Minimally invasive versus open pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) for premalignant and malignant disease; Robotic versus open pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) in patients with pancreatic head cancer (DIPLOMA-2x2)
| ISRCTN | ISRCTN27483786 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN27483786 |
| Secondary identifying numbers | NL77750.018.21 |
- Submission date
- 06/01/2022
- Registration date
- 11/01/2022
- Last edited
- 14/04/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Surgery
Plain English summary of protocol
Background and study aims
For patients with a (pre-)malignant pancreatic or periampullary (head of the pancreas) tumor, a pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) is the only treatment with curative intent. A pancreatoduodenectomy is a complex operation with high technical difficulty and challenging postoperative management. Despite major improvements in the last decade, pancreatoduodenctomy remains associated with considerable perioperative morbidity (illness around the time of surgery), strongly impacting the patient’s quality of life and healthcare resources. Minimally invasive pancreatoduodenectomy (MIPD), both robot-assisted and laparoscopic (keyhole surgery), has gained popularity in the last decade and reduces surgical trauma as compared to open pancreatoduodenectomy (OPD), aiming for faster recovery and improved outcomes. However, MIPD is associated with higher costs and a longer learning curve, and there have been conflicting results with regard to postoperative complications compared to OPD. As MIPD is increasingly being used in clinical practice worldwide, a randomized controlled trial (RCT) comparing MIPD to the open approach is needed to demonstrate that MIPD offers improved outcomes that justify the high cost, longer operative times, and steep learning curve.
Therefore, the aim of this study is to compare the outcomes of MIPD (both robotic and laparoscopic) with OPD for premalignant and malignant disease. The study is designed to primarily investigate the safety of MIPD (both robotic and laparoscopic) in terms of morbidity (illness) and mortality (death), and furthermore to assess if MIPD is superior to OPD in terms of time to functional recovery.
Who can participate?
Patients aged over 18 years who require pancreatoduodenectomy for resection of premalignant or malignant disease.
What does the study involve?
Participants are randomly allocated to either minimally invasive or open surgery. After surgery, patients receive a large abdominal dressing to mask their treatment by covering all incisions. This abdominal dressing is removed when recovery is complete on day 5 after the operation or for medical reasons, such as suspicion of a wound infection. Participants will be asked to wear a Fitbit™ Inspire 2 watch from before surgery up to 90 days after surgery. Participants complete quality of life questionnaires before surgery and at 1, 3 and 6 months after surgery. Survival rates are calculated for 1 and 3 years after the surgery.
What are the possible benefits and risks of participating?
Minimally invasive surgery may reduce the time to functional recovery, length of hospital stay and improve short-term quality of life, with similar postoperative morbidity rates. All centers have experience of more than 60 minimally invasive procedures before the study. There are no added risks.
Where is the study run from?
1. Amsterdam UMC (Netherlands)
2. Fondazione Poliambulanza Istituto Ospedaliero (Italy)
When is the study starting and how long is it expected to run for?
July 2020 to December 2026
Who is funding the study?
1. Amsterdam UMC (Netherlands)
2. Fondazione Poliambulanza Istituto Ospedaliero (Italy)
3. Intuitive Surgical Inc. (USA)
Who is the main contact?
1. Prof. Marc G. Besselink, m.g.besselink@amsterdamumc.nl
2. Prof. Mohammed Abu Hilal, abuhilal9@gmail.com
For DIPLOMA-2x2:
Background and study aims
For patients with a cancer in the pancreatic head (pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC]), a pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) is the only treatment with curative intent. A pancreatoduodenectomy is a complex operation with high technical difficulty and challenging postoperative management. Despite major improvements in the last decade, pancreatoduodenctomy remains associated with considerable perioperative morbidity (illness around the time of surgery), strongly impacting the patient’s quality of life and healthcare resources. Robot-assisted pancreatoduodenectomy (RPD) has gained popularity in the last decade. The safety of the robotic approach has recently been confirmed with comparable postoperative complications and enhanced postoperative recovery compared to open pancreatoduodenectomy (OPD). However, studies in gynecology and colorectal surgery showed that minimally invasive surgery was inferior in terms of radicality in patients with malignant disease. Hence, the oncological safety of RPD as compared to OPD remains to be determined.
