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Introduction | obesity, weight gain, IIH, Visual loss | OBESITY | Glucagon-like peptide-1 (GLP-1) is a gut neuropeptide secreted by the distal small intestine in response to a meal.Relevant to this trial is the role of GLP-1 receptor agonists in regulating fluid secretion. GLP-1 receptor agonists have been shown to reduce sodium reabsorption and promote diuresis through actions in the renal proximal tubule.IIH is characterized by increased ICP with no identifiable cause. Recent weight gain is the major risk factor for development of the condition and its occurrence is most commonly observed in women of reproductive age with obesity.Visual loss is observed in greater than 90% of those with IIHThe aim of the IIH:Pressure trial was to translate the preclinical data demonstrating efficacy of GLP-1 receptor signalling to reduce ICP into patients with raised ICP by conducting a randomized, placebo-controlled, double-blind trial in IIH. The trial aimed to evaluate both acute effects on ICP as well as effects over a 3-month time horizon. | PMC10151178 |
Materials and methods | PMC10151178 |
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Trial design and oversight | IIH | WEST | The trial was a prospective, randomized, parallel group, placebo-controlled trial in women with active IIH. Patients with a diagnosis of active IIH were identified and recruited from a single tertiary referral hospital (University Hospitals Birmingham NHS Foundation Trust). This study was approved by the West Midlands—Solihull Research Ethics Committee (17/WM/0179) and all subjects provided written informed consent according to Declaration of Helsinki principles. The trial was registered with ISTCRN (12678718). | PMC10151178 |
Participants | IIH | Women aged 18–60 years who met the diagnostic criteria for IIH were recruited. | PMC10151178 |
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Assessments | headache | Following enrolment, a 28-day headache diary was completed [capturing monthly headache days, headache severity (0–10 numerical rating scale), monthly analgesia days]. A telemetric ICP catheter (Raumedic) was implanted prior to the baseline visit through a 4 mm burr hole into the right frontal lobe.At baseline, medical history, examination (including blood pressure and heart rate) and body mass index [BMI; calculated using the formula: BMI = weight (kg) / height (m)Blood samples were collected at baseline pre-dose and post-dose at 2.5 h, 6 h, 11 h, 22 h and 24 h, at 2 weeks (pre- and 2.5 h post-dose) and 12 weeks (pre- and 2.5 h post-dose), to evaluate safety blood tests, pharmacokinetics and antidrug antibodies.ICP was recorded using a transdermal telemetric ICP monitoring system (Raumedic) at baseline, 2.5 h, 24 h and 12 weeks. In the planned exploratory analysis ICP was measured continuously for the first 2.5 h after dosing and then between 24.00 and 07.00 h overnight following the first dose. ICP data were collected at a frequency of 5 Hz and the mean ICP was calculated from each 30 min of continuous ICP monitoring over the first 2.5 h and each hour overnight. ICP was recorded with the MPR-1 monitor (Raumedic) in a standardized supine position as previously described. | PMC10151178 |
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Body composition | Dual energy X-ray absorptiometry (DEXA) was performed using a total-body scanner (QDR 4500; Hologic), as previously described, | PMC10151178 |
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Randomization and study treatment | Participants were randomized in a 1:1 ratio to either active treatment with exenatide (Byetta) or placebo using a computer-generated randomization list generated by the Birmingham Clinical Trials Unit. Treatment allocation was blinded to patient and investigators. A double check of allocation was performed by an unblinded nurse and pharmacist. The first dose was a loading dose of subcutaneous exenatide 20 μg or equivalent volume of subcutaneous 0.9% saline placebo. Subjects were then dosed for 12 weeks (self-administered at home) with either subcutaneous exenatide 10 μg or equivalent volume of placebo twice daily. There was no provision for access to treatment after the study concluded. | PMC10151178 |
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Blood analysis | high-density lipoproteins, TG | The following fasted blood tests were processed at the hospital laboratory: creatinine (μmol/l), alanine aminotransferase (ALT; IU/l), high-density lipoproteins (HDL; mmol/l), total cholesterol (mmol/l), triglycerides (TG; mmol/l), haemoglobin A1c (HbA1C; mmol/mol). Samples not analysed immediately were centrifuged (10 min at 1500 | PMC10151178 |
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Fasting insulin and homeostasis model assessment of insulin resistance | INSULIN RESISTANCE | Fasting insulin (Mercodia) was measured using a commercially available assay, according to the manufacturer’s instructions. Homeostasis model assessment of insulin resistance (HOMA2-IR) was calculated using the program HOMA calculator v2.2.3. | PMC10151178 |
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Pharmacokinetics | Exenatide concentration was evaluated by ELISA. ELISA was performed on serum samples from seven patients receiving the active drug. Serum was collected at 10 time points: baseline, 2.5 h, 6 h, 11 h, 22 h and 24 h, Week 2 at baseline and 2.5 h post-dose, Week 12 at baseline and 2.5 h post-dose. An exenatide fluorescent ELISA (Phoenix Pharmaceuticals Inc) was used. This was a competitive enzyme immunoassay wherein the primary antibody is competitively bound by either a biotinylated peptide or the targeted peptide in samples. All samples were run in triplicate. The assay was performed according to the manufacturer’s protocol. | PMC10151178 |
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Anti-exendin-4 antibody levels in serum | TYPE 2 DIABETES MELLITUS | In the light of reports of the development of anti-exenatide antibody in human studies administering exenatide in type 2 diabetes mellitus | PMC10151178 |
