Conditions: Hip Fractures
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
Prospective, low-level, non-commercial intervention, comparative clinical trial (phase IV) of balanced, randomized groups, to compare the analgesic efficacy of the local anesthetics Ropivacaine and Levobupivacaine in peripheral nerve block in hip fracture surgery in the elderly .

Detailed description:
There are several studies that try to identify the ideal anesthetic for the management and control of pain in hip fracture surgery in the elderly. The optimum would be to use an anesthetic with the lowest possible latency, since this will favor the start of surgery. And, at the same time, with a more lasting analgesia with the least motor impairment. Therefore, it is essential to collect data on efficacy (effective block that allows us to mobilize the patient), latency, and analgesic scales appropriate to the cognitive state of the study sample.

Arms:
arm 1: Patients treated with Levobupivacaine Altan 7.5 mg / ml solution for injection and infusion arm 2: Patients treated with Ropivacaine Altan 2 mg / ml solution for infusion

Interventions: intervention 1: Levobupivacaine intervention 2: Ropivacaine
Intervention descriptions: intervention 1: Local anaesthetic drug belonging to the amino amide group. It is the S-enantiomer of bupivacaine intervention 2: Local anaesthetic drug belonging to the amino amide group. The name ropivacaine refers to both the racemate and the marketed S-enantiomer.

Protocol document:
Prot_SAP_000.pdf: 
Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1 
 
TITLE: PHASE IV CLINICAL TRIAL, RANDOMIZED AND CONTROLLED ON THE 
ANALGESIC EFFICACY OF THE COMBINED BLOCK (PENG -PERICAPSULAR NERVE 
GROUP- AND OF THE FEMORAL LATERAL CUTANEOUS NERVE) IN HIP FRACTURES OF 
THE 
ELDERLY. 
COMPARATIVE 
STUDY 
BETWEEN 
LEVOBUPIVACAINE 
AND 
ROPIVACAINE. 
Protocol Code: PENG-CAD 
EudraCT Number: 2020-004697-21 
Version Number: 1 
Release Date: September 1, 2020 
 
Development phase: IV, low level of intervention 
 
Promoter: IBSAL 
 
Principal Investigator: Agustín Díaz Álvarez 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
2 
 
 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
3 
 
 
 
 
PENG-CAD Protocol 
 
I have read this protocol and agree to supervise and direct the conduct of this study in compliance with 
all the stipulations of the protocol and in accordance with the Directives on Good Clinical Practice of the 
International Conference on Harmonization (ICH) and the Declaration of Helsinki. 
 
 
 
Ms. María Lorenzo Santiago (Representative of the Promoter of the study) 
 
 
 
_ 
_ 
__ 
 
 
 
Signature 
Date 
 
 
 
Mr. Agustín Díaz Álvarez (Principal Investigator) 
 
 
 
_ 
_ 
 
  _ 
_ 
Signature 
 
Date 
 PROTOCOL SIGNATURES  PAGE 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
4 
 
 
 PROTOCOL TITLE: PHASE IV, RANDOMIZED AND CONTROLLED CLINICAL TRIAL ON THE ANALGESIC 
EFFICACY  OF THE COMBINED BLOCKADE (PENG -PERICAPSULAR NERVE GROUP- AND THE FEMORAL 
LATERAL CUTANEOUS NERVE) IN HIP FRACTURES OF THE ELDERLY. COMPARATIVE STUDY BETWEEN 
LEVOBUPIVACAINE AND ROPIVACAINE. 
 
Protocol Code: PENG-CAD 
EudraCT Number: 2020-004697-21 
CONFIDENTIALITY AND DECLARATION OF CONFORMITY OF THE PCBS 
I have read the protocol of the previous clinical study entitled: PHASE IV, RANDOMIZED AND CONTROLLED 
CLINICAL TRIAL ON THE ANALGESIC EFFICACY  OF THE COMBINED BLOCKADE (PENG -PERICAPSULAR NERVE 
GROUP- AND THE FEMORAL LATERAL CUTANEOUS NERVE) IN HIP FRACTURES OF THE ELDERLY. COMPARATIVE 
STUDY BETWEEN LEVOBUPIVACAINE AND ROPIVACAINE and I agree that it contains all the necessary 
information to carry out the study. 
I hereby confirm that I have thoroughly read and understood this clinical study protocol, and I agree 
that my staff and I will conduct the study in accordance with the protocol and comply with its 
requirements, including ethical and safety considerations. 
I understand that if the Promoter decides to terminate or suspend the study prematurely for any 
reason, such decision will be communicated to me in writing. On the other hand, if I decide to 
withdraw from the implementation of the study, I will immediately communicate that decision to the 
Sponsor. 
I agree not to publish any portion of the results of the study conducted under this clinical study 
protocol without the prior written consent of the Sponsor. 
 
 
Principal Investigator: Agustín Díaz Álvarez 
Hospital Center: University Healthcare Complex of Salamanca 
 
 
 
 
 
 
 
Signature  
Date 
 
 
 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto de 
Investigación Biomédica de Salamanca (IBSAL) 
University Hospital of Salamanca 
Virgen de la Vega Building, 10th floor Pº San Vicente, 55-182.  
37007 Salamanca 
  MAIN INVESTIGATOR SIGNATURE PAGE 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
5 
 
 
PROTOCOL SIGNATURES PAGE3 
 
PRINCIPAL INVESTIGATOR'S SIGNATURE HOME PAGE4 
 
INDEX OF FIGURES7 
 
ABBREVIATIONS8 
 
1. SUMMARY AND GENERAL INFORMATION10 
  
1.1. TYPE OF REQUEST 
10 
1.2. IDENTIFICATION OF THE PROMOTER  
10 
1.3. CLINICAL TRIAL TITLE  
10 
1.4.  PROTOCOL CODE 
10  
1.5.  PRINCIPAL INVESTIGATOR 
10 
1.6. CENTRES WHERE THE STUDY IS PLANNED 
10 
1.7. CEIM 
10 
1.8.  RESPONSIBLE FOR MONITORING 
10  
1.9. DESCRIPTION OF THE PRODUCTS OF ESTUDIO 
10 
1.10. CLINICAL TRIAL PHASE 
10 
1.11. OBJECTIVES 
11 
1.12. STUDY DESIGN 
11 
1.13.  STUDY DISEASE 
11 
1.14. STUDY VARIABLES 
11 
1.15. STUDY POPULATION AND TOTAL NUMBER OF PATIENTS 
11 
1.16. DURATION OF TREATMENT 
11 
1.17. CLINICAL  TRIAL SCHEDULE 
11 
1.18.  COLLABORATING RESEARCHERS OF THE TRIAL 
12 
2.  INTRODUCTION14 
2. JUSTIFICATION FOR THE STUDY 
15 
2.1.   STUDY PERTINENCE15 
 
2.2   STUDY DRUGS  
15 
2.2.1 Ropivacaine 
15 
2.2.2 Levobupivacaine 
16
 
INDEX 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
6 
 
2.3. JUSTIFICATION OF THE SELECTED VARIABLES 
17 
3. ASSUMPTIONS AND OBJECTIVES 
18 
3.1. HYPOTHESES: 
18 
3.2. OBJECTIVES: 
18 
3.2.1. MAIN: 
18 
3.2.2. SECONDARY: 
18 
4. TYPE OF STUDY 
18 
5. JUSTIFICATION FOR LOW LEVEL OF INTERVENTION 
18
 
6. MATERIAL AND METHODS 
19 
6.1. SCOPE OF STUDY 
19 
6.2. STUDY PERIOD AND RECRUITMENT PLAN 
19 
6.3.   INCLUSION CRITERIA 
19 
6.4.  EXCLUSION CRITERIA 
19 
6.5.   RANDOMIZATION PROCESS 
19 
6.6. WITHDRAWAL CRITERIA FOR STUDY SUBJECTS 
20 
6.7. MEASUREMENTS 
20 
6.8.  ANESTHETIC PROTOCOL 
20 
6.9. JUSTIFICATION OF SAMPLE SIZE 
21  
6.10.  STATISTICAL ANALYSIS 
21 
6.11. EFFECTIVENESS ASSESSMENT 
21 
6.12. POLICY REGARDING INTERMEDIATE ANALYSES AND CRITERIA FOR EARLY COMPLETION OF THE 
TRIAL.  
22 
6.13. ASSESSMENT OF ADVERSE EFFECTS 
22 
6.13.1-Definition of Adverse Event: 
22 
6.13.2-Classification of Adverse Events: 
22 
6.13.3-Relationship with treatment: 
23 
6.14. DATA AND DOCUMENTS SOURCE 
24 
6.14.1.  MEDICAL HISTORY 
24 
6.14.2. WHAT IS CONSIDERED A SOURCE DOCUMENT IN THIS ESSAY 
24
 