Therefore, the aim of this study is to compare the oncological outcome of RPD with OPD for cancer in the pancreatic head (PDAC and DCC). The study is designed to primarily investigate the radicality (R0 resection rate), and furthermore to assess if RPD is superior to OPD in terms of time to functional recovery in patients with cancer in the pancreatic head.
Who can participate?
Patients aged over 18 years who require pancreatoduodenectomy for resection of PDAC or DCC.
What does the study involve?
Participants are randomly allocated to either robot-assisted or open surgery. After surgery, patients receive a large abdominal dressing to mask their treatment by covering all incisions. This abdominal dressing is removed when recovery is complete on day 5 after the operation or for medical reasons, such as suspicion of a wound infection. Participants complete quality of life questionnaires before surgery and at 1, 3, 6 months and 1, 3, and 5 years after surgery. Survival rates are calculated for 1, 3, and 5 years after the surgery.
What are the possible benefits and risks of participating?
Robot-assisted surgery may reduce the time to functional recovery, length of hospital stay, and the time to start adjuvant therapy, with similar postoperative morbidity rates. All centers have experience of more than 60 minimally invasive procedures before the study. There are no added risks.
Where is the study run from?
Amsterdam UMC (Netherlands)
When is the study starting and how long is it expected to run for?
December 2023 to February 2026
Who is funding the study?
1. Amsterdam UMC (Netherlands)
2. Intuitive Surgical Inc. (USA)
3. Dutch Cancer Society (KWF)
Who is the main contact?
1. Prof. Marc G. Besselink, m.g.besselink@amsterdamumc.nl
2. Prof. Mohammed Abu Hilal, abuhilal9@gmail.com
Contact information
Principal Investigator
De Boelelaan 1117
Amsterdam
1081HV
Netherlands
 ORCID ID |
0000-0003-2650-9350 |
|---|---|
| Phone | +31 (0)625126464 |
| m.g.besselink@amsterdamumc.nl |
Principal Investigator
Via Leonida Bissolati 57
Brescia
25124
Italy
| ORCID ID |
0000-0002-3162-4639 |
|---|---|
| Phone | +39 (0)303518028 |
| abuhilal9@gmail.com |
Study information
| Study design | Multicenter international patient-blinded randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 40905_PIS_v1.5_18Nov21.pdf |
| Scientific title | Minimally invasive versus open pancreatoduodenectomy for pancreatic and periampullary neoplasms (DIPLOMA-2): an international multicenter patient-blinded randomized controlled trial; Robotic versus open pancreatoduodenectomy in patients with primary resectable pancreatic head cancer (DIPLOMA-2x2): an international multicenter patient and assessor blinded randomized controlled trial |
| Study acronym | DIPLOMA-2; DIPLOMA-2x2 |
| Study objectives | Current study hypothesis as of 06/02/2025: The DIPLOMA-2 trial is designed to primarily investigate the safety of minimally invasive pancreatoduodenectomy (MIPD) (both robotic and laparoscopic) in terms of morbidity and mortality, and furthermore to assess if MIPD is superior to open pancreatoduodenectomy (OPD) in terms of time to functional recovery. The trialists hypothesise that MIPD has similar postoperative morbidity and mortality as compared to OPD, and is superior to OPD in terms of postoperative recovery; The DIPLOMA-2x2 trial is designed to primarily investigate the oncological safety of robot-assisted pancreatoduodenectomy (RPD) in terms of radicality (R0 resection rate), and furthermore to assess if RPD is superior to open pancreatoduodenectomy (OPD) in terms of time to functional recovery. The trialists hypothesis that RPD has a similar radicality as compared to OPD, and is superior to OPD in terms of postoperative recovery. _____ Previous study hypothesis: The DIPLOMA-2 trial is designed to primarily investigate the safety of minimally invasive pancreatoduodenectomy (MIPD) (both robotic and laparoscopic) in terms of morbidity and mortality, and furthermore to assess if MIPD is superior to open pancreatoduodenectomy (OPD) in terms of time to functional recovery. The trialists hypothesise that MIPD has similar postoperative morbidity and mortality as compared to OPD, and is superior to OPD in terms of postoperative recovery. |