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Outcomes measure | Diabetic Retinopathy, headache | DIABETIC RETINOPATHY | The primary outcome was ICP at 2.5 h, 24 h and 12 weeks post-drug administration. ICP was recorded with p-Tel telemetric ICP catheter and MPR-1 reader (Raumedic). ICP was recorded continuously for 30-min periods at specified time points in a standardized supine position. For the first 2.5 h post-dosing, mean ICP was calculated from each 30 min of continuous ICP monitoring. For the overnight recording the mean ICP was calculated from each hour of continuous ICP monitoring. ICP was sampled at 5 Hz. Recordings were downloaded and analysed in Dataview version 1.2 (Raumedic). ICP was recorded in mmHg (conversion factor to cmCSF was 1.36).Secondary outcomes included: monthly headache days, headache severity and monthly analgesia days, logMAR visual acuity measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts; PMD using Humphrey 24–2 SITA central threshold automated perimetry; BMI and health-related quality of life (measured by SF-36 and HIT-6). Evaluations were at baseline 2.5 h, 24 h and 12 weeks (with additional blood sampling at 2 weeks). | PMC10151178 |
Adverse event reporting | ADVERSE EVENT | Adverse events were recorded as was drug compliance (unused medication in the injector pens documented). | PMC10151178 |
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Sample size calculation | In a study of 25 patients, Sinclair | PMC10151178 |
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Statistical analyses | SE, PMD | REGRESSION, SECONDARY, INTRAOCULAR PRESSURE | All primary analyses (primary and secondary outcomes including safety outcomes) were evaluated by intention-to-treat (ITT) analysis. Analysis was completed on received data, with every effort made to follow-up participants to minimize potential for bias. Final analyses were conducted after the final visit of the final patient of the main trial once the data had been cleaned and locked, then unblinded. No imputation of missing data was conducted. The analysis of visual data included data from the most affected eye at baseline as defined by PMD, analysis of intraocular pressure was performed on the mean average of both eyes. Statistical analysis was performed in R v4.0.0 (R Foundation for Statistical Computing, Vienna, Austria). Data were reported as means and SD [with median and interquartile range (IQR) for non-normal data], and standard error (SE) and 95% CI where appropriate. Hierarchical linear regression models were used to analyse repeated measures of the primary and secondary outcomes and to estimate differences adjusted for baseline values. In these models, population-level effects (also known as fixed effects) comprised the intercept, time as a factor variable and the two-way interaction of treatment arm and time as a factor variable to model changing treatment effects over time. Group-level effects (also known as random effects) comprised patient-level adjustments to the intercept. The threshold for statistical significance was pre-specified at 0.1. | PMC10151178 |
Data availability | Anonymized individual participant data will be made available along with the trial protocol and statistical analysis plan. Proposals should be made to the corresponding author and will be reviewed by the Data Sharing Committee in discussion with the Chief Investigator. A formal Data Sharing Agreement may be required between respective organizations once release of the data is approved and before data can be released. | PMC10151178 |
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Results | PMC10151178 |
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Patients | Between 1 November 2017 and 17 September 2018, 18 participants were screened, 16 enrolled and 15 randomly assigned to either the exenatide group (
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Adherence to the protocol | DISEASE PROGRESSION | One participant was withdrawn before randomization due to disease progression requiring urgent CSF shunting ( | PMC10151178 |
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Demographics and baseline characteristics | IIH | Baseline characteristics confined a cohort of patients with active IIH ( | PMC10151178 |
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Primary outcome measure | The primary clinical outcome was the difference in ICP between exenatide and placebo, as measured by telemetric ICP monitoring at 2.5 h, 24 h and 12 weeks. The difference in ICP between arms at 2.5 h was −4.2 (2.1) [mean (SD) mmHg],
Primary outcome measures | PMC10151178 |
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Secondary clinical outcomes | headache | SECONDARY | The key secondary outcome was monthly headache days, which reduced significantly in the exenatide arm, −7.7 (9.2) days [mean (SD)],
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Vision | Visual acuity significantly improved in the exenatide arm compared to the placebo arm −0.1 (0.05) logMar units, | PMC10151178 |
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Intraocular pressure | INTRAOCULAR PRESSURE | There was no significant change in intraocular pressure, difference between arms −0.1 (1.1), | PMC10151178 |
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Quality of life | Analysis of quality of life, using the SF-36, showed no significant changes in either the physical or mental component scores ( | PMC10151178 |
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Body mass index | BMI in the placebo arm baseline was 38.6 (4.7) kg/m | PMC10151178 |
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Safety blood test results | No significant changes were seen in the safety monitoring blood tests ( | PMC10151178 |
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Adverse events | nausea | ADVERSE EVENTS, ADVERSE EVENT, THYROTOXICOSIS | Twelve adverse events were reported during the trial. Eight adverse events occurred in the exenatide arm, seven of which were nausea related to exenatide initiation. Four adverse events occurred in the placebo arm. One unrelated serious adverse event, thyrotoxicosis, was reported in the placebo arm. No patients withdrew due to adverse events ( | PMC10151178 |
