Patient factors associated with embolization or splenectomy within 30 days of initiating surveillance for splenic trauma.

BACKGROUND: Non-operative management of hemodynamically stable patients with splenic trauma has been recommended for more than 25 years, but in practice embolization and/or splenectomy (intervention) is often needed within the first 30 days. Identifying the risk factors associated with the need for intervention could support more individualized decision-making. METHODS: We used data from the SPLASH randomized clinical trial, a comparison of outcomes of surveillance or embolization. 140 patients were randomized, 133 retained in the study (embolization n = 66; surveillance n = 67) and 103 screened and registered in the non-inclusion register. Multivariate Cox proportional hazards models with time-varying covariates were used to identify risk factors contributing to embolization and/or splenectomy within 30 days after initiating surveillance only for splenic trauma. RESULTS: 123 patients (median age, 30 [23; 48] years; 91 (74%) male) initially received non-operative management. At the day-30 visit, 34 (27.6%) patients had undergone an intervention (31 (25.2%) delayed embolization and 4 (3.3%) splenectomy). Multivariate analysis identified patients with OIS grade 4 or 5 splenic trauma (HR = 4.51 [2.06-9.88]) and (HR = 34.5 [6.84-174]); respectively) and splenic complications: arterial leak (HR = 1.80 [1.45-2.24]), pseudoaneurysm (HR = 1.22 [1.06-1.40]) and pseudocyst (HR = 1.41 [1.21-1.64]) to be independently associated with increased risk of need for an intervention within 30 days of initiating surveillance. CONCLUSIONS: Our study shows that more than 1 in 4 patients who received non-operative management needed embolization or splenectomy by day 30. Arterial leak, pseudoaneurysm, pseudocyst, and OIS grade 4 or 5 were independent risk factors linked to the need for an intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT02021396.

Resuscitative thoracotomy in France: For whom? By whom?

Resuscitative thoracotomy is preferentially addressed to patients with penetrating thoracic injury and suffering from severe treatment-resistant hemodynamic instability, without pulse or in cardiopulmonary arrest for at most 15minutes. It is practicable in an emergency room, or ideally, in an operating theater. The procedure always begins with left anterolateral thoracotomy and can be prolonged through transversal bi-thoracotomy or, more rarely and according to the presumed origin of the hemorrhage, through median sternotomy. In most cases the procedures to be carried out are relatively simple, and when they are more complex, it is possible to effectuate temporary hemostasis while awaiting the assistance of a second surgeon. We are persuaded that the above procedure should imperatively be learned and become part and parcel of the therapeutic arsenal of the surgeon tasked with management of trauma patients.

SAME day amBulatory c (SAMBA): a multicenter, prospective, randomized clinical trial protocol.

BACKGROUND: A recent meta-analysis concluded that outpatient appendectomy appears feasible and safe, but there is a lack of high-quality evidence and a randomized trial is needed. The aim of this trial is to demonstrate that outpatient appendectomy is non-inferior to conventional inpatient appendectomy in terms of overall morbi-mortality on the 30th postoperative day (D30). METHODS: SAMBA is a prospective, randomized, controlled, multicenter non-inferiority trial. We will include 1400 patients admitted to 15 French hospitals between January 2023 and June 2025. Inclusion criteria are patients aged between 15 and 74 years presenting acute uncomplicated appendicitis suitable to be operated by laparoscopy. Patients will be randomized to receive outpatient care (day-surgery) or conventional inpatient care with overnight hospitalization in the surgery department. The primary outcome is postoperative morbi-mortality at D30. Secondary outcomes include time from diagnosis to appendectomy, length of total hospital stay, re-hospitalization, interventional radiology, re-interventions until D30, conversion from outpatient to inpatient, and quality of life and patient satisfaction using validated questionnaires. DISCUSSION: The SAMBA trial tests the hypothesis that outpatient surgery (i.e., without an overnight hospital stay) of uncomplicated acute appendicitis is a feasible and reliable procedure in establishments with a technical platform able to support this management strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05691348. Registered on 20 January 2023.

