Clinical Study Verifying C-REX LapAid in Clinical Practice
Clinical Study Verifying C-REX LapAid in Clinical Practice
In colorectal surgery, hand suturing and stapling are routine methods for performing
 intestinal anastomoses, and these methods appear to be similar in terms of clinical safety.
 Despite several years of experience with surgical procedures as well as improvements to the
 medical devices, problems with disturbed anastomotic healing leading to leakage and stenosis
 after colorectal surgery remain a significant challenge for surgeons. A frequency of
 anastomotic leakage after stapling or suturing has been reported to range from 3% to 20%. In
 addition, preoperative radiotherapy has been shown to increase the risk of anastomotic
 leakage even further.

 The methods that are used today to detect leakages are unfortunately inaccurately and limited
 to monitoring symptoms, temperature, CRP-levels, and performing abdominal examinations and
 CT-scans. These clinical signs and parameters usually become apparent several days after
 onset of the leakage, which leads to a delayed diagnosis. Anastomotic leakage is not only a
 significant cause of increased morbidity of complications and mortality in patients, but also
 associated with increased risk of local recurrence and poor prognosis. Moreover, when
 reoperation is required to fix the leakage, a permanent stoma may be made at the level of the
 sigmoid colon and this procedure impacts live quality of patients negatively.

 Based on the above considerations, a novel, adaptive anastomotic method has been developed by
 CarpoNovum to achieve a safer anastomosis. The method's working name is C-REX Ring-locking
 Procedure. C-REX is referred to our Colorectal anastomotic rings for Re-join the intestinal
 ends and validate the anastomosis, with function of Extract samples for analysis and conduct
 X-ray through connected catheters.

 The novel adaptive anastomotic medical devices, C-REX LapAid and C-REX DMH/DMHC are easy to
 use, with unique possibility to control the anastomosis during and after surgery. The
 previous successful preclinical study encourages a clinical verification in patients
 undergoing colonic resection to evaluate the safety and performance of C-REX Ring-locking
 Procedure by use of C-REX LapAid and C-REX DMH/DMHC.
OVERALL DESIGN The study is a prospective, multicenter, single arm study Possible study
 candidates are patients requiring resection of the left colon (descending colon and sigmoid)
 or the upper rectum (15cm above the anal rim) due to malign or benign disease. After informed
 consent has been achieved, and after physical examination and checking of inclusion/exclusion
 criteria, potential subjects will be enrolled in the study, and the investigational surgery
 will be performed during hospitalization. The devices, i.e. C-REX LapAid and C-REX DMH/DMHC,
 included in C-REX Ring-locking Procedure are applied to the inside of the intestine and
 connected to catheters that allow monitoring of the anastomosis (if DMC is applied).

 The healing period is expected to be approximately 10 ± 2 days. The short-term implant, i.e.
 the anastomotic ring, detaches via necrosis on the inner part of the intestinal surface and
 is expelled the natural way during hospitalization.

 The subject can be discharged from the hospital when the short-term implant has been
 evacuated, and the subject has begun to eat and has normal bowel movements. The observation
 period lasts until 30 days after surgery. The subject then continues follow-up according to
 local routine.

 QUALITY CONTROL Authorization to perform C-REX Ring-locking Procedure According to
 CarpoNovum's regulation (Document 0041: Procedure, Accreditation of Surgeons for Clinical
 Studies), clinical investigators must be authorized to conduct the C-REX Ring-locking
 Procedure with C-REX LapAid and C-REX DMH/DMHC by performing at least one surgery on pigs and
 at least one train-in surgery on patients with the person in charge of the study (MD, PhD,
 Senior colorectal surgeon Anders Grönberg). When the clinical investigator is authorized to
 perform the C-REX Ring-locking Procedure with C-REX LapAid System, he or she receives a
 certificate. This certificate could also admit the clinical investigator the right to
 authorize other surgeons to perform C-REX Ring-locking Procedure with C-REX LapAid and C-REX
 DMH/DMHC (i.e. to perform at least one operations on pigs and at least one train-in
 operations on patients with the authorized clinical investigator).

 Monitoring To ensure that the study is appropriately conducted, a monitor appointed by the
 sponsor will visit the investigation site regularly and oversee the investigator's compliance
 with the CIP, perform source-data verification and report to the sponsor on the progress of
 the study.