Anti-exenatide antibodies | No anti-exenatide antibodies were detected in samples collected at baseline. In total, two of the seven patients on exenatide developed antibodies by Week 12. At Week 2 one patient had antibodies present (> 0.1 µg/ml) and these were also present at 12 weeks (> 0.1 µg/ml). A further patient was noted to have antibodies at 12 weeks (>1.0 µg/ml). | PMC10151178 |
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Drug concentrations measurements | The two patients with anti-exenatide antibodies at 12 weeks had higher (3- and 6-fold higher) than predicted exenatide concentrations at 12 weeks and were excluded from the 12 weeks data analysis. At baseline, Week 2 and Week 12, there was a sharp increase in exenatide concentrations in patient serum at 2.5 h following subcutaneous administration of exenatide. This was followed by a sharp decline in peptide concentrations at 6 h. The mean exenatide concentrations at 2.5 hours are higher at baseline than at Week 2 and Week 12 (575.4, 380.7 and 205.4 pg/ml, respectively), which is expected as 20 μg of exenatide was administered at baseline, compared to 10 μg administered at Weeks 2 and 12 ( | PMC10151178 |
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Glucose and insulin | hypoglycaemia | HYPOGLYCAEMIA | No hypoglycaemia was encountered during the trial. There was no significant difference in fasted glucose and fasted insulin between the two trial arms at 12 weeks ( | PMC10151178 |
Vital signs | BLOOD | Blood pressure and heart rate were stable during the trial, mean arterial pressure was lower at 12 weeks in the exenatide group compared to placebo, −6.7 mmHg (3.6), | PMC10151178 |
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We looked in more detail at the changes in ICP in the first 2.5 h following drug administration. ICP was significantly lower in recordings taken over time points 90–120 min [mean (SD): −4.6 (2.1) mmHg,
ICP was then measured overnight between 24.00 and 07.00 h on the first day of dosing ( | PMC10151178 |
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DEXA | IIH | We determined that IIH patients had a similar fat mass, lean mass and android–gynoid ratio in those treated with exenatide as compared to those on placebo with no significant differences detected at 12 weeks ( | PMC10151178 |
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Discussion | Headache, nausea, IIH, traumatic brain injury, meningitis, stroke, Weight loss, headache, headaches and visual loss | SIDE EFFECT, MENINGITIS, STROKE, HYDROCEPHALUS, OPTIC NERVE, SECONDARY, PATHOGENESIS, SYNDROME, TYPE 2 DIABETES, DISEASES | This is the first randomized controlled trial comparing the efficacy of the GLP-1 receptor agonist exenatide, with placebo to reduce ICP in patients with active IIH. We have found a significant and clinically meaningful reduction in ICP in the treatment arm as compared to the placebo arm both acutely and after 12 weeks of dosing. The drug was safe and well-tolerated. This trial establishes the successful translation of preclinical data into humans and is the first to demonstrate a new drug treatment for IIH that significantly reduces ICP in IIH.The hallmark of IIH is raised ICP, which causes headaches and visual loss (through compression of the optic nerve and papilloedema).A significant reduction in ICP was also noted after prolonged dosing at 12 weeks (−4.1 mmHg equivalent to −5.6 cmCSF; Headache is a key disabling feature for IIH patients and listed in the top 10 priority areas for research by patient groups.There was a significant improvement in visual acuity between the trial arms at 12 weeks (Weight loss has been shown to reduce ICP in IIH.Exenatide is widely used to treat type 2 diabetes and has an established long-term safety record (licensed in 2005).This is the first trial, to our knowledge, to use telemetric intracranial monitoring to measure ICP in IIH. Patient input into the trial design advocated for telemetric ICP monitoring over multiple lumbar punctures to facilitate data validity and reduce patient discomfort from multiple lumbar punctures. This has permitted detailed characterization of ICP changes and the ability to measure ICP for prolonged periods over several weeks without further invasive procedures.This study has several limitations. As an early phase study, it was powered to the primary end points of ICP reduction with single and repeated dosing. Thus, the study was underpowered to detect differences in patient-centred outcomes and secondary clinical end points such as headache and visual field perimetry. Powering the study for those end points would have required a large increase in number of participants; however, telemetric ICP monitors would not be feasible in large trial cohort. No stratification was used at randomization and groups were unmatched for baseline headache days and visual field perimetry. Additionally, patients with minimal visual field defects were not excluded as in prior studies, thus making the study more clinically representative, but visual effects more difficult to detect due to the ceiling effect of the measurement. With the main side effect of exenatide being nausea, patients could have been unmasked; however, the primary end point was a physiological measure, which should minimize this risk.The results of this study may have wide reaching implications for many other diseases of raised ICP as the drug does not target the specific pathogenesis of IIH, but CSF secretion. Given the tolerability of exenatide and its direct and early effect on ICP, it may be beneficial in other conditions such as hydrocephalus, traumatic brain injury, raised ICP in stroke and meningitis and space flight–associated neuro-ocular syndrome. In addition, GLP-1 receptor agonists have been shown to demonstrate neuroprotective properties and hence may have additional benefits in conditions such as traumatic brain injury.We had previously identified a novel pathway to modulate ICP in an animal model. | PMC10151178 |