6.14.3 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
24


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
7 
 
INDEX OF FIGURES 
 
6.14.4 QUALITY CONTROL AND ASSURANCE 
24
 
7. ETHICAL AND LEGAL ASPECTS AND OBTAINING INFORMED CONSENT 
25
 
8. DATA PROTECTION AND CONFIDENTIALITY 
26
 
9.    PROTOCOL CHANGES 
26 
10. ANALYSIS AND COMMUNICATION OF RESULTS 
26
 
ANNEX I. - ANESTHETIC PROTOCOL 
28
 
 
ANNEX II.-   ANALGESIC RESCUE TREATMENT: 
28 
ANNEX II.-  PAIN  ASSESSMENT SCALES 
29
 
 
ANNEX III. DATA COLLECTION NOTEBOOK 
31
 
 
BIBLIOGRAPHY 
32
 
 
 
 
 
 
 
 
 
 
Figure 1. Visual Numerical Scale ................................................................................................................. 29 
 
Figure 2. Algoplus Scale .............................................................................................................................. 29 
 
Figure 3. PAINAD30 scale ........................................................................................................................... 30 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
8 
 
 
 
 
AAG: Serious Adverse Event 
 
AEMPS: Spanish Agency for Medicines and Health Products 
NSAIDs: Non-Steroidal Anti-Inflammatory 
AL: Local Anesthetic 
 
ASA: American Society of Anesthesiologist 
BPC: Good Clinical Practice 
BCFI: Iliac Fascia Compartment Block BNF: Femoral 
Nerve Block 
BNFCL: Femoro Nerve BlockLateral Body CAUSE: 
University Care Complex of Salamanca CCAA: 
Autonomous Communities 
CEIC: Clinical Research Ethics Committee 
 
CEIM: Ethics Committee of Research with Medicines CRD: 
Data Collection Notebook 
CTCAE: Common Terminology Criteria for Adverse Events 
ECG: ElectroCardioGram 
EVN: Numerical Visual Scale 
 
IBSAL: Biomedical Research Institute of Salamanca ICCA: 
ItelliSpace Critical Care and Anesthesia 
ICH: International Conference on Harmonisation 
 
IECSCYL: Instituto de Estudios de Ciencias de la Salud de Castilla y León 
IQR: InterQuartil Range 
NFCL: Cutaneous Femoral Nerve Lateral 
NVPO: Postoperative Nausea and Vomiting 
PAINAD: Paint Assessment in Advanced Dementia 
PENG: PEricapsular Nerve Group 
SatpO2: Peripheral Oxygen Saturation 
ABBREVIATIONS 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
9 
 
SEDAR: Spanish Society of Anesthesiology, Resuscitation and Pain Therapeutics TA: 
Blood Pressure 
URPA:  Post-Anesthetic  Reuperation Unit 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
10 
 
1.1. TYPE OF APPLICATION 
1.2. IDENTIFICATION OF THE SPONSOR 
1.3. TITLE OF THE CLINICAL TRIAL 
1.4.  PROTOCOL  CODE 
1.5. MAIN INVESTIGATOR  
1.6. CENTRES WHERE  THE STUDY IS PLANNED  
1.7. CEIM 
1.8. RESPONSIBLE FOR  MONITORING  
1.9. DESCRIPTION OF  THE STUDY  PRODUCTS 
 
 
 
Non-commercial Phase IV clinical trial of low level of intervention. 
 
 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto de Investigación 
Biomédica de Salamanca (IBSAL). 
 
IECSCYL-IBSAL Foundation. 
 
 
Phase IV clinical trial randomized and controlled on the analgesic efficacy of the combined block (PENG -
pericapsular nerve group- and the femoral lateral cutaneous nerve) in hip fractures of the elderly. 
Comparative study between Levobupivacaine and Ropivacaine. 
 
 
PENG-CAD. 
 
 
Agustín Díaz Álvarez. Anesthesiology and Resuscitation Service. CAUSE. Biomedical Research Institute of 
Salamanca (IBSAL). 
 
 
University Care Complex of Salamanca. 
 
 
Ethics Committee of Research with Medicines Health Area of Salamanca. 
 
 
The sponsor shall designate the monitor to monitor the progress of the test 
 
Coordinator in the Promoter: Carmen Arias De La Fuente. Clinical Trials Area. IBSAL. 
 
 
Group R (Ropivacaine), Group L 
(Levobupivacaine) Route of administration: 
perineural ecoguided. 
 
1.10.  CLINICAL TRIAL PHASE 
1. SUMMARY AND GENERAL INFORMATION 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
10.11. OBJECTIVES 
1.12.  STUDY  DESIGN 
1.13.  STUDY  DISEASE 
1.14.  STUDY  VARIABLES 
1.15.   STUDY POPULATION AND TOTAL NUMBER OF PATIENTS 
1.16. DURATION OF PROCESSING 
Phase IV of low level of intervention. 
 
 
Main: To compare the analgesic efficacy of both local anesthetics in the regional blockade of hip fracture 
surgery in the elderly. 
 
Secondary: 1) Describe the behavior of this combined technique in hip fractures, establishing latency of 
onset and duration of analgesia. 
 
2) Describe the side effects derived from the described combined technique. 
 
 
Prospective clinical trial (phase IV) of low level of non-commercial intervention, comparative of 
balanced, randomized groups, to compare the analgesic efficacy of the local anesthetics Ropivacaine 
and Levobupivacaine in peripheral nerve block in hip fracture surgery of the elderly. 
 
 
The hip fracture of the elderly, subjected to both partial prostheses and endomedullary nailing. 
 
 
A. Main endpoint: duration of nerve block (analgesic efficacy of the two local anesthetics). 
 
B.  Secondary variables: 
 
1.  analgesia  latency 
 
2. duration of analgesia 
 
3. adverse effects of the drugs used 
 
4. scores of the analgesic scales: EVN, Algoplus, PAINAD. 
 
 
Patients over or equal to 65 years of age who are going to undergo hip surgery for fracture. 
 
The necessary sample size will be 108 patients, 54 patients per branch (Ropivacaine and Levobupivacaine), 
assuming 10% of losses. 
 
 
The duration of the treatment of each patient will be considered until the evaluation of the analgesic 
scale corresponding to the 48 h of the performance of the procedure. Patients may also be discontinued 
from the study at the discretion of the investigator at an earlier time or if they withdraw their consent at 
any time. 
 
 
 
 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
1.17. CLINICAL  TRIAL SCHEDULE 
1.18. COLLABORATING INVESTIGATORS  OF THE TRIAL 
 
From October 2020 until full recruitment. Approximately 15 patients/month will be recruited, which would 
mean a total of 7 months, that is, until April 2021. 
 
 
Mr. Alberto de Diego Fernández. Anesthesiology and Resuscitation Service. CAUSE. 
 
Mr. Daniel Escobar Macías. Anesthesiology and Resuscitation Service. CAUSE. 
 
Dr. D. José Luis González Rodríguez. Anesthesiology and Resuscitation Service. CAUSE. 
Ms. Rocío López Iglesias. Anesthesiology and Resuscitation Service. CAUSE. 
Mr. Daniel Salgado García. Anesthesiology and Resuscitation Service. CAUSE. 
 
Mr. Eduardo Sánchez López. Anesthesiology and Resuscitation Service. CAUSE. 
 
Mr. David Sánchez Poveda. Anesthesiology and Resuscitation Service. CAUSE. 
 