| Ethics approval(s) | 1. Approved 02/12/2021, Medical Ethics Review Committee of the Academic Medical Center (Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands; +31 (0) 20 5669111; mec@amc.nl), ref: 2021_137 2. Approved 04/10/2021, Comitato Etico di Brescia (Piazzale Spedali Civili 1, 25123, Brescia, Italy; +39 (0)303996507; comitato.etico@asst-spedalicivili.it) 3. Amendment for DIPLOMA-2x2: approved 28/09/2023, Medical Ethics Review Committee of the Academic Medical Center (Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands; +31 (0) 20 5669111; mec@amc.nl), ref: 2021_137 |
| Health condition(s) or problem(s) studied | Pancreatoduodenectomy for premalignant and malignant disease For DIPLOMA-2x2: Pancreatoduodenectomy for cancer in the pancreatic head (pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC]) |
| Intervention | Current interventions as of 06/02/2025: This study is designed for patients with an indication for an elective pancreatoduodenectomy for premalignant and malignant disease. After inclusion, patients are randomly allocated in a 2:1 ratio to either a minimally invasive (MI) procedure or an open procedure, respectively. Randomization is stratified by: 1. Postoperative fistula risk: normal/high (based on pancreatic duct size and BMI) 2. Pancreatic ductal adenocarcinoma: yes/no 3. Intended MI procedure (in case of randomization to the MI arm): robot-assisted/laparoscopic Randomization will take place as soon as the surgery can be planned, using Castor EDC, with variable block sizes of 3/6/9. Patients will have a pre-surgery assessment conforming to local protocol. Patients are blinded for the type of surgery they will receive. Patients will receive a large 40 cm x 40 cm abdominal dressing directly after surgery to mask their treatment (minimally invasive or open) by covering all incisions. This abdominal dressing will be removed when all criteria for functional recovery are met or at postoperative day 5. The dressing can be removed in case of any medical reasons (i.e. wound infection). If earlier inspection is required, attempts are made to maintain patient blinding. This blinding has been proven successful in previous multicenter (European) trials. A complete double-blinding, including medical and nursing ward staff, is considered not feasible. However, a blinded adjudication committee will assess the primary endpoint. Patients are asked to wear a personal, display-blinded Fitbit™ Inspire 2 device up to 90 days after surgery, that will measure activity. A preoperative baseline activity will be captured. Patients are asked to complete quality of life questionnaires at baseline, 1 month, 3 months and 6 months after surgery. Survival rates will be calculated for 1 and 3 years postoperative; The DIPLOMA-2x2 study is designed for patients with an indication for an elective pancreatoduodenectomy for PDAC and DCC. After inclusion, patients are randomly allocated in a 2:1 ratio to either a minimally invasive (MI) procedure or an open procedure, respectively. Randomization is stratified by: 1. Postoperative fistula risk: normal/high (based on pancreatic duct size and BMI) 2. Pancreatic ductal adenocarcinoma: yes/no 3. Intended MI procedure (in case of randomization to the MI arm): robot-assisted/laparoscopic Randomization will take place as soon as the surgery can be planned, using Castor EDC, with variable block sizes of 3/6/9. Patients will have a pre-surgery assessment conforming to local protocol. Patients are blinded for the type of surgery they will receive. Patients will receive a large 40 cm x 40 cm abdominal dressing directly after surgery to mask their treatment (robot-assisted or open) by covering all incisions. This abdominal dressing will be removed when all criteria for functional recovery are met or at postoperative day 5. The dressing can be removed in case of any medical reasons (i.e. wound infection). If earlier inspection is required, attempts are made to maintain patient blinding. This blinding has been proven successful in the previous DIPLOMA-2 trial. A complete double-blinding, including medical and nursing ward staff, is considered not feasible. However, blinded pathologists will assess the primary endpoint. Patients are asked to complete quality of life questionnaires at baseline, 1 month, 3 months and 6 months after surgery. Survival rates will be calculated for 1, 3, and 5 years postoperatively. _____ Previous interventions: This study is designed for patients with an