Supplementary Material | Click here for additional data file. | PMC10151178 |
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Funding | THORN, BRAIN | This study was funded by University of Birmingham, UK, from 1 August 2016. Further funding was sought and from 1 August 2019 an investigator-led grant was obtained from Invex therapeutics. J.L.M. was funded by the Ministry of Defence for the duration of the study. A.Y. was funded by an Association of British Neurologists and Guarantors of Brain fellowship. O.G. was funded by Brain research UK. Y.L. and N.H.G. are supported by the Intramural Research Program, National Institute on Aging, NIH (AG000333). A.J.S. was funded by a National Institute for Health Research (NIHR) clinician scientist fellowship (NIHR-CS-011-028) and the Medical Research Council, UK (MR/K015184/1) for the duration of the study. A.J.S. is funded by a Sir Jules Thorn Award for Biomedical Science. The views expressed are those of the authors and not necessarily those of the UK National Health Service, MoD, NIHR or the UK department of Health and Social Care. Role of Funder/Sponsor: The MoD, NIHR, MRC and Invex Therapeutics had no role in the design or conduct of the study; no role in collection, management or interpretation of the data; writing of the manuscript; and no role in the decision to submit the manuscript for publication. | PMC10151178 |
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Competing interests | Chugai-Roche | J.L.M. was funded by the UK Ministry of Defence for the duration of the study. O.G. reports scientific consultancy fees from Invex therapeutics (2020). A.Y. reports receiving speaker fees from Teva, UK, outside the submitted work. K.B. works for UCB. Professor Mollan reports other Invex Therapeutics, other Heidelberg engineering during the conduct of the study; other from Chugai-Roche Ltd, other from Janssen, other from Allergan, other from Santen, other from Roche, other from Neurodiem, outside the submitted work. Professor Sinclair reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study (since 28.06.2019); other from Allergan, Novartis, Cheisi and Amgen outside the submitted work. All other authors declare no competing interests. | PMC10151178 |
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Supplementary material | PMC10151178 |
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References | PMC10151178 |
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Background | hypotension | The optimal treatment of hypotension during spinal anaesthesia is uncertain. A novel double intravenous vasopressor automated (DIVA) system reduces hypotension compared to standard care, and was subsequently modified to an advanced-DIVA (ADIVA) system. The primary objective was to compare ADIVA versus DIVA on incidence of hypotension (systolic BP (SBP) < 80% baseline). | PMC9878794 |
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Methods | We conducted a randomized-controlled trial in women undergoing elective cesarean delivery under spinal anesthesia. SBP and heart rate were measured continuously using a Nexfin monitor. ADIVA delivered 25 μg phenylephrine (heart rate > 60 beats.min | PMC9878794 |
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Results | We analyzed 94 parturients (ADIVA: | PMC9878794 |
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Conclusion | hypotensive | HYPOTENSIVE | ADIVA was associated with a greater proportion of hypotensive SBP readings, reduced phenylephrine consumption, and increased umbilical arterial pH than DIVA. Further research is needed to determine the optimal method of vasopressor delivery in parturients undergoing cesarean delivery. | PMC9878794 |
Trial registration | This study was registered on Clinicaltrials.gov registry (NCT03620942) on 08/08/2018. | PMC9878794 |
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Keywords | PMC9878794 |
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Introduction | Hypotension, hypotension | Hypotension occurs in up to 80% of women during cesarean delivery under spinal anesthesia [The optimum method of preventing or treating hypotension during cesarean delivery is uncertain, although vasopressors have demonstrated efficacy and are mainstays of contemporary clinical practice [We have previously described a novel double intravenous vasopressor automated (DIVA) closed-loop system that analyzed beat-to-beat systolic blood pressure data (SBP) from a continuous non-invasive hemodynamic monitor (Nexfin, BMEYE, B.V., Amsterdam) [ | PMC9878794 |
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Methods | loss of sensation, premature rupture of amniotic membranes, cardiac disease, diabetes | HYPERTENSIVE DISORDER, COLD, CARDIAC DISEASE, DIABETES | This randomized controlled study was conducted from January 2020 to September 2021 at KK Women’s and Children’s Hospital, Singapore, after approval by the SingHealth Centralized Institutional Review Board (Ref: 2018/2213) on 06/04/2018 and registration on clinicaltrials.gov (NCT03620942) on 08/08/2018. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki, and this manuscript adhered to the relevant Consolidated Standards of Reporting Trials (CONSORT) guidelines.We included parturients aged 21 to 45 years old, weighing 40 to 100 kg, 145 to 170 cm in height, American Society of Anesthesiologists (ASA) physical status 2, with singleton full term pregnancies undergoing spinal anesthesia for elective cesarean delivery. Parturients with contraindication to spinal anesthesia, hypertensive disorders requiring medication, premature rupture of amniotic membranes for > 48 h, diabetes requiring insulin, and uncontrolled medical conditions such as cardiac disease were excluded.Parturients were randomized (1:1 ratio) to receive ADIVA or DIVA using a computer-generated random number generator. The allocation sequence was created by the study statistician and concealed using sequentially numbered opaque sealed envelopes. Prior to spinal anesthesia, the study investigator opened the envelope containing the group allocation. Parturients, obstetricians, nurses, and anesthesiologists involved in anesthesia management and data collection were blinded to the group allocation.Baseline SBP was measured in the ward as the mean of three consecutive readings taken at one-minute intervals using an oscillometric device on the right arm with the patient supine and left uterine displacement. Intravenous access was obtained using an 18-gauge cannula, pulse oximeter and electrocardiogram were applied, and the Nexfin finger cuff was attached to the right second or middle finger. Spinal anesthesia was performed in the sitting flexed position with a 27-gauge Whitacre needle (BD Medical, New Jersey, USA), 11 mg hyperbaric bupivacaine 0.5%, 15 μg fentanyl, and 100 μg morphine. The parturient was then positioned supine with left uterine displacement, free flowing infusion of lactated ringers solution was commenced, and the ADIVA system was initiated by the study investigator.SBP and heart rate measurements by Nexfin were uploaded continuously to a laptop computer which integrated the data every 10 s to form a moving average value (LabVIEW running on Windows XP, Microsoft Corporation, Washington, USA). The drug delivery system consisted of two syringe driver pumps (B.Braun, Melsungen, Germany) with one 50 ml syringe filled with 100 μg.mlSchematic diagram of the algorithm used in (Five minutes after spinal anesthesia, sensory block was assessed using loss of sensation to cold while motor block was measured using the modified Bromage scale [ | PMC9878794 |
Percentage performance error (PE) | Percentage performance error was defined as the percentage difference between each SBP value from the baseline, and is calculated for the i | PMC9878794 |
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Median absolute performance error (MDAPE) | MDAPE indicates the absolute magnitude of differences between measured and baseline SBP, and is a measure of inaccuracy. It is defined as the median of absolute PE (|PE|) values, calculated as follows where N | PMC9878794 |
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Median performance error (MDPE) | MDPE is a measure of bias, and indicates whether SBP was systematically above or below the baseline, calculated as follows: | PMC9878794 |
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Wobble | Wobble measures how much PE fluctuates around the MDPE with time for each parturient, calculated as follows: | PMC9878794 |
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Divergence | REGRESSION | Divergence is the slope obtained from linear regression of each parturient’s |PE| with time, and assesses the trend of |PE| change over time, thereby indicating if the system accuracy is improving (negative divergence) or worsening (positive divergence) with time. Divergence (per minute) was calculated as follows where t | PMC9878794 |
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Statistical analyses | hypotension | Continuous and categorical variables were summarized as mean ± standard deviation (SD) or median (interquartile range (IQR) [range]) as appropriate, or number (proportion) respectively. Categorical and continuous variables were compared using the XA sample size of 92 parturients (46 in each group) is required to detect 25.5% absolute difference in the incidence of hypotension, based on the following assumptions: incidence of hypotension in ADIVA group of 13.5%, incidence of hypotension in DIVA group of 39.0% based on previous DIVA studies on reported incidence and difference in incidence [ | PMC9878794 |
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Discussion | bradycardia, hypertension, hypotensive, hypotension | ADVERSE EVENTS, HYPERTENSION, HYPOTENSIVE, COLD | In this randomized controlled study, we compared the performance of ADIVA versus DIVA in managing hypotension during spinal anesthesia for cesarean delivery. The use of ADIVA did not significantly change the incidence of hypotension, hypertension, bradycardia, ephedrine consumption, and other relevant clinical outcomes compared to DIVA. However, ADIVA was associated with a greater proportion of hypotensive SBP readings, reduced phenylephrine consumption, and increased umbilical arterial pH than DIVA. Lastly, ADIVA exhibited greater MDAPE and wobble than DIVA, although MDPE and divergence were comparable between the two systems.Three modifications were incorporated into ADIVA that we postulated will improve hemodynamic stability. First, ADIVA delivered low vasopressor doses at SBP was between 90 to 110% of baseline, in contrast to DIVA which administered the same vasopressor dose when SBP fell between 90 to 100% of baseline. We hypothesized that pre-emptive use of small vasopressor doses may prevent SBP from dropping below baseline levels and reduce the incidence of hypotension, albeit at the theoretical cost of increased hypertension risk. However, we did not detect a significant difference in the incidence of hypotension and hypertension between ADIVA and DIVA, which may suggest that the vasopressor dose (25 μg phenylephrine or 2 mg ephedrine) was insufficient to forestall the development of hypotension. Future studies should investigate if a higher pre-emptive vasopressor dose delivered between 90 to 110% of baseline reduces the incidence of hypotension, without concomitant increase in the risk of hypertension.Second, hypotensive parturients with SBP readings below 80% of baseline received larger vasopressor doses (75 μg phenylephrine or 6 mg ephedrine) from ADIVA, in contrast to the 50 μg phenylephrine or 4 mg ephedrine administered by DIVA. We postulated that larger vasopressor doses will rapidly return SBP above 80% of baseline and minimize the duration of hypotension, but paradoxically, our results showed that ADIVA had greater proportion of hypotensive SBP readings compared to DIVA. Given that SBP was monitored continuously in a beat-to-beat fashion, it is possible that