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Protocol IROA
1 Version 1.2 01/05/2015
Protocol
Trial ID:
IROA
(International Register of Open Abdomen)
Authors:
Dr. Federico Coccolini
Dr. Luca Ansaloni
General, Emergency and Trauma Surgery, Papa Giovanni XXIII hospital, P.zza OMS 1, 24128 Bergamo, Italy
E-‐mail: [email protected], [email protected], [email protected]
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List of abbreviations
AE adverse event
ASA American Society of Anesthesiologists
CRF case report form
CRO contract research organisation
FPFV first patient first visit
ICMJE The International Committee of Medical Journal Editors
MedDRA Medical Dictionary for Regulatory Activities
SAE serious adverse event
SD standard deviation
BMI body mass index
SAP severe acute pancreatitis
IAP intra-‐abdominal pressure
IAH intra-‐abdominal hypertension
ACS abdominal compartment syndrome
ICU intensive care unit
APP abdominal perfusion pressure
HR hazard ratio
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Time and event chart
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5, 6
Nomenclature Surgery 1
ICU+
Dressing
Surgery 2 Surgery 3 Follow-‐up (1 month, 1 year)
1st Intervention
Dressing OA replacement
OA closure Follow-‐up
Informed consent √
Inclusion/exclusion criteria √
Demographic data √
Medical History/ Concomitant illness
√
Physical examination √ √ √ √ √
ASA classification √
Patient Provenience √
Body weight & height √
Intra-‐abdominal pressure √ √ √ √
Abdominal compartment syndrome
√ √ √
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Intra-‐abdominal hypertension causative event
√ √ √
Concomitant medication# √ Continuously
Injury Severity Score (ISS) √
Pancreatitis grade assessment
√ √ √
Peritonitis grade assessment
√ √ √
Blood Product Transfusion √ √ √ √
Contamination assessment √ √ √
Intestinal resection √ √ √
Stoma creation √ √ √
Surgical complications √ √ √ √
Indication to revise OA √ √
Time of revision of OA √ √
OA classification (Bjorck) √ √ √ √
Post-‐operative dressing data
√ √ √
Post-‐operative nutrition data
√ √ √
Closure technique √
OA technique √ √ √
Surgery report √ √ √
Post surgical complications √ √ √ √
Length of stay in hospital √ √ √
Mortality √ √ √ √ √
Adverse events √ Continuously
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1 INTRODUCTION:
The indications for Open Abdomen (OA) are generally trauma, abdominal sepsis, severe acute
pancreatitis and in general situations in which is ongoing the development an intra-‐abdominal
hypertension condition (IAH), in order to prevent the development of abdominal compartmental
syndrome (ACS). The concept of abdominal damage control surgery has two basic components;
controlling bleeding and contamination in the abdominal cavity, and leaving the abdomen open,
to decompress or facilitate return at planned re-‐laparotomy. Maintaining the abdomen domain
requires a temporary abdominal closure (TAC). Unlike in trauma patients with massive bleeding,
the main aims of the OA approach both in severe secondary peritonitis and severe acute
pancreatitis (SAP) are sepsis control and expedite subsequent surgical interventions. In case of ACS
goal directed therapy to achieve early opening and early closure is the key: paradigm of closure
shifts to combination of therapies including negative pressure wound therapy and dynamic
closure, in order to reduce complications and avoid incisional hernia. There have been huge
studies and progress in survival of critically ill trauma and septic surgical patients: this in part has
been through the great work of pioneers, scientific societies and their guidelines; however further
studies and continued innovation are needed to better understand optimal treatment strategies
and to define more clearly the indications, either in adults either in pediatrics patients, because
OA by itself is still a morbid procedure. Mortality rates are high, usually over >30% (1) depending
on the patient cohort. The challenging situation to manage requires a multidisciplinary approach
by the surgeon and the ICU team in a specific staged process.
The World Society of the Abdominal Compartment Syndrome convened in 2004 to create a
consensus statement on the definition, diagnosis, and treatment of ACS (2). The abdomen and
pelvis, while anatomically distinct, represent a single space and thus should be considered as one
in discussion of intra-‐abdominal pressure (IAP) and ACS. The abdomino-‐pelvic cavity is a closed
space, and the elasticity of its walls and the character of its contents determine the IAP. The IAP is
fairly uniform throughout and therefore measurement anywhere within the cavity reflects the
entire cavity. The IAP varies with diaphragmatic excursion: it increases with diaphragmatic
contraction (inspiration) and decreases with expiration. The abdominal perfusion pressure (APP),
analogous to the cerebral perfusion pressure, has been proposed as a more accurate predictor of
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visceral perfusion and consequently a target for intervention. A target APP of >60 mmHg is
associated with improved survival in the setting of IAH and ACS (2, 3). Normal IAP is actually below
0 mmHg. In the setting of conditions such as morbid obesity, pregnancy, liver disease with ascites,
IAP may be chronically elevated to 10-‐15 mmHg without evidence of altered physiology (6). During
illness or following surgery, IAP is higher, on the order of 5-‐7 mmHg, due to factors such as tissue
edema or ileus. The point at which IAP becomes IAH has been a matter of debate; the consensus
definition settled on 12 mmHg as this is the lowest point at which pathologic effects are noted (2).