Oncological outcomes and hospitalization cost of hyperthermic intraperitoneal chemotherapy (HIPEC) open and closed abdomen techniques: Results from two French expert centers.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) associated with CC0 excision is performed using either an open (OPEN_HIPEC) or closed abdominal technique (CLOSED_HIPEC). However, little data is available on the costs of this treatment, as there is no code for HIPEC in the French Classification of Medical Acts. Oncological outcomes and the mean cost of hospitalization were compared. METHODS: Between 2017 and 2021, 144 patients with peritoneal carcinomatosis (all etiologies) were included (OPEN_HIPEC, n = 70; CLOSED_HIPEC, n = 74) in this retrospective two-center study. Morbi-mortality, overall survival (OS), recurrence-free-survival (RFS) and mean cost of hospitalization were compared. RESULTS: The median OS and RFS were 71.3 months [63-71.5] and 26.8 months [20-35.3] respectively, and were similar for both techniques; and after stratification by histology. Multivariate analysis adjusted on PCI score of OS identified mitomycin as a protective factor (HR = 0.31 [0.10-0.90], p = 0.032) and ASA score>2 (HR = 2.32 [1.32- 4.06], p = 0.003) and number of resection (HR = 1.21 [1.06-1.39], p = 0.006) as a risk factors of RFS. Complication rates at day 30 were similar between OPEN and CLOSED_HIPEC, 31 (44.3 %) vs 42 (56.8 %); p = 0.135. OPEN_HIPEC had more severe complications (11 (35.5 %) vs 6 (14.3 %); p = 0.034). The mean cost of hospitalization was estimated as €15,627 for OPEN_HIPEC and €14,211 for CLOSED_HIPEC for a mean length-of-stay of 12.7 and 16.7 days respectively. The mean amount received by the hospital per hospitalization was estimated at €16,399 and €15,536 respectively. CONCLUSIONS: OS and RFS were similar for open and closed HIPEC. Severe complications at day 30 were more frequent in OPEN_HIPEC group. The amount received by hospital for both HIPEC techniques is sufficient.

Early Evaluation of a New French Surgery Course in the Best Practice of Dealing With Major Incidents and Mass Casualty Events.

OBJECTIVE: The main objective of this study is to evaluate the impact of a nationwide 5-month course aimed to prepare surgeons for Major Incidents through the acquisition of key knowledge and competencies. Learners' satisfaction was also measured as a secondary objective. DESIGN: This course was evaluated thanks to various teaching efficacy metrics, mainly based on Kirkpatrick's hierarchy in medical education. Gain in knowledge of participants was evaluated by multiple-choice tests. Self-reported confidence was measured with 2 detailed pre and post training questionnaires. SETTING: Creation in 2020 of a nationwide, optional and comprehensive Surgical Training in War and Disaster Situation as part of the French surgery residency program. In 2021, data was gathered regarding the impact of the course on participants' knowledge and competencies. PARTICIPANTS: The study included 26 students in the 2021 cohort (13 residents and 13 practitioners). RESULTS: Mean scores were significantly higher in the post-test compared to the pre-test, showing significant increase in participants' knowledge during the course: 73,3% vs. 47,3% respectively (p ≤ 0.001). Average learners' confidence scores to perform technical procedures showed at least a +1-point increase on the Likert scale for 65% of items tested (p ≤ 0.001). 89% of items showed at least a +1-point increase on the Likert scale when it came to average learners' confidence score on dealing with complicated situations (p ≤ 0.001). Our post-training satisfaction survey showed that 92% of all participants have noticed the impact of the course on their daily practice. CONCLUSION: Our study shows that the third level of Kirkpatrick's hierarchy in medical education was reached. This course therefore appears to be meeting the objectives set by the Ministry of Health. Being only 2 years old, it is on the road to gathering momentum and further development.