short periods of hypotension occurring during vasopressor administration or the subsequent 10 s lockout period were not treated, hence preventing higher vasopressor doses from reducing the proportion of hypotensive readings.Third, ADIVA calculated the SBP trend and administered vasopressors rapidly if SBP trended downward in the ten-second interval preceding vasopressor delivery, while the same vasopressor dose would be delivered over 30 s if SBP trended upward. In comparison, DIVA delivered all vasopressors over 30 s, regardless of SBP trend. We hypothesized that delivering vasopressors rapidly may halt the decline in SBP and hence forestall the onset of hypotension, while slow infusion of vasopressors with rising SBP may reduce the incidence of hypertension. However, our results showed that this was not the case, as no significant difference in the incidence of hypotension was found between ADIVA and DIVA groups.When evaluated with performance measures used to evaluate similar closed-loop systems, ADIVA exhibited significantly higher MDAPE of 13.1% compared to DIVA (9.5%), indicating that ADIVA resulted in greater deviation of SBP values above and below the baseline. Also, ADIVA was associated with a MDPE of 5.4%, showing that SBP values were maintained at a median of 5.4% above baseline, compared to 3.2% with DIVA. Similarly, wobble was higher in ADIVA (8.3%) than DIVA (6.3%), indicating that the former was associated with greater fluctuation of SBP values around MDPE. The combination of these findings suggests that ADIVA tended to maintain SBP values higher above baseline with greater SBP fluctuation than DIVA. This may be due to the addition of pre-emptive vasopressor delivery starting at 110% of baseline, as well as the rapid administration of vasopressors that may introduce greater fluctuation in SBP readings.It should be noted that the incidence of hypotension in this study was markedly greater than in our previous randomized controlled study comparing DIVA with manual vasopressor boluses [The use of a closed-loop feedback system for vasopressor delivery was firstly described by Ngan Kee et al. by maintaining the maternal blood pressure in Cesarean patients with a simple on–off algorithm to activate phenylephrine infusion of 100 μg/min [We acknowledge several limitations in this study. Our study may have been inadequately powered to detect small differences in the incidence of hypotension between parturients receiving ADIVA compared to those receiving DIVA, although the clinical significance of such differences is debatable. In this study, we chose to use a validated non-invasive blood pressure monitoring, Nexfin, rather than intra-arterial measurement which is invasive with accompanying risk of adverse events. The accuracy and precision of Nexfin for continuous SBP measurement may be affected by movement or cold temperature leading to peripheral vasoconstriction, nonetheless, the accuracy of Nexfin has been validated against intra-arterial measurements [ | PMC9878794 |
Conclusion | hypotensive | HYPOTENSIVE | ADIVA did not significantly improve hemodynamic control and clinical outcomes during spinal anesthesia compared to DIVA. However, ADIVA was associated with a greater proportion of hypotensive SBP readings, reduced phenylephrine consumption, and increased umbilical arterial pH than DIVA. Further research is needed to determine the optimal method of vasopressor delivery in parturients undergoing cesarean delivery. | PMC9878794 |
Acknowledgements | The authors would like to thank the clinical research coordinators (Agnes Teo, Liu Juan, Dora Gan) and the staff of the major operating theaters at KK Women’s and Children’s Hospital, Singapore, for their support. | PMC9878794 |
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Authors’ contributions | RS | HST, SN: Conceptualization, methodology, investigation, formal analysis, writing – original draft, review, and editing. JJIC: Methodology, investigation, writing – review and editing. CWT: Conceptualization, methodology, formal analysis, writing – review and editing. RS: Methodology, formal analysis, writing – review and editing. ATHS, BLS: Conceptualization, methodology, investigation, formal analysis, writing – review and editing, supervision. The author(s) read and approved the final manuscript. | PMC9878794 |
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Funding | We would like to acknowledge the SingHealth Foundation Grant SHF/CTG061/2017 Clinical Trials Grant for the funding support of this study. | PMC9878794 |
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Availability of data and materials | The datasets generated and/or analyzed during this study are not publicly available due to institutional policy on data confidentiality but are available from the corresponding author on reasonable request. | PMC9878794 |
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Declarations | PMC9878794 |
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Ethics approval and consent to participate | This study received approval by SingHealth Centralized Institutional Review Board (Ref: 2018/2213) on 06/04/2018, with registration on Clinicaltrials.gov (NCT03620942) on 08/08/2018. Written informed consent was obtained from every participant by the investigators, and that this work was conducted in accordance with the Declaration of Helsinki. | PMC9878794 |
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Consent for publication | Not applicable. | PMC9878794 |
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Competing interests | Ban Leong Sng is an associate editor of BMC Anesthesiology. All other authors declare that they have no competing interests. | PMC9878794 |
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References | PMC9878794 |
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Background | ULCERATIVE COLITIS | There are no prospective trials comparing the two main reconstructive options after colectomy for Ulcerative colitis, ileal pouch anal anastomosis and ileorectal anastomosis. An attempt on a randomized controlled trial has been made but after receiving standardized information patients insisted on choosing operation themselves. | PMC10122388 |