A grading system was proposed by the Denver General Hospital group in 1996, in the interest of
guiding interventions (6). The WSACS consensus definition varies slightly and is as follows: Grade I
(12-‐15 mmHg); Grade II (16-‐20 mmHg); Grade III (21-‐25 mmHg); Grade IV (>25 mmHg) (2). ACS
develops as a result of alterations in perfusion related to IAH. Early literature on the syndrome
variably defined the ACS; generally speaking, it was felt that ACS represented a pathologic
elevation of IAP that was associated with organ dysfunction. The consensus definition selected a
sustained IAP >20 mmHg, recognizing that lower levels of IAH may be associated with organ
dysfunction. The final common pathway of organ dysfunction is hypo-‐perfusion.
For these reasons, OA should be reserved for selected cases only and with the aim of obtaining
early abdominal closure, possibly with primary fascial repair (7). The prevalence of ACS in trauma
patients has fallen in centers with advanced medical care, some reporting falls from 30 to almost
0% (5). Where trauma and emergency surgery systems are not so advanced IAH and ACS can be
expected to occur in up to 40% of ICU admission respectively. Untreated post-‐injury ACS is an
independent predictor of organ failure (8) that is often difficult to reverse, and should be
prevented using different strategies. delayed decompression may not reverse the sequelae of IAH
and ACS (9).
In severe secondary peritonitis, a staged approach may be required for three different reasons,
although they are often used in combinations.
Firstly, the inability to control the source of contamination in a single operation: Instead of the
traditional model of one definitive operation and possible reoperation only performed as needed
(re-‐laparotomy on-‐demand strategy), there are two other options to manage a severely
contaminated peritoneal cavity. One, termed planned re-‐laparotomy refers to a technique where
the need for a second operation is recognized and decided at the initial operation. Another option,
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the open abdomen technique, is leaving the abdomen open and treating the infected peritoneal
cavity like an “open abscess” with frequent irrigations and TAC techniques (10).
Secondly, if the surgeon feels the patient wont tolerate a definitive repair and/or abdominal wall
closure, the operation is deliberately abbreviated due to the severe physiological derangement
and suboptimal local conditions for healing, and restoration of intestinal continuity is deferred to
the second operation (deferred anastomosis technique) This is particularly important in
hypotensive patients who are already received inotropes. (11).
Thirdly, the presence of extensive visceral edema may increase the risk of ACS development, if
primary fascial closure is attempted (12). To prevent ACS, the abdominal incision is left open and
the viscera are covered with one of the TAC methods. ACS can develop from a number of
complications related to intra-‐abdominal sepsis including but not limited to large volume fluid
resuscitation resulting in visceral edema and intra-‐abdominal free fluid collection, retroperitoneal,
intra-‐abdominal and abdominal wall bleeding and ileus, pseudo-‐obstruction and mechanical
obstruction of the bowel.
It was suggested that a significant proportion of patients with SAP dying of early multiple organ
dysfunction syndrome in effect died of unrecognized and untreated ACS caused by massive fluid
resuscitation, capillary leak and visceral edema (13, 14).
Although percutaneous drainage of pancreatic ascites can, in some cases, decrease IAP at least
temporarily, surgical decompression is the most reliable method to relieve IAH and restore vital
organ functions, especially in the pulmonary, cardiovascular and renal systems.
Basic information:
Rationale for the trial: To evaluate the different indications to OA, the different techniques used to perform it, it’s management, it’s definitive closure and mortality rates linked to the different variables. Moreover to evaluate the 1 month and 1 year follow up in patients underwent to OA.
Objectives and endpoints
Objectives
- Primary objective: to evaluate the indications, the techniques, the management and the definitive closure techniques for OA
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- Secondary objective: evaluate the differences in mortality and morbidity rate and the other different outcomes linked to the different techniques utilized to perform and maintain the OA.
Type of trial
This is a prospective, cohort multicenter trial
The promoter and Italian coordinator centre is General Surgery I, Papa Giovanni XXIII hospital, Bergamo, Italy). The protocol will be registered and published centres that will ask to participate will be considered for admission.
Actually the other participating centres are:
- Emergency surgery dept. Parma University hospital, Parma, Italy
- Emergency and Trauma Surgery dept., Virginia Commonwealth University, Richmond, Virginia (USA)
Rationale for trial design
Treatment of subjects
All patients who may require to be undergone to OA procedures.