indication for an elective pancreatoduodenectomy for premalignant and malignant disease. After inclusion, patients are randomly allocated in a 2:1 ratio to either a minimally invasive (MI) procedure or an open procedure, respectively. Randomization is stratified by: 1. Postoperative fistula risk: normal/high (based on pancreatic duct size and BMI) 2. Pancreatic ductal adenocarcinoma: yes/no 3. Intended MI procedure (in case of randomization to the MI arm): robot-assisted/laparoscopic Randomization will take place as soon as the surgery can be planned, using Castor EDC, with variable block sizes of 3/6/9. Patients will have a pre-surgery assessment conforming to local protocol. Patients are blinded for the type of surgery they will receive. Patients will receive a large 40 cm x 40 cm abdominal dressing directly after surgery to mask their treatment (minimally invasive or open) by covering all incisions. This abdominal dressing will be removed when all criteria for functional recovery are met or at postoperative day 5. The dressing can be removed in case of any medical reasons (i.e. wound infection). If earlier inspection is required, attempts are made to maintain patient blinding. This blinding has been proven successful in previous multicenter (European) trials. A complete double-blinding, including medical and nursing ward staff, is considered not feasible. However, a blinded adjudication committee will assess the primary endpoint. Patients are asked to wear a personal, display-blinded Fitbit™ Inspire 2 device up to 90 days after surgery, that will measure activity. A preoperative baseline activity will be captured. Patients are asked to complete quality of life questionnaires at baseline, 1 month, 3 months and 6 months after surgery. Survival rates will be calculated for 1 and 3 years postoperative. |
| Intervention type | Procedure/Surgery |
| Primary outcome measure | Current primary outcome measure as of 06/02/2025: Overall postoperative morbidity and mortality, measured in terms of the comprehensive complication index (CCI), representing the accumulative morbidity up to 90 days after surgery, scored using the Clavien-Dindo classification for complications; For DIPLOMA-2x2: radicality (R0 resection rate) _____ Previous primary outcome measure: Overall postoperative morbidity and mortality, measured in terms of the comprehensive complication index (CCI), representing the accumulative morbidity up to 90 days after surgery, scored using the Clavien-Dindo classification for complications |
| Secondary outcome measures | 1. Days to functional recovery after surgery, which requires that all the following criteria are met: adequate pain control with oral analgesia only; ability to maintain sufficient (≥50% of required) caloric intake; absence of intravenous fluid administration; restoration of mobility to an independent level (or to preoperative level); no signs of active infection (no fever, decreasing C-reactive protein below 150 mg/L). Measured by the local surgical team every postoperative day until all criteria are reached. 2. Postoperative activity, measured using a personal, display-blinded Fitbit™ Inspire 2 device at baseline (1-2 weeks preoperative) and up to 90 days postoperatively 3. Intraoperative parameters: total operative time (first skin incision to fully closed skin incisions, min); time of reconstruction phase; blood loss; serious intra-operative complications; conversion; reason for conversion; surgeon’s mental strain and ergonomics. All variables are collected by the surgical team using an intraoperative electronic case report form (eCRF), completed at the end of surgery. 4. Pancreatic surgery specific complications including pancreatic fistula; delayed gastric emptying; postoperative bleeding; bile leak; chyle leak; other gastrointestinal leakage; wound infection; pneumonia; re-interventions (radiographic, endoscopic, surgical); in hospital, 30- and 90-day mortality. All variables are collected by the local study team using a postoperative eCRF up to 90 days after surgery. 