Mr. Ignacio Trejo González. Anesthesiology and Resuscitation Service.  CAUSE. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
 
 
The increase in life expectancy together with very low birth rates is causing an accelerated growth in the 
percentage of older people, which results in an increase in the aging of the population, especially in the 
industrialized world. In our country, the phenomenon of aging is even more accelerated, since in less 
than 30 years the number of people over 65 years of age has doubled. Current data in Spain show that 
the population over 65 years of age is around 17% of the total population, with more than 7 million 
people (National Institute of Statistics-INE, 2008), of which approximately 25% are octogenarians. As a 
consequence, it is increasingly common to find in clinical practice elderly patients who require 
treatment of diseases and complications that are typical of advanced age. 
 
Among these is the hip fracture, which presents a serious problem of morbidity and mortality for 
patients, and has a great impact on health costs due to both its treatment and the complications 
derived. It is estimated that there are 1.6 million fractures per year worldwide, with more than 610,000 
fractures per year in Europe, and in Spain 45,000 fractures occur annually in older people(1, 2) of 65 
years, being 80% over 75 years of age and with an associated annual mortality of about 30%(3,  4). Hip 
fracture is one of the most frequent surgical diagnoses in our environment. A very old and 
multipathological population, generally polymedicated and in which the presence of neurodegenerative 
diseases is not uncommon, makes it a very fragile population, which can sometimes have difficulty 
expressing its feelings, including pain, which is usually underdiagnosed(5). We must offer these patients 
an effective analgesic treatment from the first moment, avoiding the use of opioids and any drug that 
may deteriorate their cognitive faculties, and minimizing the use of usual analgesics (some of them, such 
as NSAIDs, can affect the control of blood pressure and already decreased renal function). Pain control 
in these patients is very important because it facilitates post-surgery recovery and early mobilization, 
and reduces the time of hospitalization after surgery, and the appearance of complications such as 
delirium, infections or thromboembolism(6). In addition, it accelerates the initiation of rehabilitation 
and functional recovery of elderly patients. 
 
The debate on the most appropriate anesthetic technique for the surgery of the hip fracture of the 
elderly is still valid, between general and neuraxial anesthesia(7-11), as well as the different peripheral 
blocks combined or not with general or neuraxial anesthesia(12-16). Different anesthetic techniques 
have been used, such as femoral nerve block -BNF-, iliac fascia compartment block -BCFI-, lateral 
cutaneous femoral nerve block -NFCL-, among others. Although all of them have been shown to be 
effective in the surgery of the hip fracture of the elderly, they are insufficient in analgesic control. 
 
Pain is a problem of special relevance in the elderly patient. It is estimated that between 50-80% of 
those over 65 years of age suffer some type of pain(17). Due to the presence of pluripathology and 
functional impairment, they become patients of great fragility who may also have cognitive impairment 
associated with them. In this type of patients the assessment of pain becomes complicated, being of 
enormous importance to be able to make a correct approach to the patient and achieve an adequate 
analgesic control. To all this, it is added that all scales and questionnaires have limitations, being 
convenient the assessment of more than one for the correct evaluation of the painful process(18-21). 
Thus, we will use 3 assessment scales: Visual Numerical Scale (EVN), Algoplus Scale (ALGSC), and Paint 
Assessment in Advanced Dementia Scale (PAINAD). 
2. INTRODUCTION 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
2. JUSTIFICATION OF THE STUDY 
2.1. RELEVANCE OF THE STUDY 
2.2 STUDY DRUGS   
2.2.1 ROPIVACAINE 
Since 2018, it has become popular to perform a technique known as PENG (pericapsular nerve group) 
that, because it affects only sensory endings, should not cause any degree of motor block of the affected 
nerves(22-25). This last aspect is of special interest, since muscle weakness due to femoral nerve block 
has traditionally been responsible for patients' falls when they begin postoperative ambulation. 
 
Despite evidence that peripheral nerve blocks, and PENG in this case, are beneficial to the patient, 
neither adequate doses nor local anesthetic (AL) have been determined(13, 23, 24, 26, 27). 
 
 
 
 
 
The realization of the PENG technique for the surgical management of the hip fracture of the elderly, 
has been incorporated into the usual practice, because it offers an adequate analgesia for the 
mobilization of the patient, makes it necessary to have a lower dose of local anesthetic in the spinal 
block, and achieves a correct postoperative analgesia,  allowing the early mobilization of the patient 
without pain. Although performing surgery requires the help of other anesthetic techniques, peng 
blockade allows us to use fewer doses of anesthetics intrathecally, which translates into better 
hemodynamic stability, both intra and postoperative. Likewise, the postoperative analgesia that it 
produces will avoid the consumption of concomitant analgesia, avoiding pharmacological interference, 
with less risk of toxicity, both hepatic and renal. 
 
We have at our disposal different local anesthetics that can be used in the nerve block, and, although 
with a series of common characteristics, they differ in some pharmacological aspects, which can be 
translated into the cynical one in that the selection of a certain local anesthetic can have an impact on 
the time of initiation of surgery,  in which better or worse analgesic control is achieved, and in which the 
duration of said analgesic is greater or lesser duration and intensity in the postoperative period. 
 
However, there is no scientific evidence of which local anesthetic is appropriate, nor what would be the 
ideal doses that would produce the balance between good analgesic control and minimal side effects. 
 
In addition, it is intended to validate the assessment of pain in the elderly by combining three scales: 
EVN, Algoplus, PAINAD. 
 
 
 
 
 
Ropivacaine is a long-acting local amide-type anesthetic with both analgesic and anesthetic effects, 
approved in our country since March 2012. At high doses it produces surgical anesthesia, while at low 
doses it causes a sensory block accompanied by a limited and non-progressive motor block. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
2.2.2 LEVOBUPIVACAINE 
The mechanism is a reversible reduction of the permeability of the nerve fiber membrane to sodium 
ions. As a consequence, the rate of depolarization decreases and the threshold necessary to produce 
excitation is increased, resulting in a local blockage of nerve impulses. 
 
The most characteristic property of ropivacaine is the prolonged duration of action. The onset and 
duration of action of local anesthetic efficacy depends on the site of administration and dose, but are 
not influenced by the presence of a vasoconstrictor agent (e.g. adrenaline (epinephrine)). 
 
Ropivacaine is indicated in the treatment of acute pain in adults and adolescents over 12 years of age in: 
Continuous epidural perfusion or intermittent bolus administration during the postoperative period or 
in labor pain; Peripheral locks; and Continuous peripheral nerve block by continuous infusion or 
intermittent bolus injections, e.g. treatment of post-surgical pain. 
 
For the treatment of postoperative pain, ropivacaine can be used for epidural block using an epidural 
catheter, so that adequate analgesia can be achieved with only a slight and non-progressive motor block 
in most cases of postoperative pain with a moderate to severe character. The maximum duration of the 
epidural block is 3 days, and a significant reduction in the need to use opioids has been observed. It can 
also be used in association with fentanyl for the treatment of postoperative pain for a period of up to 72 
hours. The combination of Ropivacaine and fentanyl may provide better pain relief, but cause side 
effects of opioids. 
 
Ropivacaine is well tolerated and does not require adjustment in patients with impaired renal function 
when administered for single-dose or short-term treatment. It is metabolised in the liver and should 
therefore be used with caution in patients with severe liver disease. Cytochrome P450 (CYP) 1A2 is 
involved in its metabolism, so potent CYP1A2 inhibitors, such as fluvoxamine and enoxacin, may interact 
with Ropivacaine and concomitant use should be avoided. 
 
The adverse reaction profile of Ropivacaine is similar to that of other long-acting local amide-type 
anaesthetics and varies by route of administration. The most frequently reported adverse reactions, 
nausea and hypotension, are very common during anesthesia and surgery in general and it is not 
possible to distinguish those produced by the clinical situation from those caused by the drug or 
blockage. In addition, common adverse reactions of paresthesias, dizziness, headache, bradycardia, 
tachycardia, hypertension, vomiting, stiffness, back pain, urine retention, temperature elevation, and 
chills have been reported. 
 
 
 
 
Levobupivacaine is a long-acting local amide-type anesthetic with both analgesic and anesthetic effects, 
approved in our country since November 2013. 
 