Impact of Body Mass Index on Postoperative Pain and Opioid Administration After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, developed for the treatment of peritoneal carcinomatosis (PC). In this retrospective observational study we assessed the impact of body mass index (BMI) on postoperative pain and opioid consumption. METHODS: We analyzed pain scores after 100 PIPAC procedures using either oxaliplatin or doxorubicin-cisplatin performed in 49 patients with PC between July 2016 and September 2020. The patients were divided into 3 groups (BMI <18.5, 18.5 ≥ BMI < 25, BMI≥25). Pain was self-rated on a visual analogue scale (VAS) from 0 to 10. RESULTS: Univariate logistic regression analysis identified oxaliplatin and PCI score to be associated with moderate to severe pain (VAS 4-10 at 8 am D1) after adjustment on BMI (OR [95% CI]; 3.26[1.00 - 10.65] p=0.050) and (OR [95% CI]; 1.09[1.01 - 1.17] p=0.019). The level of pain appeared significantly different between the treatment groups (median 2.5[0; 5] vs 0[0; 2.5] p=0.0017) irrespective of BMI (p =0.705 and p=0.118). Multivariate logistic regression analysis identified moderate to severe pain and synchronous PC to be associated with greater use of opioids (OR [95% CI]: 3.91 [1.24 - 12.32]) and (OR [95% CI]: 5.16 [1.71 - 15.58]; respectively. Opioids were administered after 45 procedures (45%) and was comparable between the treatment groups. Opioid administration and length-of-stay were similar among BMI bands. CONCLUSION: BMI is not related to postoperative pain or opioid use, howevermoderate to severe pain and synchronous PC are factors associated with requiring opioids.

Preventive Proximal Splenic Artery Embolization for High-Grade AAST-OIS Adult Spleen Trauma without Vascular Anomaly on the Initial CT Scan: Technical Aspect, Safety, and Efficacy-An Ancillary Study.

The spleen is the most commonly injured organ in blunt abdominal trauma. Its management depends on hemodynamic stability. According to the American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS ≥ 3), stable patients with high-grade splenic injuries may benefit from preventive proximal splenic artery embolization (PPSAE). This ancillary study, using the SPLASH multicenter randomized prospective cohort, evaluated the feasibility, safety, and efficacy of PPSAE in patients with high-grade blunt splenic trauma without vascular anomaly on the initial CT scan. All patients included were over 18 years old, had high-grade splenic trauma (≥AAST-OIS 3 + hemoperitoneum) without vascular anomaly on the initial CT scan, received PPSAE, and had a CT scan at one month. Technical aspects, efficacy, and one-month splenic salvage were studied. Fifty-seven patients were reviewed. Technical efficacy was 94% with only four proximal embolization failures due to distal coil migration. Six patients (10.5%) underwent combined embolization (distal + proximal) due to active bleeding or focal arterial anomaly discovered during embolization. The mean procedure time was 56.5 min (SD = 38.1 min). Embolization was performed with an Amplatzer™ vascular plug in 28 patients (49.1%), a Penumbra occlusion device in 18 patients (31.6%), and microcoils in 11 patients (19.3%). There were two hematomas (3.5%) at the puncture site without clinical consequences. There were no rescue splenectomies. Two patients were re-embolized, one on Day 6 for an active leak and one on Day 30 for a secondary aneurysm. Primary clinical efficacy was, therefore, 96%. There were no splenic abscesses or pancreatic necroses. The splenic salvage rate on Day 30 was 94%, while only three patients (5.2%) had less than 50% vascularized splenic parenchyma. PPSAE is a rapid, efficient, and safe procedure that can prevent splenectomy in high-grade spleen trauma (AAST-OIS) ≥ 3 with high splenic salvage rates.

Deployment of the French Civil Protection Field Hospital (ESCRIM) in Gölbasi, Turkey after the February 2023 Earthquake: Lessons Learned.

