physician relationship. 
In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, 
after seeking expert advice, with informed consent from the patient or a legally authorized representative, 
may use an unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. Where possible, this intervention should be made the object of 
research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available. 
 
 
APPENDIX B. ADVERSE REACTION REPORTING 
 
GENERAL INSTRUCTIONS 
1. This form is to be used only for reporting suspected unexpected serious adverse reactions (ARs) occurring 
with investigational drugs. Both the specific investigational product and the control product are considered 
investigational drugs. 
2. Suspected fatal or life-threatening adverse reactions (those that without immediate therapeutic 
intervention would have resulted in the death of the patient) should be reported within a maximum of 7 
calendar days; if not all information is available, it may be completed within an additional 8 days. Other 
suspected serious and unexpected adverse reactions should be reported within a maximum of 15 days. 


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3. When the space available is insufficient, an additional information sheet should be added, correctly 
identified with the name of the sponsor and the number assigned to the notification. This additional 
information may include the causality assessment carried out by the reporting technician. 
 
SPECIFIC INSTRUCTIONS 
1. The protocol code is the code assigned by the sponsor to identify the assay. The sponsor's notification 
number is the one used by the sponsor for archiving. In the case of follow-up information, the same number 
should be used or, if changed, the number of the initial notification should be indicated. The shaded 
"Notification No." space should be left blank. 
2. The age should be given in years, months, weeks or days as appropriate, but always indicating it. If the 
age is not known precisely, at least the age group to which it belongs should be stated (e.g., infant, child, 
adolescent, adult, elderly). 
7. The adverse reaction should be described in full, indicating the date on which it ended and including the 
results of any complementary examinations or laboratory tests considered to be of interest. This notification 
may be accompanied by any reports deemed appropriate for the proper interpretation of the clinical picture 
suspected of being an adverse reaction. 
8-13. The categories are not mutually exclusive. Attendance in an Emergency Department of a Hospital for 
less than 24 hours shall not be considered hospitalization. 
14. Investigational medicinal products should be identified preferably by their generic name (DOE or INN), 
indicating when available the trade name, or alternatively, by the proposed name or laboratory code for the 
product.  
15. In case the administration is not daily, it should be described with one of the following possibilities: 
cyclic, weekly, monthly, yearly or number of times it has been used (in this case, the dose of each intake, 
not the total). 
 
17. The pathological process of the patient for whom the investigational product is intended, or "healthy 
volunteer" in case of such a patient, should be stated. 
19. The duration of the treatment until the onset of the adverse reaction should be stated. 
22. It should be explicitly indicated if no concomitant drugs have been taken. If any of the concomitant 
drugs are considered suspicious, they should be marked with an asterisk (e.g.: * AMOXICILLIN). Drugs 
used to treat the adverse reaction will be excluded. 
 
SUSPECTED ADVERSE REACTION NOTIFICATION 
NOTIFICATION OF SUSPECTED REACTION FOR 
INVESTIGATIONAL MEDICINAL PRODUCTS 
PROTOCOL CODE (sponsor) 
NOTIFICATION No. (Sponsor) 
 
 
PATIENT ID 
NOTIFICATION No. 
 
 
 
I. 
ADVERSE REACTION INFORMATION 
 


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1a.  
COUNTRY 
2. DATE OF BIRTH 
2a. AGE 
3.  SEX 
3a.  
WEIGHT 
3b.  
HEIGHT 
4-6.  START DATE OF THE 
REACTION 
DAY 
 
 
MONTH 
 
 
YEAR 
 
 
 
MALE 
 
FENALE 
 
 
DAY 
 
 
MONTH 
 
 
YEAR 
 
 
7.  DESCRIPTION OF ADVERSE REACTION (Including relevant examination or laboratory results, 
and date of completion, if applicable). 
8-13b. SEVERITY/OUTCOME CRITERIA 
 
   DEATH 
 
   THE PATIENT'S LIFE HAS BEEN  
      HAS BEEN THREATENED 
 
   HOSPITALIZATION 
 
   PROLONGED HOSPITALIZATION 
 
   PERMANENT 
OR 
SIGNIFICANT 
DISABILITY 
 
   CLINICALLY 
RELEVANT 
ADVERSE 
REACTION 
 
   PERSISTENCE OF ADVERSE REACTION 
 
   RECOVERY 
 
 
II. INVESTIGATIONAL DRUG INFORMATION 
 
14.  SUSPECTED DRUG 
15.  
DAILY 
DOSE 
16.  VIA  
17. 
 
DISEASE 
UNDER 
STUDY 
18.   
START/END DATE 
 
19.  
TREATMENT 
DURATION 
 
 
 
 
 
 
 
 
 
20. DID THE REACTION RECUR WHEN THE 
MEDICATION WAS DISCONTINUED? 
20a. DID THE REACTION REMIT ON 
REDUCTION OF DOSAGE? DOSE? 
21. DID THE REACTION REAPPEAR 
WHEN 
THE 
MEDICATION 
WAS 
ADMINISTERED AGAIN? 


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YES 
NO 
NOT APPLICABLE 
YES 
NO 
NOT APPLICABLE 
YES 
NO 
NOT APPLICABLE 
 
III. CONCOMITANT MEDICATIONS AND MEDICAL HISTORY 
 
CONCOMITANT DRUGS (Mark with an asterisk 
the suspected drug(s)) 
22a.  DAILY 
DOSE 
22b.  
VIA 
22c.  START7END DATE 
22d.  INDICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23.  IMPORTANT DATA FROM THE CLINICAL HISTORY (e.g., diagnoses, allergies, pregnancies, etc.) 
 