It works by blocking nerve conduction in sensory and motor nerves largely due to interaction with cell 
membrane voltage-gated sodium channels, but also blocks potassium and calcium channels. In addition, 
Levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on 
the cardiovascular and central nervous systems are the most important for the occurrence of clinical 
adverse reactions. The dose of Levobupivacaine is considered equipotente with bupivacaine. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
2.3. JUSTIFICATION OF THE SELECTED VARIABLES 
Levobupivacaine is indicated in adults in Major Surgical Anesthesia (e.g. epidural, intrathecal, peripheral 
nerve block) and Minor (e.g. local infiltration, peribulbar block in ophthalmic surgery) and for the 
treatment of pain (in continuous epidural perfusion, single or multiple bolus epidural administration for 
the treatment of pain, especially post-surgical pain). In analgesia (e.g. epidural administration for the 
treatment of pain) the lowest concentrations and doses are recommended. When deep or prolonged 
anaesthesia with complete motor block (e.g. epidural or peribulbar block) is required, the highest 
concentrations may be used. Careful aspiration is recommended before and during injection to avoid 
intravascular injection. 
 
The maximum dose should be determined by assessing the size and physical condition of the patient, 
along with the concentration of the drug and the area and route of administration. There is an individual 
variation in the onset and duration of the block. Experience gained in clinical trials shows that sensory 
block suitable for surgery occurs within 10-15 minutes after epidural administration, with a regression 
time in the range of 6-9 hours. In the treatment of post-surgical pain, the dose administered during 
surgery should be taken into account. When used for regional major nerve block, the lowest effective 
dose of local anesthetic should be used to avoid high plasma levels and serious adverse reactions. 
 
There are no relevant data on Levobupivacaine in patients with hepatic impairment, although it is 
metabolised in the liver, and should be used with caution in patients with liver disease or reduced 
hepatic blood flow. Levobupivacaine is extensively metabolized without detecting unchanged 
Levobupivacaine in urine or feces. 
 
There are no data in patients with renal impairment. It should be used with caution in debilitated 
patients, elderly patients or acute patients, and also in patients receiving antiarrhythmic drugs with local 
anaesthetic activity (e.g. mexiletine, or class III antiarrhythmic drugs) because its toxic effects may be 
additive. 
 
Experience on the safety of treatment with Levobupivacaine for more than 24 hours is limited. The 
adverse reaction profile of Levobupivacaine is similar to that of other local amide-type anesthetics. 
Adverse reactions with local amide-type anesthetics are rare, but may occur as a result of overdose or 
unintentional intravascular injection and may be serious. Some adverse reactions reported are very 
common during anaesthesia and surgery in general and it is not possible to distinguish those caused by 
the clinical situation from those caused by the drug or blockage. The most commonly reported adverse 
reactions are nausea and vomiting, hypotension, dizziness, headache, fever, pain during the procedure, 
or back pain. Cases of prolonged weakness or sensory disorders, some of which have been permanent, 
have been reported associated with treatment with Levobupivacaine. It is difficult to determine whether 
the long-term effects were the result of drug toxicity or unnoticed trauma during surgery or other 
mechanical factors, such as catheter insertion and manipulation. 
 
 
 
 
There are several studies that try to identify the ideal anesthetic for the management and control of 
pain from hip fracture surgery in the elderly. The optimal thing would be to use an anesthetic with the 
lowest possible latency, since this will favor the start of surgery. And, at the same time, with a more 
lasting analgesia with the least motor involvement. Therefore, it is essential to collect efficacy data 
(effective blockade that allows us to mobilize the patient), latency and analgesic scales appropriate to 
the cognitive state of the study sample. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
1
 
3.1. HYPOTHESIS: 
3.2. OBJECTIVES: 
3.2.1. MAIN: 
3.2.2. SECONDARY: 
4. TYPE OF STUDY 
5. JUSTIFICATION OF  LOW LEVEL OF INTERVENTION 
 
 
 
Levobupivacaine has advantages over Ropivacaine in the combined blockade (PENG - pericapsular nerve 
group- and the femoral lateral cutaneous nerve -BNFCL-) in hip fractures of the elderly, since a better 
analgesic control, similar latency period, and a longer analgesic duration are obtained. 
 
 
 
 
 
To compare the analgesic efficacy of both local anaesthetics in the regional 
blockade of hip fracture surgery. 
 
 
To describe the behavior of this combined technique in hip fractures, 
establishing latency of onset and duration of analgesia. 
Describe the side effects derived from the described combined technique. To 
validate in our population, especially in patients with cognitive impairment, the 
usefulness of the analgesic scales chosen. 
 
 
 
 
 
 
A phase IV study of low level of intervention, open, prospective, randomized and controlled is proposed 
that aims to compare the analgesic efficacy of the proposed locoregional anesthetic techniques (PENG 
AND BNFCL) with two of the most frequently used local anesthetics in patients with hip fracture 
(Levobupivacaine and Ropivacaine) to whom surgical osteosynthesis (endomedullary interlocking or hip 
hemiarthroplasty) will be performed. The study begins in the preoperative period, applying an 
anesthetic protocol in the operating room and then followed up for at least 48 hours in the 
postoperative period. 
 
The necessary sample size will be 108 patients, 54 patients per branch (Ropivacaine and 
Levobupivacaine). This figure could be increased to X patients in case of 10% losses due to complications 
during surgery. 
 
 
 
 
The medicines (Levobupivacaine and Ropivacaine) studied in this project are used in accordance with the 
authorised SmPC. 
3. HYPOTHESES AND OBJECTIVES 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
20 
 
6. MATERIAL AND METHODS 
6.1. SCOPE OF STUDY 
6.2.   STUDY PERIOD  AND RECRUITMENT PLAN 
6.3.  INCLUSION  CRITERIA 
6.4.   EXCLUSION CRITERIA 
In the present trial, no additional procedures are performed with respect to those that would have been 
performed on participants in the context of routine clinical practice, both in Spain and in the European 
Union and other international settings. 
 
 
 
 
Unicentric study, which will be carried out in the Anesthesiology and Resuscitation Service of the CAUSA. 
 
 
 
 
Start in October 2020 until the number of patients is completed. A rate of 15 patients/month is 
calculated, which means an expected completion in April 2021. 
 
Patients will be selected from among the elderly with hip fracture who come to causa. Patients will be 
provided with detailed informed consent in plain language for review and given sufficient time to 
answer all questions related to the study. After signing the consent, it will be checked if they are eligible 
for the study according to the inclusion and exclusion criteria. 
 
 
 
 
 
 
The patient will have to voluntarily sign and understand the informed consent that will be 
provided to him in writing. 
Patients over 65 years of age, with hip fracture, who are going to be operated on at the University 
Care Complex of Salamanca (CAUSA). 
 
 
 
 
Patients who meet any of the following exclusion criteria will not be eligible to participate in this study: 
 
Rejection of the technique. 
Allergy to any of the drugs. Coagulation 
disorders. Local infections instead of 
puncture. Vascular prostheses at the 
femoral level. 
 
 
 
 
 
 
 
 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
20 
 
6.5.   RANDOMIZATION PROCESS 
6.6   . WITHDRAWAL CRITERIA FOR   STUDY SUBJECTS 
6.7. MEASUREMENTS 
6.8.  ANESTHETIC PROTOCOL 
 
Randomization will be performed by means of a computer program (SPSS© v. 25.0) that generates two 
treatment groups and randomly assigns the selected patients to each of the groups in a simple random 
way (1:1). 
 
 
 
 
Patients will be removed from the trial when they meet any of the following criteria: 
 
Withdrawal of consent 
Complications during surgery that in the opinion of the researcher invalidate the results of the 
study 
Lack of collaboration or inability to evaluate the pain scales used in the study. 
 
Patients who leave the trial for any reason may not be re-included. At the time of leaving the trial, the 
main reason for withdrawal of the trial must be recorded. The data collected up to the time of 
withdrawal may be included for analysis of results. 
 