Following the two earthquakes that occurred in Turkey on February 6, 2023 with magnitudes of 7.8 and 7.5, causing over 50,000 deaths and 100,000 injuries, France proposed to deploy, via the European Union Civil Protection Mechanism (EUCPM), the French Civil Protection Field Hospital (ESCRIM [Élément de Sécurité Civile Rapide d'Intervention Médicale]): the French World Health Organization (WHO)-classified Emergency Medical Team (EMT) Level 2 (EMT2).After the acceptance from Turkey on February 8, a disaster assessment team (DAT) was sent on February 10, 2023. It was decided, with local health authorities (LHA), to set up the field hospital in Gölbasi, Adiyaman Province where the State Hospital was closed due to a structural risk.Arriving in Gölbasi on February 13 at 2:00am in -12°C (10°F) temperatures, the detachment had no choice but to begin setting up the base of operation (BoO). At dawn, the cold was so intense that one doctor suffered from frostbite. Once the BoO was installed, the team set up the hospital tents. From 11:00am, the sun melted the snow and the ground became very muddy. The objective being to open the hospital as soon as possible, installation of the hospital continued, and it opened on February 14 at 12:00pm/noon, less than 36 hours after on-site arrival.This article describes the mechanics of setting up an EMT-2 in a cold climate, the many problems encountered, and the solutions imagined and proposed.

Association between Enhanced Recovery After Surgery (ERAS) protocol, risk factors and 3-year survival after colorectal surgery for cancer in the elderly.

INTRODUCTION: As life expectancy is currently growing, more elderly and fragile patients need colorectal resection for cancer. We sought to assess the link between enhanced rehabilitation after surgery (ERAS), risk factors and overall survival at 3 years, in patients aged 65 and over. METHODS: Between 2005 and 2017, all patients undergoing colorectal resection for cancer were included. Overall survival at 3 years was compared for patients treated in following ERAS guidelines compared to conventional treatment (pre-ERAS). RESULTS: 661 patients were included (ERAS, n = 325; pre-ERAS, n = 336). The 3-year overall survival rate was significantly better regardless of age for ERAS vs pre-ERAS patients (73.1% vs 64.4%; p = 0.016). With overall survival rates of 83.2% vs 73.8%, 65.4% vs 62.8% and 59.6% vs 40% for the age bands 65-74, 75-84 and ≥ 85 years. The analysis of survival at 3 years by a multivariate Cox model identified ERAS as a protective factor with a reduction in the risk of death of 30% (HR = 0.70 [0.50-0.94], p = 0017) independently of other identified risk factors: age bands, ASA score > 2, smoking, atrial fibrillation and abdominal surgery. This result is confirmed by an analysis of the propensity score (HR = 0.67 [0.47-0.97], p = 0.032). CONCLUSIONS: Our study shows that ERAS is associated with better 3-year survival in patients undergoing colorectal resection for cancer, independent of risk factors. The practice of ERAS is effective and should be offered to patients aged 65 and over.

Oncological Outcomes After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the Treatment of Peritoneal Carcinomatosis.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to assess its oncological outcomes. METHODS: Between July 2016 and September 2020, data from 100 PIPAC procedures with oxaliplatin or doxorubicin-cisplatin in 49 patients with PC (all etiologies) were analyzed. We studied the evolution of the peritoneal cancer index (PCI), the need for radical surgery (R0), and overall survival (OS). RESULTS: The patients' median age was 65 (59; 71) years, and 55.1% were women. Median PIPAC procedures per patient were 2 (1-3), and 28 (57.1%) underwent more than one PIPAC procedure. Median PCI at the first PIPAC was 19 (15-22). PCI decreased for 37%, remained stable for 29.6%, and increased for 33.4% patients. Four (8.3%) underwent radical R0 surgery after PIPAC. After a median follow-up of 16.1 months (1.5-90.1), the median overall survival from PC diagnosis was 29.1 months (14.8-34.3), with a median gastric and colorectal PC survival of 11.3 (7.2-34.3) and 29.1 months (16.1-31) respectively. Overall survival after the first PIPAC session was 11.6 months (6-17.3), with median survival after gastric and colorectal PCs being 6 (2.9-15.5) and 13.3 months (5-17.6), respectively. Stratification of patients according to the number of lines of systemic chemotherapy, PIPAC procedures, and the chronology of PC onset did not result in a significant difference in survival. CONCLUSION: The OS was in line with the literature. PIPAC could delay oncological progression and improve survival. These encouraging results justify the ongoing and future evaluations of PIPAC by prospective randomized trials.

Hospitalization cost of Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC).