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Methods | Ulcerative colitis | ULCERATIVE COLITIS, COMPLICATIONS | Adult Ulcerative colitis patients subjected to colectomy eligible for both ileal pouch anastomosis and ileorectal anastomosis are asked to participate and after receiving standardized information the get to choose reconstructive method. Patients declining reconstruction or not considered eligible for both methods will be followed as controls. The CRUISE study is a prospective, non-randomized, multi-center, open-label, controlled trial on satisfaction, QoL, function, and complications between ileal pouch anal anastomosis and ileorectal anastomosis. | PMC10122388 |
Discussion | Reconstruction after colectomy is a morbidity-associated as well as a resource-intensive activity with the sole purpose of enhancing function, QoL and patient satisfaction. The aim of this study is to provide the best possible information on the risks and benefits of each reconstructive treatment. | PMC10122388 |
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Trial registration | ClinicalTrials.gov Identifier: NCT05628701 | PMC10122388 |
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Keywords | Open access funding provided by Linköping University. | PMC10122388 |
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Introduction | UC, IBD, Ulcerative Colitis | INFLAMMATORY BOWEL DISEASE, ULCERATIVE COLITIS | Ulcerative Colitis (UC) is a chronic inflammatory bowel disease (IBD) restricted to the mucosa of the rectum and colon [After subtotal colectomy there are four available options for patients. A reasonable option is to not proceed for further surgery and leave the rectum in place—the patient will live with a permanent ileostomy. Another option is the ileal pouch anal anastomosis (IPAA) where the rectum is removed and a pouch is created from the distal part of the ileum which is stapled or sutured to the anal canal or just above [There are no randomized controlled trials (RCT) comparing IRA to IPAA. In a decision model using a Markov simulation in comparing IRA with IPAA in UC, the former was the preferred treatment option when quality-adjusted life-years were the outcome, while higher life-years was true for the latter [ | PMC10122388 |
Method/design | PMC10122388 |
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Study objectives | stoma, UC-patients, UC | COMPLICATIONS | To compare, in a prospective setting, patient satisfaction, QoL, function, and complications between IRA and IPAA and permanent stoma among patients with UC subjected to subtotal colectomy.This study aims to answer what type of reconstruction, if any, UC-patients asks for following a colectomy, their satisfaction with the treatment, postoperative function and QoL. The results may have a large impact on future treatment recommendations. | PMC10122388 |
Study design | stoma, UC | COMPLICATIONS | The CRUISE study is a prospective, non-randomized, non-blinded, multi-center, controlled trial on satisfaction, QoL, function, and complications between IRA and IPAA and permanent stoma among adult UC patients subjected to subtotal colectomy. All adult UC patients scheduled for a subtotal colectomy will be asked for informed consent. The patients will then be presented standardized written and video recorded information on the available reconstructive options. If the patient meets the inclusion criteria, their preferred choice of IRA or IPAA will assign them to one of the study arms. Patients that do not meet the inclusion criteria or fulfill any of the exclusion criteria (e.g. not suitable for an IRA) or refrain reconstruction will be asked to participate as controls. | PMC10122388 |
Endpoints | COMPLICATIONS | The primary endpoint is satisfaction with the choice of reconstructive method or permanent stoma. Secondary endpoints are QoL, sexual function, bowel function and complications. | PMC10122388 |
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Study population | inflammation, UC | INFLAMMATION, RECTAL INFLAMMATION | The study population consists of all adult UC patients subjected to subtotal colectomy and eligible for both IRA and IPAA presenting at any of the participating centers.Inclusion criteria are patients with UC aged between 18 and 60, scheduled for or have previously undergone subtotal colectomy and ileostomy. Patients should have sufficient rectal compliance and controllable inflammation in the rectal using topical 5-ASA only (Fig. Inclusion and Exclusion criteriaExclusion criteria are rectal inflammation of Mayo Score > 1 [ | PMC10122388 |
Sample size | The only available study on patient satisfaction, our primary outcome, between IRA and IPAA reports 98% and 88% satisfaction for the methods respectively [ | PMC10122388 |
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Participating centers | Patients will be enrolled from three tertiary referral centers in Sweden (Linköping University hospital, Linköping, Sweden; Karolinska University hospital, Stockholm, Sweden; Sahlgrenska (Östra) University hospital, Gothenburg, Sweden) and one tertiary referral center in the UK (St Mark’s Hospital and Academic Institute, Harrow, UK). | PMC10122388 |
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Ethics | The study was approved by the regional ethics review board in Stockholm, Sweden (Dnr: 2017/124–31/2, 2018/2224–32) and The London Brent Research Ethics Committee (REC), UK (reference number: 18/LO/1190). The study is conducted in accordance with the Helsinki declaration and good clinical practice. | PMC10122388 |
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Trial registration | The protocol is registered and published at ClinicalTrials.gov Identifier: NCT05628701. | PMC10122388 |
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Study outline | PMC10122388 |