5. Oncological outcomes: R0 resection rate; number of resected lymph nodes / lymph node ratio; start of adjuvant therapy (if indicated); time to adjuvant therapy in days (if indicated). All variables are collected by the local study team using a postoperative eCRF up to 6 months after surgery. Overall and disease-free survival is measured using 1- and 3-year follow-up by the local study team. 6. Hospitalization parameters: days from surgery to discharge (length of hospital stay); readmission rates; total hospitalized days; intensive care admission. . All variables are collected by the local study team using a postoperative eCRF up to 90 days after surgery. 7. Patient-reported outcomes: (health-related) quality of life measured using validated European Organisation for Research and Treatment of Cancer (EORTC) questionnaires (electronic or post-distributed) at baseline, 1, 3, 6 months, 1 and 3 years; patient-reported time to return to pre-operative condition; patient satisfaction with treatment; complications of scar, all collected using validated EORTC questionnaires (electronic or post-distributed) at 6 months. 8. Costs: during the 6 months after randomization, use of hospital healthcare resources is collected from case report forms, and electronic hospital information systems; quality-adjusted life years (QALY) using the EORTC EQ-5D-5L questionnaire, calculated up to 6 months and 3 years. |
| Overall study start date | 01/07/2020 |
| Completion date | 31/12/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 288; For DIPLOMA-2x2: 396 (of which 119 patients yet included in the DIPLOMA-2 trial) |
| Key inclusion criteria | Current inclusion criteria as of 06/02/2025: 1. Age at least 18 years 2. Indication for elective pancreatoduodenectomy for a tumor located in the pancreatic head, distal bile duct, duodenum or ampulla of Vater 3. Both minimally invasive pancreatoduodenectomy and open pancreatoduodenectomy are technically feasible for radical resection, according to the local treatment team 4. Pre-operative multiphase CT scan showing no signs of vascular involvement (in case of (suspected) malignancy: maximum 28 days old CT-scan available) 5. Fit to undergo pancreatoduodenectomy according to the surgeon and anesthesiologist 6. Written informed consent For DIPLOMA-2x2 1. Age at least 18 years 2. Indication for elective pancreatoduodenectomy for cancer in the pancreatic head (PDAC and DCC) 3. Both robot-assisted pancreatoduodenectomy and open pancreatoduodenectomy are technically feasible for radical resection, according to the local treatment team 4. Pre-operative multiphase CT scan showing no signs of vascular involvement (in case of (suspected) malignancy: maximum 28 days old CT-scan available) 5. Fit to undergo pancreatoduodenectomy according to the surgeon and anesthesiologist 6. Written informed consent _____ Previous inclusion criteria: 1. Age at least 18 years 2. Indication for elective pancreatoduodenectomy for a tumor located in the pancreatic head, distal bile duct, duodenum or ampulla of Vater 3. Both minimally invasive pancreatoduodenectomy and open pancreatoduodenectomy are technically feasible for radical resection, according to the local treatment team 4. Pre-operative multiphase CT scan showing no signs of vascular involvement (in case of (suspected) malignancy: maximum 28 days old CT-scan available) 5. Fit to undergo pancreatoduodenectomy according to the surgeon and anesthesiologist 6. Written informed consent |
| Key exclusion criteria | Current exclusion criteria as of 06/02/2025: 1. A second cancer requiring resection during the same procedure 2. Chronic pancreatitis as indication (including Groove pancreatitis) 3. Any vascular involvement (portal vein, superior mesenteric vein, superior mesenteric artery, coeliac artery or hepatic artery) 4. Pregnancy 5. Body mass index >35 kg/m² 6. Participation in another study with interference of study outcomes For DIPLOMA-2x2: 1. A second cancer requiring resection during the same procedure 2. Chronic pancreatitis as indication (including Groove pancreatitis) or necrotizing pancreatitis 3. Any vascular involvement (portal vein, superior mesenteric vein, superior mesenteric artery, coeliac artery or hepatic artery) 4. Pregnancy 5. Body mass index >35 kg/m² 6. Participation in another study with interference of study outcomes _____ Previous exclusion criteria: 1. A second cancer requiring resection during the same procedure 2. Chronic pancreatitis as indication (including Groove pancreatitis) 3. Any vascular involvement (portal vein, superior mesenteric vein, superior mesenteric artery, coeliac artery or hepatic artery) 4. Pregnancy 5. Body mass index >35 kg/m² 6. Participation in another study with interference of study outcomes |