 
 
 
Demographic variables: age, sex, weight, height, comorbidity (ASA grade). 
Variables related to the injury: subcapital fracture, pertrochanteric, subpertrochanteric or others. 
Variables related to the type of surgery: partial hip arthroplasty, endomedullary nailing or others.  
Duration of  surgery. 
Variables related to  the response: 
o 
Latency: evaluated by analgesic scales up to 10 minutes. 
o 
Analgesic scales: EVN, Algoplus and PAINAD at rest and in activity. They will be carried 
out upon the patient's arrival at the operating room, continuous until 10 minutes after 
the nerve block, in the sedation for the subarachnoid block, when they are discharged 
from the URPA, and at 6, 12, 24 h after the realization of the block, and end of effect 
after the realization of the block. 
o 
Need and rescue drugs: rescue analgesia will be scheduled for the hospitalization 
floor, in case it is necessary. The need, drug and time of administration regarding the 
realization of the blockade will be collected (Annex II). 
 
 
 
 
 
 
After giving informed consent to the patient or his guardian, the patient is monitored according 
to the usual standard (SEDAR Protocol, which includes ECG, TA, SatpO2). 
The ultrasound-guided block at the femoral level (PENG) is performed in the patient's transfer 
bed or table, depositing 20 cc of local anesthetic, with a 50-80 mm needle (depending on the 
anatomical characteristics) and a low-frequency probe. Next, a 50 mm needle and the high-
frequency ultrasound probe will be used to block the NFCL by depositing 5 cc 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
21 
 
6.9. JUSTIFICATION OF  SAMPLE SIZE 
6.10.  STATISTICAL ANALYSIS 
6.11. ASSESSMENT  OF EFFICACY  
of the same anesthetic, always without exceeding the maximum recommended dose for each 
drug. (See Annex I). 
Latency in the establishment of analgesia in the affected territory is explored, as well as an 
assessment of pain (Numerical Visual Scale and Algoplus). 
We proceed to the realization of the intradural spinal anesthesia, assessing again the pain that 
manifests. Subarachnoid blockade will always be performed with the same dose: 5 mg of 
Bupivacaine 0.5% hyperbaric with 10 μg of Fentanyl. 
After the surgical intervention, he will be transferred to the URPA (Post-Anesthetic Recovery 
Unit) and, subsequently, to the hospitalization floor when his situation allows it. At all times the 
constants, the analgesic variables and the treatments that you have needed will be recorded. 
(See Annex II). 
 
 
 
Taking into account the Pharmacokinetics of both local anesthetics, and previous studies(28, 29), using 
the G*Power program, the sample size is calculated. We consider significant a difference in the duration 
of the blockade of at least 3 h, with a deviation of 50%. The security level or alpha error is 5%. The beta 
error is 20%. A total of 108 patients were obtained, 54 in each of the lines of intervention, assuming 10% 
of losses. 
 
 
 
 
A descriptive analysis of the variables collected will be carried out. Non-categorical ones shall be 
expressed as median +/- IQR (interquartile amplitude). Categorical variables shall be expressed as 
percentages or frequencies. 
 
After performing the relevant normality tests (Kolmogorov-Smirnov or Shapiro-Wilk), the sample 
differences will be determined by t-Student or Mann-Whitney U tests. In the comparison of pain scales 
we will use the analysis of variance (ANOVA or Kruskal-Wallis). 
 
The comparative analysis of the categorical variables will be carried out by means of Chi-square tests 
with cross tables. 
 
The control of the possible intermediate and confusing variables will be carried out by means of 
Multiple Linear Regression Analysis. 
 
The significance level will be, by default, 5% (p<0.05). 
 
All calculations will be carried out with the statistical program SPSS© 25.0 for Mac. 
 
 
 
 
The main endpoint of the study's effectiveness will be the difference in the duration of the blockade. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
22 
 
6.13. ASSESSMENT OF ADVERSE EFFECTS  
6.13.1-DEFINITION OF  ADVERSE EVENT: 
6.13.2-CLASSIFICATION OF  ADVERSE EVENTS: 
 
 
This clinical trial may be stopped earlier than expected by the result of an interim analysis 
demonstrating greater than expected benefit or harm in any of the treatment arms. 1 formal internal 
efficacy and safety analysis will be carried out when 50% of the expected number of participants are 
reached. Poor study performance (e.g., slow patient recruitment, high rates of follow-up losses, or poor 
quality control) may be another cause of early study discontinuation. 
 
 
 
 
 
An adverse event is defined as any event that occurs during the clinical study, whether it is either an 
intercurrent disease or accident, and that alters the well-being of the patient. The event may also take 
the form of a laboratory anomaly. 
 
The term adverse event does not imply any causal relationship with the treatment of the study. All 
adverse events, including intercurrent diseases, will be reported and documented as described below. 
 
Toxicities and adverse events shall be scored using version 5.0 of the CTCAE for reporting toxicity and 
adverse events. 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc 
e_5x7.pdf 
 
 
 
All participating researchers should have access to a copy of version 5.0 of the CTCAE. 
 
 
Adverse events will be divided into the categories of serious and non-serious, which determine the 
procedure to be followed for the notification and documentation of the same. 
 
a) Serious adverse events : 
 
A serious adverse event is defined as anyone who threatens the life of the patient or causes death and 
also as one that causes disability, permanent disability or prolongs hospitalization. Any event involving 
congenital malformations or involving cancer is also serious. 
 
b)  Non-serious adverse events  : 
 
Adverse events that do not fall into any of the above categories will be classified as non-serious. 
6.12.   POLICY REGARDING INTERMEDIATE ANALYSES AND CRITERIA FOR EARLY 
COMPLETION OF THE TRIAL.  


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
23 
 
 
 
The investigator should try to explain each adverse event and assess its relationship with the trial 
treatment (probable, possible, unrelated). Criteria for establishing the relationship between clinical 
adverse reactions and study medication include: 
 
3.1 Likely: If you meet the following three criteria: 
 
1) There is a reasonable temporal relationship between the administration of the medicinal product and 
the adverse event. 
 
2) The adverse event is a typical example of a known adverse drug reaction (If treatment is continued, 
the adverse event persists; if the drug is discontinued, the adverse event disappears; if a reexposure 
occurs, the adverse event reappears). 
 
3) If there is another explanation of the adverse event (concomitant treatment, breakthrough disease), 
this explanation is less likely as the cause of the adverse event. 
 
3.2 Possible: It is considered as an adverse reaction possibly related to the medication, one that meets 
the following two criteria: 
 
1) There is a reasonable temporal relationship between drug administration and adverse event. 
 
2) None of the criteria set out in point 2 above (probable) is met or there is another, more plausible 
explanation for the adverse event. 
 
3.3 Unrelated: The adverse event will be classified as unrelated to the medication when it meets any of 
the following requirements: 
 
1) There is no reasonable temporal relationship between the administration of the medicinal product 
and the onset of the adverse reaction. 
 
2) The causal relationship between the medication and the adverse event is not biologically plausible. 
 
3) There is another, more plausible alternative explanation for the adverse event. 
 
4-Monitoring, reporting, and documentation of adverse events 
 
-Non-serious adverse events 
 
They will be recorded on the sheet dedicated for this purpose in the CRD of each patient, and no special 
notification procedure is necessary. 
 
-Serious adverse events 
 
All serious adverse events, regardless of their relationship to study treatment, should be reported as 
soon as possible, but no later than two working days. The serious adverse event reporting form  should 
be sent to the study sponsor by email (ensayosclinicos@ibsal.es). 
6.13.3-RELATIONSHIP WITH THE TREATMENT: 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
24 
 
6.14. DATE AND SOURCE DOCUMENTS 
6.14.1. MEDICAL HISTORY  
6.14.2. WHAT IS CONSIDERED A SOURCE DOCUMENT  IN THIS ESSAY 
6.14.3 DIRECT ACCESS TO  SOURCE DATA/DOCUMENTS 
6.14.4   QUALITY CONTROL AND ASSURANCE 
Deaths and life-threatening events should be reported immediately by telephone or email to the trial 
sponsor. Subsequently, the AAG notification form will be sent by email. Preliminary notifications of AAG 
should be followed as soon as possible by means of detailed descriptions, including copies of clinical 
reports, autopsy reports and other documents requested by the sponsor. In both cases a follow-up of 
the AGAs must be completed (until they are resolved) as soon as possible, and a new completed AAG 
form faxed to the sponsor It is very important that the AAG notification forms are as complete as 
possible from the time of the initial notification, including the investigator's assessment of causation. If 
the follow-up information changes the investigator's assessment of causality, it should be noted in the 
follow-up form. Any adverse events that the investigator believes are related to the treatment of the 
study should be reported to the sponsor, regardless of the time that has elapsed since the end of the 
study. It will be the obligation of the promoter to notify the AGAs in the terms and forms according to 
current legislation to the competent authorities, AEMPS, CC.AA and CEICs involved. 
 