Rationale for treatment
The OA has been demonstrated to be fundamental in damage control surgery either in trauma, either in peritonitis either in SAP. It reduces IAP and resorbing of toxins and inflammation mediators from the abdominal cavity. However no high quality data about it use has been produced.
Trial population
Number of subjects to be studied
Planned number of subjects to be screened: almost 300 per year (patients treated/year in centres already registered as participating).
Inclusion criteria
• No age limit
• Indication to OA
• Informed consent signed
Exclusion criteria
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• Informed consent refusal
• No indication to OA
Withdrawal criteria
The subject may withdraw at will at any time. The patient may be withdrawn from the trial at the discretion of the investigator for safety concerns. If the patient withdraws or is withdrawn at any time after receiving trial product, final safety information will be obtained.
Patients who are deemed during surgery not suitable included in this protocol will be withdrawn from the study. In case a subject is being prematurely withdrawn from the trial the Investigator will ensure that the procedures for the last visit are undertaken, if possible. The primary reason (adverse event, non-‐compliance with protocol or other) for discontinuation must be specified in the CRF.
A patient withdrawn from the study will be analyzed according to evaluability of Subjects for Analysis.
Trial schedule
Planned duration of recruitment period: 3 years
Planned date for FPFV: March 2015
This trial is subject to registration before subject enrolment according to the specifications from the International Committee of Medical Journal Editors (ICMJE) (4). Investigator will ensure the trial is registered at ClinicalTrials.gov (5) according to the requirements from ICMJE (4).
Methods and assessments
Visit procedures
The study comprises of the following visits:
• Visit 1: Surgical intervention: treatment of the patient for the primary disease which require the OA
• Visit 2: ICU + dressing: any subsequent ICU recovery and dressing of the OA
• Visit 3: OA replacement: any subsequent intervention of replacement of the OA
• Visit 4: OA definitive closure: OA definitive closure intervention
• Visit 5, 6: Post surgery follow-‐up visits: at 1 and 12 months after the OA definitive closure surgical intervention
In case of any premature discontinuation of the trial, the patient will, if possible, be called in for a last visit.
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Visit 1: Surgery, 1st Intervention
Patients will be undergone to the treatment for the primary disease that requires the OA.
The Screening Visit procedures will mainly include assessments required for the evaluation of eligibility according to the inclusion/exclusion criteria.
Eligible patients that have signed informed consent will be included.
The beginning of surgery is defined as skin cut.
Each patient will undergo midline laparotomy as defined by institutional guidelines.
Guidelines for thrombosis prophylaxis
Intra operative compression stocking should be used for all patients and until patients are discharged, when possible.
Thrombosis prophylaxis with heparin or low molecular weight heparin (LMWH) will be administered according to institutional guidelines. The minimum starting dose should be according to local hospital procedure for thrombosis prophylaxis.
Guidelines for antibiotic therapy
Antibiotic therapy will be will be administered according to institutional guidelines. The minimum starting dose should be according to local hospital procedure for antibiotic therapy.
The following will be investigated/recorded/obtained:
Pre-‐operative data:
• Comorbidity • Cardiopathy / Cardiomiopathy • Hepathopathy • Nephropathy • Pneumological disorders • Neurological disorders • Immunological disorders • Cancer • Chemotherapy • Diabetes • Smoking • Obesity • AAA (aortic abd. aneurysm) • Malnutrition (> 10% weight loss in six month) • Remote infection • Immunosuppression/steroid use • Presence of Colostomy
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• Presence of Ileostomy • Presence of Urostomy
• ASA • ASA I • ASA II • ASA III • ASA IV
American Society of Anesthesiologists Physical Status Classification (ASA status):
• CLASS DESCRIPTION
• I Healthy patient
• II Mild systemic disease, no functional limitation
• III Severe systemic disease, definite functional limitation
• IV Severe systemic disease that is a constant threat to life
• V Moribund patient unlikely to survive 24 hours with or without operation
• Patient provenience • Ward • Intensive Care Unit • Emergency Department
• Intra Abdominal Pressure • grade I (IAP 12–15 mm Hg)
• grade II (IAP 16–20 mm Hg)
• grade III (IAP 21–25 mm Hg)
• grade IV (IAP >25 mm Hg)
• Abdominal Compartement Syndrome (IAP >20 mm Hg (with or without APP < 60mmHg) associated with new organ dysfunction/failure)
• Yes • No
• Abdominal Compartement Syndrome
• Primary ACS (a condition associated with injury or disease in the abdominal-‐pelvic region that frequently requires early surgical or interventional radiologic intervention)
• Secondary ACS (conditions that do not originate from the abdominal-‐pelvic region)
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• Recurrent ACS (a condition in which ACS redevelops after previous surgical or medical treatment of primary or secondary ACS)
• Open Abdomen Indication • Transplant • Trauma • Peritonitis Pancreatitis • Vascular emergencies • Massive resuscitation • Burns • Post-‐operative
• Infectious/peritonitis • Ischemic • Abdominal Hypertension / Abdominal Compartment Syndrome
• Others
• Injury Severity Score (in trauma patients)
Head and Neck Worst Injury?
Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
Face Worst Injury?
Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
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Chest Worst Injury?
Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
Abdomen Worst Injury?
Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
Extremity (Including Pelvis) Worst Injury?
Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
External Worst Injury?
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Minor +1
Moderate +2
Serious +3
Severe +4
Critical +5
Unsurvivable +6
TOTAL: the sum of the different scores
• Peritonitis classification (according to Mannheim Peritonitis Index)
• Pancreatitis classification (according to Balthazar)
Grading of pancreatitis
• A: normal pancreas 0
• B: enlargement of pancreas +1
• C: inflammatory changes in pancreas and peripancreatic fat +2
• D: ill defined single fluid collection +3
• E: two or more poorly defined fluid collections +4
Pancreatic necrosis
• none +0
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• less than/equal to 30% +2
• > 30-‐50 % +4
• > 50% +6
TOTAL: the sum of the different scores
• Stratification of pancreatitis severity
! mild pancreatitis (interstitial pancreatitis): Balthazar B or C, without pancreatic or extra-‐pancreatic necrosis
! intermediate (exudative pancreatitis): Balthazar D or E, without pancreatic necrosis; peri-‐pancreatic collections are due to extra-‐pancreatic necrosis
! severe pancreatitis (necrotising): with pancreatic necrosis
• Body weight and height, BMI
• Signed informed consent
The Investigator must keep a subject screening log and a subject enrolment log. These can be combined in one document.
Subjects enrolled in the trial will be provided with a documents stating that he/she is in a trial, contact address and telephone numbers.
In case a subject is being prematurely withdrawn from the trial the Investigator will ensure that the procedures for the last visit are undertaken, if possible.
All patients will be classified according to the American Society of Anesthesiology Physical Status Classification as described below. No restriction regarding to ASA status will be applied in this trial.
1.1.1 Visit 2: ICU + Dressing
The following will be recorded at each dressing change and during the ICU admission days:
Post-‐operative medications data (registered at each medication change):
! Aspiration pressure (mmHg) ! Volume of aspirated fluids in the canister (ml/day) ! Instillation of fluids in maintaining OA
• Which kind of fluids • Fluids Volume/day
Post-‐operative Nutritional data:
! Post-‐operative nutrition
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• Parenteral • Enteral • Oral Feeding
! Time between intervention and nutrition start (days)
1.1.2 Visit 3: OA replacement
Intraoperative data (registered at each intervention):
• Date of intervention • Indications to the intervention
• Trauma • Peritonitis • Pancreatitis • Vascular emergencies • Burns • Post-‐operative
• Infectious/peritonitis • Ischemic • Abdominal Hypertension / Abdominal Compartment Syndrome
• Revision of the open abdomen • Planned
• Every 24 hours • Every 48 hours • Every 72 hours • Every 96 hours
• A la demande • Others
• Temporary abdominal closure technique • Towel Clip Closure • Skin closure • Zipper • Bogotà bag • Vacuum Pack Technique • Wittmann Patch • Trans-‐abdominal Wall Traction (TAWT) • Open Abdomen with Vacuum and mesh-‐mediated fascial traction • V.A.C System
• Treatment/prevention of Abdominal Compartment Syndrome
• Treatment • Prevention
• Open abdomen classification (according to Bjork)
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• Grade 1A: Clean Open Abdomen without adherence between bowel and abdominal wall or fixity of the abdominal wall (lateralization of the abdominal wall).
• Grade 1B: Contaminated Open Abdomen without adherence/fixity • Grade 2A: Clean Open Abdomen developing adherence/fixity • Grade 2B: Contaminated Open Abdomen developing adherence/fixity • Grade 3: Open Abdomen complicated by fistula formation • Grade 4: Frozen Open Abdomen with adherent bowel, unable to close surgically,
with or without fistula
• Complications
• Perioperative death • Yes (date)