 Each investigation site and clinical investigator in the study will be monitored. On all
 occasions, the responsible monitor and/or the person in charge of the study will secure for
 example that:

 1. Compliance with CIP is maintained and any deviation from CIP is discussed with the
 clinical investigators, documented and reported to the sponsor; if the changes are
 significant, the competent authority and the ethical committee will be informed;

 2. The device is being used according to CIP, IB and IFU, and if modifications are required
 either to the device or its method of use or to the CIP, this need shall be reported to
 the sponsor;

 3. Signed and dated informed consent forms have been obtained from each subject at the time
 of enrolment and before any study-related procedures are undertaken;

 4. The data in CRFs are complete, are recorded in a timely manner and are consistent with
 the source data;

 5. Traceability and device accountability of the investigational device are properly
 maintained;

 6. Maintenance and calibration of equipment relevant for assessment of the study is
 performed;

 7. Possible adverse events or device deficiencies have been properly documented and
 reported;

 8. Subjects withdrawal and/or non-compliance is documented and discussed with the clinical
 investigator and reported to the sponsor;

 9. Clinical investigators have and continue to have staff and facilities to conduct the
 study safely and effectively;

 10. Clinical investigators have and continue to have access to an adequate number of
 subjects and the investigational device to complete the study.

 The responsible monitor will write a report after each visit to the medical institutions. The
 reports will be sent to the sponsor and the principal clinical investigators.

 Documentation and data processing Medical record of subjects

 The following information should be clearly documented in medical record of subjects:

 -  That the subject is informed about the study and that the subject has signed the
 informed consent forms.

 -  That the subject is participating in the study; the identification code for the subject,
 the name of the study, and the study number (i.e., CREX-005).

 -  Which treatment the study refers to (i.e., C-REX Ring-locking Procedure with use of
 C-REX LapAid and C-REX DMH/DMHC).

 -  Name of the principal clinical investigator.

 -  All AEs and device deficiencies. Document and data control Prior to commencement of the
 study, clinical investigators and their staff will be informed about CIP, CRFs and other
 study documents and procedures.

 For each subject enrolled, regardless of medical device initiation, a CRF must be completed
 and signed by corresponding investigation personnel. This applies to those subjects who fail
 to complete the study. If a subject withdraws from the study, the reason must be noted on
 CRF.

 Data and information of subjects derived from the study are considered as source data. To
 ensure that all data are complete and correct, source data verification (SDV) will be
 confirmed by the monitor.

 Comments in CRF should be made with a ballpoint pen with permanent ink in paper based CRF. In
 both paper based CRF and eCRF, if comments are missing in CRF, reasons for this must be
 stated. No questions, squares, fields or similar should be left without comments.

 CRF entries and corrections will only be performed by investigational personnel, authorized
 by the principle clinical investigator. In paper based CRF, errors should be crossed out but
 not obliterated, the correction inserted, and the change initialled and dated by the clinical
 investigator.

 Then entries will be checked by the monitor and any errors or inconsistencies will be checked
 and corrected immediately.

 The responsible clinical investigator is obliged to keep the subject identification lists
 with the subject's identification code and identity in a safe place at the investigation site
 (hospital), accessible only to the investigation personnel. These source data and subject
 identification lists will be saved for 10 years after the close of the study at the medical
 institution.

 NUMBER OF SUBJECTS The aim of this study is to verify the novel device in clinical practise
 in a big population. Since no control group is included, there is no need for power
 determinations.

 Considering that similar anastomotic devices have been used in clinic for decades, the study
 will include about 250 subjects from 5 different centres/hospitals. In which, 100 subjects
 will be included in Fudan University Shanghai Cancer Center.

 STATISTICAL ANALYSIS OF VARIABLES Descriptive methods are used to analyze the data collected
 in the study. The incidences of anastomotic leakage and other AEs/device deficiencies are
 calculated.
Inclusion Criteria:

 1. Male or female age ≥18 years and ≤80 years.

 2. Planned resection due to benign or malign disease in the left colon (descending colon
 and sigmoid) or the upper rectum (15 cm above the anal rim).

 3. Cognitive ability to take part in the study and understand the information he/she
 receives about participating in the study.

 4. The patient has signed a written informed consent.

 Exclusion Criteria:

 1. Urgent medical condition requiring immediate care.

 2. Current surgical conditions, such as intestinal obstruction or perforation, local or
 systemic infections, peritonitis, intestinal ischemia or severe dissemination
 (metastases) of cancer.

 3. Stenosis or other obstructions in the anal passage.

 4. Previous major abdominal surgery, previous radiation therapy to organs in abdomen or
 pelvis.

 5. Health condition classified as ASA III - VI .

 6. Albumin level less than 35 g/l.

 7. Inflammatory bowel disease (IBD) (ulcerative colitis or Crohn´s disease).

 8. Disease that requires more than one anastomosis during the surgical procedure.

 9. Treatment with cortisone and/or other immunosuppressive medications less than one
 month before surgery.

 10. Contraindications to general anaesthesia.

 11. Perioperative detection of extreme variants of intestinal diameters or wall thickness.

 12. Cognitive ability that limits the patient's ability to take part in the study and
 understand the information he/she received about participating in the study, or the
 patient does not agree to join the study.

 13. BMI > 35.

 14. Myocardial infarct ≤ 6 months or sever heart disease.

 15. Severe embolic disease.

 16. Other conditions which surgeons think the patient should be excluded.