INTRODUCTION: Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of unresectable peritoneal carcinomatosis. Very little data is available on the costs of this treatment in France as there is currently no code for PIPAC in the French Common Classification of Medical Acts (CCAM). Our objective was to estimate the mean cost of hospitalization for PIPAC in two French public teaching hospitals. METHODS: The mean cost of hospitalization was estimated from the mean fixed-rate remuneration paid to the hospital and the mean additional costs of treatment paid by the hospital. At discharge a patient's hospitalization is classified into a diagnosis related group, which determines the fixed-rate remuneration paid to the hospital (obtained from the national hospitals database - PMSI). Costs of medical devices and drug treatments specific to PIPAC, not covered by the fixed-rate remuneration, were obtained from the hospital pharmacies. RESULTS: Between July 2016 and November 2021, 205 PIPAC procedures were performed on 79 patients (mean procedures per patient = 2.6). Mean operating room occupancy was 165 min. The mean fixed-rate remuneration received by the hospitals per PIPAC hospitalization was €4031. The actual mean cost per hospitalization was €6562 for a mean length-of-stay of 3.3 days. Thus, each PIPAC hospitalization cost the hospital €2531 on average. CONCLUSION: The current reimbursement of PIPAC treatment by the national health system is insufficient and represents only 61% of the real cost. The creation of a new fixed-rate remuneration for PIPAC taking into account this cost differential is necessary.

Predictive factors of non-operative management failure in 494 blunt liver injuries: a multicenter retrospective study.

Non-operative management (NOM) has become the major treatment of blunt liver trauma (BLT) with a NOM failure rate of 3-15% due to liver-related complications. The aim of the study was to determine the predictive factors and a risk-stratified score of NOM failure. From 2013 to 2021, all patients with BLT in three trauma centers were included; clinical, biological, radiological and outcome data were retrospectively analyzed. Predictive factors and a risk-stratified score associated with NOM failure were identified. Four hundred and ninety-four patients with BLT were included. Among them, 80 (16.2%) had isolated BLT. Fifty-nine patients (11.9%) underwent emergent operative management (OM) on the day of admission and 435 (88.1%) had a NOM. NOM failure rate was 11.5%. Patients with a NOM failure more frequently had a hemoperitoneum (p < 0.001), liver bleeding (p < 0.001), blood transfusion (p < 0.001) and angioembolization (p < 0.001) compared to patient with a successful NOM. In multivariate analysis, the presence of hemoperitoneum (OR = 5.71; 95 CI [1.29-25.45]), angioembolization (OR = 8.73; 95 CI [2.04-38.44] and severe liver injury (AAST IV or V) (OR = 8.97; 95 CI [3.36-23.99]) were independent predictive factors of NOM failure. When these three factors were associated, NOM failure rate was 83.3%. The AAST grade, the presence of hemoperitoneum and the realization of liver angioembolization on the day of admission are three independent predictive factors of NOM failure. Our risk-score based on these three factors stratify the risk of NOM failure in BLT and could be used for a more appropriate level of medical survey adapted to each patient. Level of evidence: prospective observational cohort study, Level III.

Assessment of postoperative pain after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of peritoneal metastasis.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, for the treatment of initially unresectable peritoneal metastasis (PM). Our objective was to assess postoperative pain and morbidity. METHODS: Between July 2016 and September 2020, data from 100 consecutive PIPAC procedures with oxaliplatin (PIPAC Ox) or doxorubicin-cisplatin (PIPAC C/D) in 49 patients with PM (all etiologies) were analyzed. Pain was self-assessed using a visual analog scale (VAS) of 0-10. RESULTS: The median PIPAC procedures per patient were 2 [1-3]. Patients indicated greatest pain at 4 pm on the day of the procedure (D0) and on postoperative D1 at 8 am and 4 pm. Postprocedural moderate-to-severe pain (VAS 4-10) was more frequent with PIPAC Ox than with PIPAC C/D, respectively 14 (36.8%) vs 7 (13.5%); p = 0.010. Hospitalization was longer for patients with moderate-to-severe pain than for others (median 4 days [3-7] vs 3 days [2-4], p = 0.004). Multivariate analysis identified oxaliplatin as a factor associated with greater pain (OR [95% CI], 2.95 [1.10-7.89]. Opiate administration was similar after PIPAC Ox and PIPAC C/D procedures, p = 0.477. CONCLUSION: PIPAC was well-tolerated, and pain was well-controlled in the majority of patients. Pain was greatest at 4 pm on D0 and 8 am and 4 pm on D1. PIPAC Ox is associated with greater pain than PIPAC C/D, independently of opiate treatment. Moderate-to-severe pain was associated with longer hospital stays.