! ICU ! Ward
• No
1.1.3 Visit 4: OA definitive closure.
Definitive closure intervention data:
! Date of intervention ! Total number of medication (Temporary Abdominal Closure device) changes ! Time between open abdomen opening and definitive closure (days) ! Intraoperative blood transfusion
• Yes ! Fresh Frozen Plasma ! Platelets concentrate ! Red Blood cells concentrate
• No ! Intestinal anastomosis
• Yes ! small bowel ! large bowel ! gastro-‐esophageal ! urological
• No ! Stoma
• ileostomy • colostomy • uro / cistostomy • gastro / digiunostomy
! Prosthesis positioning • Not resorbable • Reabsorbable
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• Biological • Composite
! Prosthesis positioning • onlay (suprafascial) • inlay (no overlap) • sublay (subfascial; extraperitoneal) • underlay (subfascial; intraperitoneal)
! Fascial closure • Yes • No
! Entero-‐atmosferic fistula • Yes • No
! Skin closure • Yes • no, with VAC • no, without VAC
! Complications ! Perioperative death
• Yes (date) ! ICU ! Ward
• No General admission data:
• Total ICU admission time (days) • Total hospital admission time (days)
1.1.4 Visit 5, 6: Post surgery follow-‐up: 1, 12 months
The following will be recorded at 1, 12 months after surgery ± 2 weeks:
• Complications • Reintervention
• Yes • Indication
• Months between the first operation and the reintervention • Total ICU admission time (days) • Total hospital admission time (days) • Perioperative death (date)
• No • Death
• Yes • No
1.1.5 Evaluation by surgeon of post surgical complications
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At each Visit 2, 3, 4, 5, 6 the patient will be evaluated for post surgical complications. Complications will be evaluated by the surgeon during surgery and at discharge. Any complications will be recorded in the CRF.
If the complication leads to additional surgical interventions it needs to be noted in the CRF.
1.2 Other Assessments
1.2.1 Weight and Height
Weight (kilograms), height (centimetres) and BMI will be recorded at Visit 1.
1.2.2 Demographics
The following will be recorded at Visit 1.
• Date of birth
• Gender
1.2.3 Time of surgery
• Start of surgery is defined as time of skin cut.
1.2.4 Length of stay in hospital
At visit 5 the date of discharge from hospital will be noted in the CRF together with both the total ICU and hospital stay.
1.2.5 Medical History/Concomitant Illnesses
Details on medical history and all concomitant illnesses will be recorded at Visit 1 by a medical interview and/or review of relevant medical records.
Special emphasis should be given to:
o Cardiopathy / Cardiomiopathy o Hepathopathy o Nephropathy o Pneumological disorders o Neurological disorders o Immunological disorders o Cancer o Chemotherapy o Diabetes o Smoking o Obesity o AAA (aortic abd. aneurysm) o Malnutrition (> 10% weight loss in six month) o Remote infection
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o Immunosuppression/steroid use o Presence of Colostomy o Presence of Ileostomy o Presence of Urostomy
1.2.6 Physical Examination
A physical examination will be performed at each Visit 1, 2, 3, 4, 5, 6.
1.2.7 Bowel resection
Bowell resections will be registered in CRF divided into: no resection, gastric/small bowel resection, colonic resection and urological.
1.2.8 Stoma creation
Stoma creation will be registered in CRF divided into: no stoma, jejunal/small bowel stoma, colonic stoma and urostomy.
1.2.9 Peritonitis grade assessment (Mannheim peritonitis index)
As shown above, the peritonitis grade assessment will be recorded according to the Mannheim peritonitis index
1.2.10 Pancreatitis grade assessment (Balthazar score)
As shown above, the pancreatitis grade assessment will be recorded according to the Balthazar score.
1.2.11 Injury Severity Score (ISS)
As shown above, the severity of injuries will be calculated with the ISS
1.3 Patient Compliance
The investigator will reinforce compliance with the protocol by ensuring that only patients willing to follow the trial procedures are enrolled in the trial.
1.4 Screening Logs
The Investigator must generate and keep a patient screening-‐ and patient enrolment log
Trial supplies
Patients will be treated according to local hospital procedure. No additional costs (materials, salaries, other) due to the study will be charged to the hospital.
Trial product
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Trial products will be those commonly used in the hospital according to the local rules.
Concomitant illnesses and medication
Definitions:
Concomitant illness: Any illness that is present at the start of the trial (i.e., at Visit 1).
Concomitant medication: Any medication that is taken at the start of the trial.
Details of all concomitant illnesses and medication must be recorded at trial entry (i.e., at Visit 1).
Transfusion products (RBC, FFP, PC and other) during surgery and post-‐surgery until hospital discharge (Visit 1, 2, 3, 4, 5, 6) must be recorded in the CRF.
Adverse events and clinical complaints
1.5 Definitions adverse events
Adverse event (AE)/Complications:
Any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Note: This includes events from the first trial related activity after the subject has signed the informed consent and until post treatment follow-‐up period as defined in the protocol.
The following should not be recorded as AEs:
• Pre-‐planned procedures unless the condition for which the procedure was planned has worsened from the first trial related activity after the subject has signed the informed consent.
• Pre-‐existing conditions found as a result of screening procedures. These should be recorded as medical history/concomitant illness.