 
 
The data will be collected from the electronic medical record (Jimena IV) and, where appropriate, the 
paper medical record. Also part of the medical record are the records of the ICCA applications. 
 
 
Source Data: All information in original documents and certified copies of original records of clinical 
results, observations, or other activities of a clinical trial necessary for the reconstruction and evaluation 
of the trial. The source data will be included in the source documents (original records or certified 
copies). 
 
Source documents: original documents, data and records (e.g., patient records, medical or consultation 
records, laboratory notes, memoranda, records, data recorded on automated instruments, certified 
copies or transcripts after verification, microfiche, photographic negatives, microfilm or magnetic media, 
radiographs, subject files and pharmacy records in laboratories and in medical-technical departments 
involved in the clinical trial). 
 
Patients must have allowed their medical history to be read in writing by staff authorized by the sponsor 
and regulatory authorities. This information is included in the informed consent. 
 
 
The Promoter shall sign appropriate agreements to appoint a monitor who will supervise this study and 
shall periodically contact the centre, including the management of visits to the centre. The researcher 
agrees to allow the monitor direct access to all relevant documents and to devote his or her and his or 
her staff's time to the monitor to comment on the results and any matters of interest. 
 
 
In order to ensure the quality of the data, the sponsor shall: 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
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7. ETHICAL  AND LEGAL ASPECTS AND OBTAINING  INFORMED CONSENT 
• 
Instructions and quality training will be provided to the research staff before the start of the 
study. Training topics include, but are not limited to: GCP certificates, AA reports, study details 
and procedures, study documentation, informed consent, and patient recruitment. 
• 
Perform regular monitoring in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP). The data will be evaluated for adherence to protocol and 
accuracy relative to the source documents. The monitors will verify that the clinical trial is carried 
out, that the data is generated, documented and reported in compliance with the protocol, good 
clinical practice and any applicable local regulatory requirements. 
 
Direct access to the data will be granted to the principal investigators, monitors, members of the 
evaluating CEIm and the AEMPS, as well as to the authorities that are necessary, in order to allow 
monitoring and surveillance related to the study, audits and inspections. At each center, they will be 
able to review the study records and compare them directly with the source documents, they could 
discuss how to conduct the study with the researcher, and verify that the facilities remain acceptable. 
Audit reports shall be treated confidentially 
 
 
 
 
This study has been designed in accordance with the general ethical principles set out in the Declaration 
of Helsinki (64th General Assembly, Fortaleza, Brazil, October 2013). The researchers will carry out the 
study in accordance with the Good Clinical Practices (PCB), described in harmonized Tripartite 
Guidelines of the ICH of Good Clinical Practices and the Document of instructions of the Spanish Agency 
of Medicines and Health Products for the conduct of clinical trials in Spain (Version 9 of July 27, 2018). 
 
The researcher will prepare the documents to request evaluation by the Ethics Committee of Research 
with medicines of the Health Area of Salamanca, and will respond, where appropriate, to the request for 
clarifications. Approval of the CEIm will be obtained before the start of the study. The study will be 
notified to the Spanish Agency for Medicines and Health Products (AEMPS). 
 
The researcher will facilitate the performance of monitoring visits and audits by the Promoter, reviews 
of the CEIm, and regulatory inspection(s) if necessary, providing direct access to the facilities where the 
study was carried out, to the source documents, to the CRDs, and to all 
other study documents. 
 
The investigator shall obtain the informed consent of a patient or his/her legal representative before 
initiating any procedure related to the study, in accordance with the PCBs, as stipulated in the ICH 
guidelines. It will be recorded in the patient's source documents (medical history) that informed consent 
has been obtained prior to the patient's entry into the study. The original consent form, signed and 
dated by the patient and by the investigator will be kept in the study investigator's file. When the 
investigator proposes to the patient his inclusion in the study, he will inform him in depth about the 
objectives, possible risks and benefits of his participation, he will answer all the questions that the 
patient may ask, who will have time to decide his participation in the study. When the patient is legally 
incapacitated or is not in a position to sign the consent, his legal representative will do so, in accordance 
with the hospital's policy and the legislation in force in this matter. In the event that a family member 
signs the consent because the patient is not in a position to sign the consent, and is not legally 
incapacitated, consent will be requested as soon as possible, when he meets the appropriate conditions, 
to ratify the consent given by his family. 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
26 
 
9.    PROTOCOL CHANGES 
10. ANALYSIS AND COMMUNICATION OF RESULTS 
 
 
 
REGULATION (EU) No 536/2014 requires that subject data be treated in accordance with Union data 
protection legislation. In Spain, Organic Law 3/2018, of December 5, on the Protection of Personal Data 
and guarantee of digital rights, complementary to Regulation (EU) 2016/679 of the European Parliament 
and of the Council, of April 27, 2016, on the protection of natural persons with regard to the processing 
of personal data and on the free movement of these data and repealing Directive 95/46/ CE. This 
legislation requires the application of high-level security measures in the handling of health data, so that 
the distribution of the media is carried out by encrypting said data or using another mechanism that 
guarantees that said information is not accessible or manipulated during its transport. 
 
Study data will be protected and confidentiality will be maintained in accordance with current 
legislation. Patients will be identified by a code and only the research team, qualified personnel in 
charge of monitoring, health authorities, or other authorized third parties may review the medical 
records of patients. The code used will not allow the identification of the subject, and will not include or 
collect identifying data such as the medical record number or similar assigned by the Administration, the 
name, surname, initials of the subject, the postal address or email address, the telephone number, the 
tax identification number, the fingerprint,  THE DNA, a photograph, the social security number, ... 
 
The collected data (CRD) will be stored encoded in a database hosted on causa's servers, under the 
supervision of the principal investigator. Causa servers are subject to security controls and regulations in 
accordance with hospital policy and applicable data protection regulations. 
 
The researcher will ensure that the records and documents of the study as original signed consents, any 
type of source document (hospital records, medical records, ultrasound records of the procedure
 
, will be kept for the time 
required by current legislation. Likewise, you agree to comply with the procedures of conservation of 
documents / records by signing the protocol. 
 
 
 
 
If a modification to the test protocol is necessary, the modification or a new version of the trial protocol 
(modified protocol) will be notified to the CEIm of the Salamanca Health Area, to be approved by it 
before its application. 
 
 
 
 
The analysis of the data will be carried out by the research team and will be communicated in meetings 
and scientific articles in peer-reviewed journals. Regardless of the results of the study, the sponsor 
agrees to present them to the medical community through scientific publications, congresses or other 
means. 
8.  DATA  PROTECTION AND CONFIDENTIALITY 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
27 
 
ANNEX II.- RESCUE  ANALGESIC  TREATMENT: 
 
 
 
• Standard patient monitoring in the operating room. 
• Intravenous sedoanalgesia for puncture. We will not use, and in any case we will avoid long-acting 
benzodiazepines (if essential Midazolam 0.5-1mg). 
• Ultrasound puncture with patient in supine position, without moving him in bed. 
• Anesthetics to use: 
• -Group R: Ropivacaine 0.375% (25 cc): will be administered: 20 cc for PENG and 5 cc for BNFCL 
• -Group L: Levobupivacaine 0.25% (25 cc): 20 cc will be administered for PENG and 5 cc for 
BNFCL. 
• Assess latency: explore until pain disappears on passive mobilization. maximum 10 minutes. 
• Performance of the subarachnoid block in a sitting position on the operating table. Dose: 0.5% 
hyperbaric bupivacaine (5 mg) + 10 μg of Fentanyl. 
• Record the required surgical variables on the collection sheet. 
 