Effect of implementation of enhanced recovery after surgery (ERAS) protocol and risk factors on 3-year survival after colorectal surgery for cancer-a retrospective cohort of 1001 patients.

PURPOSE: Several recent studies have shown that the enhanced recovery after surgery (ERAS) protocol reduces morbidity and mortality and shortens the length of stay compared to conventional recovery strategy (pre-ERAS). The aim of this study was to evaluate the effect of the implementation of this protocol on 3-year overall survival and postoperative outcome in patients undergoing colorectal resection for cancer. METHODS: This was a retrospective, single-center, comparative, and non-randomized study. Between January, 2005, and December, 2017, 1001 patients were included (ERAS, n = 497; pre-ERAS, n = 504). RESULTS: The 3-year overall survival rate was significantly better for ERAS than for pre-ERAS patients (76.1 vs 69.2%; p = 0.017). The length of hospital stay (median 10 days vs 15; p = ≤ 0.001) and the 90-day readmission rate (15 vs 20%; p = 0.037) were significantly lower in the ERAS group. Three-year recurrence-free survival (p = 0.398) and 90-day complications (p = 0.560) were similar in the two groups. Analysis of 3-year survival by a multivariate Cox model identified ERAS as a protective factor with a 30% reduction in the risk of death: (HR = 0.70 [0.55-0.90]). CONCLUSION: The implementation of the ERAS protocol was associated with an improvement in 3-year survival, a reduction of the length of hospital stay and the rate of readmission. ERAS is associated with better 3-year survival, independent of other commonly considered parameters. An ASA score > 2, smoking, a history of cancer, and atrial fibrillation are deleterious risk factors linked to earlier mortality.

Effect of Pressurized Intraperitoneal Aerosol Chemotherapy on the Survival Rate of Patients with Peritoneal Carcinomatosis of Gastric Origin.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to compare the results of PIPAC associated with systemic chemotherapy (PIPAC_CHEM) with those of systemic chemotherapy alone (ONLY_CHEM) in patients with gastric PC without metastasis other than peritoneal, and the WHO performance status < 3. METHODS: This was a retrospective, single center, comparative non-randomized study. Seventeen PIPAC_CHEM patients were compared to 29 ONLY_CHEM patients. The primary endpoint was overall survival at 6 months from diagnosis of PC. RESULTS: Ninety-eight patients were screened and 46 were included (PIPAC_CHEM, n = 17; ONLY_CHEM, n = 29). The PIPAC_ CHEM population was significantly younger (median 64 years [56; 68] vs 74 years [61; 79]; p = 0.0054). Median PIPAC session per patient is 2 [1-3]. Six-month survival was significantly higher in the PIPAC_CHEM group than in the ONLY_CHEM group 16/17 (94.1% [65-99.2]) vs 19/29 (65.5% [45.4-79.7]), respectively; p = 0.029. Over the entire follow-up, median survival [95% CI] was 12.8 months [7.2-34.3] with PIPAC vs 9.1 months [5.4-11.5] without, p = 0.056. At 6 months, median length of additional hospitalization was significantly less for PIPAC_CHEM (median 2 days [2-7]) than without PIPAC (median 11 days [3-21]) (p = 0.045). CONCLUSION: The overall survival at 6 months after the diagnosis of carcinomatosis was significantly better for PIPAC_CHEM patients. This difference appears to continue until at least 18 months. At 6 months, days of additional hospitalization was significantly less in the PIPAC_CHEM group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT 04,879,953.