An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e. an abnormality that suggests a disease and/or organ toxicity and is of a severity which requires active management (i.e. discontinuation of trial product, more frequent follow-‐up or diagnostic investigation).
The following events will not be recorded as adverse events, as such discomforts are expected to be related to the surgical procedure:
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• Post operative nausea/vomit
• Post operative sore throat due to intubation
• Post-‐operative pain due to surgical intervention within 3 months from the operation.
Serious adverse event (SAE)/Complications:
A SAE is an experience that at any dose results in any of the following:
• Death
• A life-‐threatening* experience
• In-‐subject hospitalization or prolongation of existing hospitalization
• A persistent or significant disability/incapacity
• Important medical events that may not result in death, be life-‐threatening*, or require hospitalization may be considered a SAE when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
*The term “life-‐threatening” in the definition of SAE refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it was more severe.
Non-‐serious adverse event:
A non-‐serious AE is any AE that does not fulfil the definition of a serious AE.
Severity assessment definitions:
• Mild – No or transient symptoms, no interference with the subject’s daily activities.
• Moderate -‐ Marked symptoms, moderate interference with the subject’s daily activities.
• Severe -‐ Considerable interference with the subject’s daily activities, unacceptable.
Outcome categories and definitions:
• Recovered -‐ Fully recovered, or by medical or surgical treatment the condition has returned to the level observed at the first trial related activity after the subject signed the informed consent.
• Recovering -‐ The condition is improving and the subject is expected to recover from the event. This term should only be used when the subject has completed the trial.
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• Recovered with sequelae -‐ As a result of the AE the subject suffered persistent and significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with sequelae should be rated as an SAE.
• Not recovered.
• Fatal.
• Unknown -‐ This term should only be used in cases where the subject is lost to follow-‐up.
1.6 Clinical technical complaints
Any malfunction of the OA device should be reported as medical device incidents or complaints following the definition in Section 1.8.
1.7 Definitions technical complaints
An OA Incident is a malfunction* of the device that results in or might have resulted in death or in a serious injury*.
*Malfunction is a failure of the device to meet its performance specifications or otherwise perform as intended.
*Serious injury is an injury that is life-‐threatening*, results in permanent damage to body structure or necessitates medical or surgical intervention by health care professionals to preclude permanent impairment of a body function or permanent damage to body structure.
*The term life threatening in the definition of a serious adverse event refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death if it was more severe.
1.8 Collection, recording and reporting of adverse events
All events meeting the definition of an AE must be collected and reported. At each contact with the trial site, the subject must be asked about adverse events.
All AEs, either observed by the Investigator or reported by the subject, must be recorded by the Investigator and evaluated.
The Investigator should record the diagnosis, if available. If no diagnosis is available the Investigator should record each sign and symptom as individual adverse events.
For serious adverse events, the safety information form must also be completed.
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The Investigator must report initial information on all serious AEs to Coordinating Center Principal investigator within 24 hours of obtaining knowledge about the event and directly to the company that produces the device.
Coordinating Center Principal Investigator contact information:
Name: Dr. Federico Coccolini, General Surgery, Papa Giovanni XXIII hospital, Bergamo, Italy Phone: 0039-‐331-‐8981061
E-‐mail: [email protected]
The investigator must complete and forward electronically/fax/courier copies of the adverse event form and the safety information form to Investigator sponsor within 5 calendar days of obtaining knowledge about the serious adverse event.
The investigator sponsor must inform the regulatory authorities and IECs in accordance with the local requirements in force and ICH GCP.
The investigator sponsor will notify the investigator of trial product related suspected unexpected serious adverse reactions in accordance with the local requirements. In addition, the Investigator will be informed of any trial related procedure SAE that may warrant a change of any trial procedure.
Investigators will be notified of trial-‐related SAEs in accordance with the local requirements in force.
Follow-‐up of adverse events
During and following a subject’s participation in a clinical trial, the Investigator/institution should ensure that adequate medical care is provided to the subject for any adverse events, including clinically significant laboratory values related to the trial. The Investigator/institution should inform the subject when medical care is needed for adverse event(s) of which the Investigator becomes aware.
The follow up information should only include new (updated and/or additional) information that reflects the situation at the time of the Investigator’s signature.
All non-‐serious AEs classified as severe or possibly/probably related to the trial product must be followed until the subject has recovered and all queries have been resolved. However, cases of chronic conditions can be closed with an outcome of “recovering” or “not recovered”. If subjects die from another event, these cases can be closed with an outcome of “recovering” or “not recovered”.
The Investigator must ensure that the worst case severity and seriousness is kept consistent through the series of adverse event form and related adverse event follow-‐up form(s).
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The Investigator must forward follow-‐up information on non-‐serious AEs on the adverse event follow-‐up form.