 
 
 
Review patient treatment in URPA and in the hospitalization floor.  Do not administer scheduled 
analgesia unless the patient demands it, and for the same reason always leave a scheduled 
rescue . If necessary, notify the Resident of the Anesthesiology Guard (Virgen de la Vega Hospital 
building). Evaluate your pain and write down the elapsed time. 
Paracetamol 1 gr/ 6 h iv. If contraindication or allergy: Metamizol 2g/8 h iv.   
If you need more analgesia and the 6 h has not passed: 
Dexketoprofen 50 mg iv/ 8 h. 
If contraindication to NSAIDs or pain persists: 
Ondansetron bolus 4mg iv and Tramadol  infusion 200 mg iv + Metamizol 6 gr diluted in 500 cc S. 
Physiological to pass in 24 h (20ml/h). And discontinue Paracetamol, except in those allergic to 
Metamizole. 
Follow-up of the patient 48 h. 
ANNEX I.  - ANESTHETIC PROTOCOL 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
28 
 
 
 
 
 
 
Figure 1. Numerical Visual Scale 
 
 
 
They do not wish to have elements of illustrations. 
 
Figure 2. Algoplus Scale 
ANNEX II.-  PAIN  ASSESSMENT SCALES 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
30 
 
Items· 
0 
2 
Score 
Fae to the exprtts 
on 
Consolab Ll Ty 
Tota" 
 
PAINAD score 
 
 
 
 
 
 
 
Figure 3.   PAINAD scale 


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
31 
 
 
 
 
 
Group 
Levobupivacaine/Ropivacaine 
Hospital stay 
In days 
Age 
In years 
Sex 
Female/Male 
Weight 
In kg 
Size 
In m 
 Body Mass Index 
Type of Fracture 
Subcapital/Pertrochanteric/Subpertrochanteric/Other 
Type of Surgery 
Partial athroplasty/Interlocking/Other 
Duration of  Surgery 
On arrival at the operating 
room 
EVN/Algoplus/Painad 
  Latency time 
When sitting 
EVN/Algoplus/Painad 
At Discharge of 
Resuscitation  
EVN/Algoplus/Painad 
At 6 o'clock from the 
blockade 
EVN/Algoplus/Painad 
At 12 o'clock of the 
blockade 
EVN/Algoplus/Painad 
Within 24 hours of the 
blockade 
EVN/Algoplus/Painad 
At the end of the blockade 
EVN/Algoplus/Painad 
 Analgesic rescue 
Drug used 
Minutes to rescue  
Time elapsed from lock to rescue 
 Morphic equivalence 
Equivalence in morphics of the rescue used 
Nausea and vomiting 
Toxicity 
Toxicity developed by local anesthetics 
Delirium 
Infection 
 Clinically and analytically diagnosed 
Exitus 
ANNEX III.  DATA COLLECTION NOTEBOOK    


Clinical trial PENG-CAD, v1 of 1 of September of 2020 
32 
 
 
 
1. 
Ojeda-Thies C, Saez-Lopez P, Currie CT, Tarazona-Santalbina FJ, Alarcon T, 
Munoz-Pascual A, et al. Spanish National Hip Fracture Registry (RNFC): analysis of its 
first annual report and international comparison with other established registries.  
Osteoporos Int.  2019;30(6):1243-54. 
2. 
Tim JS Chesser DI, Antony Johansen, Alberto Belluati, Carlota Pari, Achile 
Contini, Stijn C Voeten, Johannes H Hageman, Kornelis J Ponsen, Nuria Montero- 
Fernández, Alberto Delgado-Martínez, Francisco Chana-Rodríguez Hip fractur systems- 
European experience.  OTA International.  2020;3(1):1-6. 
3. 
Saez-Lopez P, Ojeda-Thies C, Alarcon T, Munoz Pascual A, Mora-Fernandez J, 
Gonzalez de Villaumbrosia C, et al. [Spanish National Hip Fracture Registry (RNFC): 
First-year results and comparison with other registries and prospective multi-centric 
studies from Spain].  Rev Esp Public  Health. 2019;93. 
4. 
Fernández García M MJ, Olmos JM, González-Macías J, Hernández JL. Review 
of the incidence of  hip fracture in Spain. Rev Osteoporos Metab Miner.  
2015;7(4):115-20. 
5. 
Haslam L, Lansdown A, Lee J, van der Vyver M. Survey of Current Practices: 
Peripheral Nerve Block Utilization by ED Physicians for Treatment of Pain in the 
Hip Fracture Patient Population.  Can Geriatric J.  2013;16(1):16-21. 
6. 
Poeran J, Cozowicz C, Zubizarreta N, Weinstein SM, Deiner SG, Leipzig RM, et al.  
Modifiable factors associated with postoperative delirium after hip fracture repair: An 
age-stratified retrospective cohort study.  Eur J Anaesthesiol.  2020;37(8):649-58. 
7. 
Chen DX, Yang L, Ding L, Li Sy, Qi YN, Li Q.  Perioperative outcomes in 
geriatric patients undergoing hip fracture surgery with different anesthesia 
techniques: A systematic review and meta-analysis.  Medicine (Baltimore).  
2019;98(49):e18220. 
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Zheng X, Tan Y, Gao Y, Liu Z. Comparative efficacy of Neuraxial and general 
anesthesia for hip fracture surgery: a meta-analysis of randomized clinical trials. BMC 
Anesthesiol.  2020;20(1):162. 
9. 
Shin S, Kim SH, Park KK, Kim SJ, Bae JC, Choi YS. Effects of Anesthesia 
Techniques on Outcomes after Hip Fracture Surgery in Elderly Patients: A Prospective, 
Randomized, Controlled Trial. J Clin Med. 2020;9(6). 
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Nishi T, Maeda T, Imatoh T, Babazono A. Comparison of regional with general 
anesthesia on mortality and perioperative length of stay in older patients after hip 
fracture surgery. Int J Qual Health Care. 2019;31(9):669-75. 
11. 
Maxwell BG, Spitz W, Porter J. Association of Increasing Use of Spinal 
Anesthesia in Hip Fracture Repair With Treating an Aging Patient Population. JAMA 
Surg.  2019. 
12. 
Stephan SR, Garlich JM, Debbi EM, Johnson CR, Polakof LS, Noorzad AS, et al. A 
Comparison in Outcomes of Preoperative Single-shot versus Continuous Catheter 
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26. 
Bilal B, Oksuz G, Boran OF, Topak D, Dogar F. High volume pericapsular nerve 
group (PENG) block for acetabular fracture surgery: A new horizon for novel block. J 
Clin Anesth.  2020;62:109702. 
27. 
Ahiskalioglu A, Aydin ME, Ahiskalioglu EO, Tuncer K, Celik M. Pericapsular nerve 
group (PENG) block for surgical anesthesia of medial thigh. J Clin Anesth.  2020;59:42-
3. 
28. 
Li A, Wei Z, Liu Y, Shi J, Ding H, Tang H, et al. Ropivacaine versus 
levobupivacaine in peripheral nerve block: A PRISMA-compliant meta-analysis of 
randomized controlled trials.  Medicine (Baltimore).  2017;96(14):e6551. 
29. 
Fournier R, Faust A, Chassot O, Gamulin Z. Levobupivacaine 0.5% provides 
longer analgesia after sciatic nerve block using the Labat approach than the same dose 
of ropivacaine in foot and ankle surgery.  Anesth Analg. 2010;110(5):1486-9. 

ICF_001.pdf: 
 
 
 
 
 
Version 1.0 of September 1, 2020 
 
INFORMATION SHEET AND INFORMED CONSENT 
 
Title: 
Randomized and controlled Phase IV clinical trial on the analgesic 
efficacy of the combined block (PENG -pericapsular nerve group)  
and the femoral lateral cutaneous nerve in hip fractures of the 
elderly. 
Comparative 
study 
between 
levobupivacaine 
and 
ropivacaine 
Code:  
PENG-CAD 
EudraTC No. 
2020-004697-21 
Version: 
1.0 of 1 September 2020 
Promoter: 
Biomedical Research Institute of Salamanca (IBSAL) 
Principal 
Investigator 
Agustin Diaz Alvarez 
 
Introduction 
We approach you because you have fractured your hip, to inform you about a clinical trial in 
which you are invited to participate.  You should know that your participation in this study is 
voluntary and that you may choose not to  participate. Please take the time you need to read 
the following information and refer to what you want. Ask the researcher in this study if there's 
anything that's not clear to you or if you want to learn more. 
 