 
 
 
 
IV. SPONSOR AND INVESTIGATOR INFORMATION 
 
24a. NAME AND ADDRESS OF SPONSOR 
 
 
24b. NAME AND ADDRESS OF INVESTIGATOR 
24c. LABORATORY CODE 
 (AEM No.) 
25a. REPORT TYPE 
INITIAL 
FOLLOW-UP 
24c. SPONSOR’S TECHNICIAN REPORTING 
NAME: 
PHONE: 
SIGNATURE: 
24e. REPORT DATE 
 
24f. DATE OF ENTRY AT AEM 
25b. SUPPLEMENTARY REPORT ATTACHED 
 
 


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APPENDIX C. SODIUM CHLORIDE ADMINISTRATION SCHEDULE 
ACCORDING TO WEIGHT 
 
With each oral dose, 250 mL of water should be administered, ensuring a minimum daily intake 
of 750 ml of water. 
WEIGHT (Kg) 
and total dose 
IV ADMINISTRATION 
(NaCl 0.9%) 
ORAL ADMINISTRATION  
(NaCl capsules 500 mg)* 
 
50 - <55 
 
85 mEq 
 
550 mL 
 
1 hour pre-test        150 mL 
0-4 hours post-test    400 mL 
5 g (10 capsules) 
 
48 hours pre-test        1 capsule 
40 hours pre-test        1 capsule 
32 hours pre-test        1 capsule 
24 hours pre-test        1 capsule 
16 hours pre-test        1 capsule 
  8 hours pre-test          2 capsules 
       0 hours                   2 capsules 
12 hours post-test      1 capsule 
 
55 - <60 
 
93,5 mEq 
605 mL 
 
1 hour pre-test         165 mL 
0-4 hours post-test    440 mL 
5.5 g (11 capsules) 
 
48 hours pre-test        1 capsule 
40 hours pre-test        1 capsule  
32 hours pre-test        1 capsule 
24 hours pre-test        1 capsule 
 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
      0 hours                       2 capsules 
12 hours post-test      1 capsule 
 
 
60 - <65 
 
102 mEq 
660 mL 
 
1 hour pre-test         180 mL 
0-4 hours post-test    480 mL 
6 g (12 capsules) 
 
48 hours pre-test        1 capsules 
40 hours pre-test        1 capsules 
32 hours pre-test        1 capsules 
 24 hours pre-test        2 capsules 


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 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
      0 hours                       2 capsules 
12 hours post-test      1 capsule 
 
65 - <70 
 
110,5 mEq 
715 mL 
 
1 hour pre-test         195 mL 
0-4 hours post-test    520 mL 
6.5 g (13 capsules) 
 
48 hours pre-test        1 capsule 
40 hours pre-test        1 capsule 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
      0 hours                       2 capsules 
12 hours post-test      1 capsule 
 
70 - <75 
 
119 mEq 
770 mL 
 
1 hour pre-test         210 mL 
0-4 hours post-test    560 mL 
7 g (14 capsules) 
 
48 hours pre-test        1 capsule 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
      0 hours                       2 capsules 
12 hours post-test      1 capsule 
 
75 - <80 
 
127,5 mEq 
825 mL 
 
1 hour pre-test         225 mL 
0-4 hours post-test    600 mL 
7.5 g (15 capsules) 
 
48 hours pre-test        1 capsule 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
      0 hours                       2 capsules 
 12 hours post-test      2 capsules 
 


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80 - <85 
 
136 mEq 
880 mL 
 
1 hour pre-test         240 mL 
0-4 hours post-test    640 mL 
8 g (16 capsules) 
 
 48 hours pre-test        2 capsules 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        2 capsules 
 8 hours pre-test          2 capsules 
     0 hours                   2 capsules  
12 hours post-test      2 capsules 
 
85 - <90 
 
144,5 mEq 
935 mL 
 
1 hour pre-test         255 mL 
0-4 hours post-test    680 mL 
8.5 g (17 capsules) 
 
48 hours pre-test        2 capsules 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        2 capsules 
 8 hours pre-test         3 capsules 
      0 hours                  2 capsules 
 12 hours post-test      2 capsules 
 
90 - <95 
 
153 mEq 
990 mL 
 
1 hour pre-test         270 mL 
0-4 hours post-test    720 mL 
9 g (18 capsules) 
 
48 hours pre-test        2 capsules 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules  
16 hours pre-test        2 capsules 
 8 hours pre-test          3 capsules 
      0 hours                   3 capsules 
 12 hours post-test      2 capsules 
 
95 - <100 
 
161,5 mEq 
1045 mL 
 
1 hour pre-test         285 mL 
9.5 g (19 capsules) 
 
48 hours pre-test        2 capsules 


PNIC-Na Protocol 
Date & Version No: 02-Aug-2013 V2.0 (ENG) 
 
38 
 
0-4 hours post-test    760 mL 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        2 capsules 
 16 hours pre-test        3 capsules 
 8 hours pre-test          3 capsules 
      0 hours                  3 capsules 
 12 hours post-test      2 capsules 
 
 
 
>100 
 
177 mEq 
1100 mL 
 
1 hour pre-test         300 mL 
0-4 hours post-test    800 mL 
10 g (20 capsules) 
 
48 hours pre-test        2 capsules 
 40 hours pre-test        2 capsules 
 32 hours pre-test        2 capsules 
 24 hours pre-test        3 capsules 
 16 hours pre-test        3 capsules 
 8 hours pre-test          3 capsules 
      0 hours                   3 capsules 
 12 hours post-test      2 capsules