All serious AEs must be followed until the outcome of the event is recovered, recovered with sequelae or fatal and until all queries have been resolved. For cases of chronic conditions and cancer or if the subject dies from another event follow-‐up until the outcome categories are “recovered”, ”recovered with sequelae” or ”fatal” is not required, as these cases can be closed with an outcome of “recovering” or “not recovered”.
1.9 Rules for completing CRFs
The investigator staff must ensure that all information derived from source documentation is consistent with the source information. By uploading the complete dataset, the Investigator confirms that the information is complete and correct.
1.10 Corrections to CRFs
Corrections to the data on the CRFs can only be made by communicating to the Data Manager the alphanumeric code linked to the name of the patient and asking to modify the data.
1.11 CRF flow
CRFs will be supplied on electronic set at the web site www.clinicalregisters.org after the registration of the centre/investigator.
2 Data management
Data management is the responsibility of the principal investigator Dr. Federico Coccolini -‐ Dr. Luca Ansaloni
Data will be stored in an electronic database.
The subject will be identified by an alphanumeric code linked to the name of the patient that the enrolling investigator can see. Appropriate measures such as encryption or deletion will be enforced to protect the identity of human subjects in all presentations and publications as required by local/regional/national requirements.
During the patients entering in the database, data quality will be ensured.
Evaluability of subjects for analysis
At least one report analysis will be performed each year.
Major protocol deviations will lead to exclusion of data from the analysis, while data will not be excluded because of minor protocol deviations. The list of major protocol deviations will be detailed and documented in the clean file document prior to database release.
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Major protocol deviations will be summarized by treatment group. Furthermore all protocol deviations (minor and major) will be listed in patient data listings prior to statistical analyses.
Statistical considerations
It is not acceptable that anyone, neither Investigator nor sponsor investigator makes any form of between treatment group comparisons before database release.
All statistical comparisons will be based on two sided tests with a 5% significance level.
The investigator will be responsible for conducting the statistical analysis after data base release.
Sample size calculation
Sample size calculation: No sample size has been calculated, as this is a prospective cohort study that aims to enrol as much patients as possible.
However with a hypothesized number of 300 patients per year (the number of treated patients in the actually participating centres) with a CI of 95% the error and an expected death rate of 30%, the error margin (confidence interval) will be of 5.19.
Moreover, considering the expected death rate of 30% the different Hazard Ratio (HR) that can be detected linked to different variables (80% power, 0.05 alpha error), depending on different number of patients enrolled (100/150/200/250/300), is presented below:
Statistical methods
Demographics and other baseline characteristics
Demographics and baseline characteristics will be summarized by treatment group and listed.
Medical history, concomitant illnesses and concomitant medication
Medical history, concomitant illnesses, risk factors will be listed. Furthermore, the same factors will be summarized by treatment group.
Endpoint assessments
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Tabulations of categorical data will be summarized using counts and percentages, while continuous data will be presented using the number of patients (N), mean, standard deviation, median, minimum and maximum. All endpoints will be summarized in tables.
Univariate and multivariate analysis will be performed to evaluate the weight of the different variables on outcomes regarding the different OA technique.
Ethics
The trial will be conducted in accordance with the Declaration of Helsinki and according to local and regional ethical standards.
2.1 Informed consent form for trial subjects
In obtaining and documenting informed consent, the Investigator must comply with the applicable regulatory requirements and adhere to the requirements in the Declaration of Helsinki.
A voluntary, signed and personally dated, informed consent form will be obtained from the subject prior to the trial inclusion.
In those cases where the patient will not be able to sign the informed consent before the procedure, an informative module will be given to relatives to ask the temporary permission to collect data; once the patient will have recovered the possibility to express the consensus, if positive, data will be inserted into the database.
The responsibility for obtaining informed consent must remain with that of a medically qualified person and cannot be delegated to a non-‐medically qualified person. The written informed consent must be signed and personally dated, by the person who obtained the informed consent.
If information becomes available that may be relevant to the subject’s willingness to continue participating in the trial, the Investigator must inform the subject in a timely manner, and a revised written informed consent must be obtained.
2.2 Data handling
If the subject withdraws the previously given informed consent the subject’s data will be handled as follows:
• Data collected will be used as part of the full analysis set and safety population.
• Safety events will be reported to the regulatory authorities.
If data is used, it will always be in accordance with local law and IEC procedures.
2.3 Institutional review boards/independent ethics committee
Prior to commencement of the trial, the protocol, any amendments, subject information/informed consent form, any other written information to be provided to the subject, subject recruitment
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procedures (if any), the Investigator’s current CV and/or other documentation evidencing qualifications, and other documents as required by the independent ethics committee (IEC) should be submitted. The submission letter should clearly identify (by trial identification number, including version, EudraCT no., title and/or date of the document) which documents have been submitted to the IEC. Written approval/favourable opinion must be obtained from IEC prior to commencement of the trial.