Objective of the study 
The objective of the study is to find the effectiveness in pain control of two local anesthetics 
(levobupivacaine and ropivacaine) through a technique in which painkillers are injected directly 
into the area surrounding the hip joint and into a nerve (the femoral) whose irritation from 
fracture and surgical manipulation produces pain.  
 
This research study has been approved by the Ethics Committee of Research with Medicines of 
Salamanca, and is carried out in accordance with current legislation, Royal Decree 1090/2015 of 
December 4 and European Regulation 536/2014 of April 16, which regulates clinical trials with 
medicines. 
 
Study procedures and possible risks and discomfort 
This clinical trial will be held at the University Care Complex of Salamanca, and a total of 108 
patients over 65 years of age who have fractured their hips and are going to be operated on will 
participate.  Half of the patients will receive one of the study drugs (levobupivacaine) and the 
other half the other drug (ropivacaine). The assignment to each treatment group will be made 
randomly, which means that the decision on the local anesthetic used during the surgical 
process (levobupivacaine or ropivacaine) will be random.  Both drugs are marketed and 
approved in our country for this indication, and are used in routine clinical practice since 2012 
and 2013, respectively.  
 
Participation in this study would not produce any additional discomfort to those of the surgical 
intervention to which you are going to be subjected.  The side effects of the drugs under study 
are the same as those of other local anesthetics of the same class, especially nausea, vomiting 
and headache can occur. However, you should know that during the surgical intervention and 
in the postoperative period you will receive treatment to treat these side effects and others that 


 
 
 
 
 
Version 1.0 of September 1, 2020 
 
may appear during the intervention, in accordance with usual clinical practice.  Being drugs 
approved by the competent health authorities, there is information available to everyone about 
the side effects of levobupivacaine and ropivacaine.  Please speak with your study physician for 
a complete list of side effects reported with these drugs and in any case, if desired, you will be 
given the package leaflet for both medications.  
 
The duration of the study will be from the signing of the informed consent until 48 hours after 
the surgical intervention.  
Data will be collected on the efficacy to calm pain, the time it takes for medications to take 
effect, the duration of the same, and possible side effects, and scales and questionnaires will be 
carried out to assess pain at different times after the intervention, up to 48 hours after it. In 
addition, other data will be collected about you relevant to this research study, such as your 
weight, height, and constants during the surgical intervention and in the hours after.  
 
In the present work, no biological samples are collected for research purposes, nor are 
procedures or tests carried out that are not part of routine clinical practice. 
 
All information about this study will be stored encrypted, and will be used exclusively for the 
purposes specified herein. In the event that your data is transferred to other research groups, it 
will always be carried out in accordance with current legislation, keeping your data encrypted, 
to carry out studies related to the objectives of this work, and with the prior authorization of 
the Research Ethics Committee.  In the event that the objectives of the research work proposed 
by other research groups are different from those of this project, a new consent will be 
requested. 
Voluntary participation and withdrawal 
You can freely decide whether or not you want to take part in this study, participation is entirely 
voluntary. If you decide to participate, you still have the possibility to withdraw at any time, 
without having to give explanations, and without any penalty or negative consequences for you. 
If you change your mind in relation to your data, you have the right to request its destruction or 
anonymization, through your doctor/researcher. However, you should know that the data that 
have been obtained in the analyses carried out up to that moment may be used for the 
requested purposes and may be kept in compliance with the corresponding legal obligations. 
 
Possible benefits 
You may not get any health benefits from participating in this study. However, the information 
obtained from this trial may contribute to medical advancement and could help other patients 
suffering from hip fracture in the future to better manage pain.   
 
Alternative treatments 
In case of not participating in the study, you will receive treatment according to usual clinical 
practice, and it is even possible that, if your anesthesiologist so decides, you will  be able to 
receive the same drugs that are offered in this study.   You may want to give the study doctor 
more information about alternative treatments. 
 
Data protection and confidentiality 
All information about your results will be treated strictly confidentially. Both the center and the 
promoter and the research team are responsible for the processing of their data and undertake 
to comply with the data protection regulations in force, currently Organic Law 3/2018, of 


 
 
 
 
 
Version 1.0 of September 1, 2020 
 
December 5, on the Protection of Personal Data and guarantee of digital rights and Regulation 
(EU) 2016/679 of the European Parliament and of the Council of April 27, 2016 on Data 
Protection (RGPD ). The data collected for the study will be identified by a code, so that no 
information that can identify you is included, and only the research team will be able to relate 
this data to you.  Therefore, your identity will not be disclosed to any other person except to the 
health authorities, when required or in cases of medical emergency. The Research Ethics 
Committees, the representatives of the Health Authority in matters of inspection and the 
personnel authorized by the Promoter, will only be able to access to verify the personal data, 
the procedures of the clinical study and the fulfillment of the norms of good clinical practice 
(always maintaining the confidentiality of the information). 
Your data will be kept under the appropriate security conditions and it is guaranteed that the 
subjects cannot be identified through means considered reasonable by persons other than those 
authorized.  The research team will analyse your data based on the legitimate  interest of 
achieving the purposes of the study.  The Investigator and the Sponsor are obliged to keep the 
data collected for the study for at least 25 years after its completion.  Subsequently, your 
personal information will only be retained by the health care center and by the research team 
for other scientific research purposes if you have given your consent to do so and if permitted 
by applicable law and ethical requirements. 
 
If the results of the study are susceptible to publication in scientific journals, at no time will 
personal data of the participants in this research be provided. We inform you that you have the 
right to access, rectify or cancel your data, and you can limit the processing of data that are 
incorrect, request a copy or transfer to a third party the data that you have provided for the 
study. To exercise their rights, or in case the participant wishes to expand information on the 
processing of their personal data, they may contact the main researcher of the study whose data 
are specified at the end of this document, the Data Protection Delegate of the Regional Health 
Management (dpd@saludcastillayleon.es) or our center (dpd.husa@saludcastillayleon.es).  We 
remind you that data cannot be deleted even if you stop participating in the trial to ensure the 
validity of the research and comply with legal duties.  You also have the right to contact the Data 
Protection Agency if you are not satisfied. 
 
Information about results 
In the event that you request it, at the end of the study and in accordance with article 27 of Law 
14/2007 on Biomedical Research, you may be provided with information about the results of 
this research work. 
 
 
I consent to the future use of the data that has been collected in the present research study to 
conduct other research related to the medical specialty or research area of this study. 
        □ YES □ NO 
 
I consent to the future accessing my medical record again to collect data that is considered 
important for conducting other research related to the medical specialty or research area of this 
study. 
        □ YES □ NO 
 
 
Contact details of the research team: 


 
 
 
 
 
Version 1.0 of September 1, 2020 
 
If you have any questions or need more information, please contact:  
Name: Dr. Agustín Díaz Álvarez 
Phone: . 923 29 11 00 Ext 55483 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
Version 1.0 of September 1, 2020 
 
INFORMED CONSENT 
Title: 
Randomized and controlled Phase IV clinical trial on the analgesic 
efficacy of the combined block (PENG -pericapsular nerve group)  
and the femoral lateral cutaneous nerve in hip fractures of the 
elderly. 
Comparative 
study 
between 
levobupivacaine 
and 
ropivacaine 
Code:  
PENG-CAD 
 
 
I (First and Last Name) 
_______________________________________________________________________ 
I have read the information sheet I have been given about the study. 
I have been able to ask questions about the study. 
I have received enough information about the study. 
I have read the information sheet that has been given to me 
I have spoken with the Investigator 
_______________________________________________________________________ 
I understand that my participation is voluntary. 
I understand that I can withdraw from the study: 
 
 
1º Whenever you want 
 
2º Without having to give explanations 
 
3º Without having any negative impact 
I voluntarily agree to participate in the clinical trial and authorize the use of all 
information obtained. I understand that I will receive a signed copy of this informed 
consent. 
 
 
 
_______________ 
Participant's signature 
Date
 
 
 
 
 
 
_______________ 
Name and signature of the researcher 
date 
 
 
 
 
_______________ 
Signature of the legal representative, family member or related person in fact  Date