| Date of first enrolment | 17/01/2022 |
| Date of final enrolment | 01/02/2026 |
Locations
Countries of recruitment
- Belgium
- France
- Germany
- Italy
- Luxembourg
- Netherlands
- Russian Federation
- Spain
- United States of America
Study participating centres
Amsterdam
1081 HV
Netherlands
Brescia
25124
Italy
-
Netherlands
-
Netherlands
-
Netherlands
-
Netherlands
-
Netherlands
-
Belgium
-
France
-
France
-
Italy
-
Italy
-
Italy
-
Luxembourg
-
Germany
-
Germany
-
Belgium
-
Italy
-
Germany
-
Italy
-
Sweden
-
Spain
-
United States of America
Sponsor information
Hospital/treatment centre
De Boelelaan 1117
Amsterdam
1081 HV
Netherlands
| Phone | +31 (0)204444444 |
|---|---|
| secretariaatrvb@amc.nl | |
| Website | https://www.amsterdamumc.org/research/institutes/cancer-center-amsterdam.htm |
"ROR" |
https://ror.org/05grdyy37 |
Hospital/treatment centre
Via Leonida Bissolati 57
Brescia
25124
Italy
| Phone | +39 (0)303518028 |
|---|---|
| cge.segreteria@poliambulanza.it | |
| Website | http://www.poliambulanza.it/english-area |
|
"ROR" |
https://ror.org/03kt3v622 |
Funders
Funder type
Hospital/treatment centre
Private sector organisation / Universities (academic only)
- Alternative name(s)
- Academic Medical Center, AMC
- Location
- Netherlands
Private sector organisation / Trusts, charities, foundations (both public and private)
- Location
- Italy
Private sector organisation / For-profit companies (industry)
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/01/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The study protocol and statistical analysis plan will be published before the end of participant inclusion. The results of this study will be submitted to a high-impact peer-reviewed medical journal regardless of the study outcome. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 1.5 | 18/11/2021 | 11/01/2022 | No | Yes |
| Protocol article | 12/10/2023 | 16/10/2023 | Yes | No |
Additional files
Editorial Notes
14/04/2025: The study participating centre Johns Hopkins Hospital was added.
03/03/2025: Contact details updated.
06/02/2025: The following changes were made to the trial record:
1. The public title was changed from "Minimally invasive versus open pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) for premalignant and malignant disease" to "Minimally invasive versus open pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) for premalignant and malignant disease; Robotic versus open pancreatoduodenectomy (surgery to remove the head of the pancreas, duodenum, gallbladder and other nearby tissues) in patients with pancreatic head cancer (DIPLOMA-2x2)".
2. The scientific title was changed from "Minimally invasive versus open pancreatoduodenectomy for pancreatic and periampullary neoplasms (DIPLOMA-2): an international multicenter patient-blinded randomized controlled trial" to "Minimally invasive versus open pancreatoduodenectomy for pancreatic and periampullary neoplasms (DIPLOMA-2): an international multicenter patient-blinded randomized controlled trial; Robotic versus open pancreatoduodenectomy in patients with primary resectable pancreatic head cancer (DIPLOMA-2x2): an international multicenter patient and assessor blinded randomized controlled trial".
3. The acronym was changed from DIPLOMA-2 to DIPLOMA-2; DIPLOMA-2x2.
4. The study hypothesis was changed.
5. The ethics approval (3) was added.
6. The condition was updated.
7. The interventions were changed.
8. The primary outcome measure was changed.
9. The inclusion criteria were changed.
10. The target number of participants was updated.
11. The exclusion criteria were changed.
12. The recruitment end date was changed from 01/01/2024 to 01/02/2026.
13. The country of recruitment Sweden was added.
14. The study participating centre Moscow Clinical Scientific Center was removed and Antwerp University Hospital, University of Verona Hospital Trust, Hamburg Eppendorf University Hospital, Azienda Ospedaliero Universitaria Pisana, Linköping University Hospital, Hospital Universitari Germans Trias I Pujol were added.
15. The plain English summary was updated to reflect these changes.
16/10/2023: Publication reference added.
12/01/2022: Internal review.
11/01/2022: Trial's existence confirmed by the Medical Ethics Review Committee of the Academic Medical Center.