During the trial, the Investigator must promptly in accordance with local requirements report the following to the IEC: unexpected SAEs where a causal relationship cannot be ruled out, substantial amendments to the protocol, non-‐substantial amendments according to local requirements, deviations to the protocol implemented to eliminate immediate hazards to the subjects, new information that may affect adversely the safety of the subjects or the conduct of the trial (including new risk/benefit analysis in case it will have an impact on the planned follow-‐up of the subjects), annually written summaries of the trial status and other documents as required by the local IEC.
Substantial amendments must not be implemented before approval/favourable opinion, unless necessary to eliminate hazards to the subjects.
The Investigator must maintain an accurate and complete record of all submissions made to the IEC. The records should be filed in the investigator’s trial file and copies must be sent to the sponsor investigator.
2.4 Regulatory authorities
Regulatory authorities will receive the protocol, substantial/non-‐substantial amendments to the protocol, reports on SAEs, and the clinical trial report according to national requirements.
3 Premature termination of the trial
The Sponsor investigator, Investigator or a pertinent regulatory authority may decide to stop the trial or part of the trial at any time but agreement on procedures to be followed must be obtained.
If a trial is prematurely terminated or suspended, the Investigator should promptly inform the subjects and assure appropriate therapy and follow-‐up. Furthermore, the Investigator and/or sponsor investigator should promptly inform the IEC and provide a detailed written explanation. The pertinent regulatory authorities should be informed according to national regulations.
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation should be provided to the IEC in case it will have an impact on the planned follow-‐up of the subjects who have participated in the trial. If so, the actions needed to protect the subjects should be described.
4 Protocol compliance
Deviations from the protocol should not occur.
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If deviations occur, the Investigator must inform the Coordinating centre principal investigator and the implications of the deviation must be reviewed and discussed.
Protocol deviations must be documented stating the reason, date, the action(s) taken, and the impact for the subjects and/or the trial except for protocol deviations where no corrections are required as described in the trial specific validation checks.
The documentation for the protocol deviations must be kept in the investigator’s trial file.
5 Critical documents
Before the Investigator starts the trial (i.e., obtains informed consent from the first subject), the following documents must be available:
• Regulatory approval and/or notification as required
• Signed and dated agreement on the final protocol
• Signed and dated agreement on any substantial amendment(s), if applicable
• Approval/favourable opinion from IEC clearly identifying the documents reviewed: the protocol, any substantial amendments, subject information/informed consent form and any other written information to be provided to the subject, subject recruitment procedures
• Financial agreement(s)
6 Responsibilities
The Investigator is accountable for the conduct of the trial. If any tasks are delegated, the Investigator should maintain a list of appropriately qualified persons to whom he/she has delegated specified significant trial-‐related duties.
The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician.
The Investigator will take all necessary technical and organizational safety measures to prevent accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent any unauthorized access to data or any other processing of data against applicable law.
Upon request from the sponsor investigator, the Investigator will provide the Sponsor investigator with the necessary information to enable the Sponsor investigator to ensure that such technical and organizational safety measures have been taken.
7 Reports and publications
The information obtained during the conduct of this trial is considered confidential and belongs to the investigator group for the purpose of a scientific publication. No confidential information shall
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be disclosed to others. Such information shall not be used except in the performance of this trial. The information obtained during this trial may be made available to other physicians who are conducting other clinical trials with the trial product, if deemed necessary by the investigators.
When the trial is final a clinical trial report will be written. This report will be reviewed by all involved investigators and signed off.
7.1 Authorship
Authorship of publications should be in accordance with guidelines from The International Committee of Medical Journal Editors’ Uniform Requirements44.
Dr. Federico Coccolini will be responsible for authoring the intended publication(s). To the Investigators that entered patients will be warranted authorship in one publication per year.
Each investigator which entered patients can at any time ask for his own data. In publishing these data He/She must include the two coordinating centre principal investigators (Dr. Federico Coccolini and Dr. Luca Ansaloni)
7.2 Publications
The trial results shall be reported in an objective, accurate, balanced and complete manner, with a discussion of the strengths and limitations of the trial. All authors will be given the relevant statistical tables, figures, and reports needed to support the planned publication. In the event of any disagreement about the content of any publication, all Investigators’ opinions shall be fairly and sufficiently represented in the publication.
8 Retention of clinical trial documentation
Subject notes must be kept for the maximum period permitted by the hospital, institution or private practice.
The Investigator must agree to archive the documentation pertaining to the trial in an archive after completion or discontinuation of the trial if not otherwise notified.
Clinical trial documentation must be retained until at least 2 years.
9 Indemnity statement
The study is covered by the insurance of the structure where it is conducted in.
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