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Recruitment | Inflammation | INFLAMMATION, RECTAL INFLAMMATION | After colectomy, patients will receive standardized written as well as oral information from a consultant regarding the collection of QoL measurements, functional scores and the different treatment modalities before being asked for consent to participate in the study. The patient will be prescribed topical 5-ASA according to local principles, usually 500–1000 mg twice daily. 3–6 months after the colectomy patients will be subjected to rectal endoscopic examination to assess rectal inflammation and compliance and sphincter function. Inflammation is assessed by Mayo score while the assessment of rectal compliance and sphincter function is based on patient history and the subjective evaluation by the responsible surgeon. Based on these factors it is determined if the patient is eligible for IRA as well as IPAA. Patients that are deemed eligible for both reconstructions, and otherwise fulfill inclusion criteria, will be analyzed in the study arms and will henceforth be referred to as the study arms in contrast to the controls (Fig. Flow chart describing the selection of patients eligible for the study (green). The other patients (yellow) will be asked to participate as controls | PMC10122388 |
IRA | The IRA can be performed both as an open or laparoscopic procedure, of which the latter is more common and preferred in modern practice. The ileostomy is closed, and the neoterminal ileum is in most cases anastomosed to the tip of the rectal remnant in the abdomen using a circular transanal stapling device or in some cases a handsewn anastomosis will be performed. The reconstruction is rarely protected by a temporary diverting loop ileostomy. | PMC10122388 |
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IPAA | The IPAA can be performed both as an open or, preferably as a laparoscopic or robotic procedure. A trans-anal minimal invasive method (TaTME) may be used to facilitate proctectomy [ | PMC10122388 |
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Controls | proctitis, UC | PROCTITIS | In order to obtain a comprehensive overview of all UC patients that undergo colectomy, patients that decline reconstruction or those eligible only for one method of reconstruction (e.g. only IPAA due to refractory proctitis) will be asked to participate as controls. | PMC10122388 |
Failure | Patients converted from IRA to IPAA or from either reconstruction to a permanent ileostomy will be analyzed in an “intention-to-treat” manner. | PMC10122388 |
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Data collection | PMC10122388 |
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Instruments | bleeding, UC | BLEEDING, PERIOPERATIVE COMPLICATION | General QoL will be assessed with the SF-36 form [Data will also be obtained on smoking status, UC medication, age, indication for colectomy (chronic active disease/acute flare/dysplasia), BMI, endoscopic status in pouch/rectum, reoperations and for each operation: operation technique, operative time, bleeding, perioperative complications and hospital stay.The data is collected and managed using REDCap (Research Electronic Data Capture) [ | PMC10122388 |
Time frame | Baseline data will be collected after colectomy for all patients. The reconstructed patients will then be followed at 2 months, 6 months, 1 year, 2 years and 5 years. Those patients that receive a loop ileostomy at reconstruction will also be followed 2 months after reconstruction before closure of the loop. For those patients the loop closure is considered the index operation. The patients that choose to (or are deemed to) keep their end ileostomies will be followed at 6 months, 1 year, 2 years and 5 years after colectomy (Fig. Timeline describing the collection of QoL and functional score questionnaires in the study population | PMC10122388 |
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Statistical analysis | EVENTS, STILL | Analysis will be conducted according to the intention-to-treat principal. The primary outcome satisfaction, a proportion, will be compared with chi-square test. For the primary outcome two-tailed tests will be applied since the null hypothesis is that there is no difference between the two reconstructive methods. Secondary outcomes assumed to be normally distributed will be compared between the two study arms using t-tests. Functional and QoL variables will be analyzed with mixed model ANOVA analysis. Time to failure will be analyzed with multivariate cox-regression analysis. Kaplan–Meier curves will be constructed and compared with log-rank tests. Repeating events, such as reoperations, will be analyzed with multivariate Poisson-regression.There is no data and safety monitoring committee since all treatment is according to established practice. We do not plan to perform any interim analysis.From a statistical point of view our choice of primary endpoint is not optimal because we have no reason to expect any difference between the two study arms. Still, to our opinion, this is the most important outcome measure. | PMC10122388 |
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Discussion | IPAA, bowel movements, proctitis, UC, UC [Failure, pouchitis, IBD | STILL, DISEASE, PROCTITIS, COMPLICATION, POUCHITIS, RECTAL CANCER, COMPLICATIONS | Reconstruction after colectomy is a morbidity-associated as well as a resource-intensive activity with the sole purpose of enhancing function, QoL and patient satisfaction. The actual disease has already been treated with the colectomy. Hence it is crucial to provide patients and care givers with the best possible information on the risks and benefits of each reconstructive treatment. They should be informed of what to expect if they choose to keep their end ileostomy permanently. There are no prospective head-to-head comparisons between IRA and IPAA in UC patients published.The aspects to consider when evaluating a reconstruction after colectomy are early as well as late complications of the reconstruction, bowel function as well as urogenital and sexual function, quality of life (QoL), patient satisfaction as well as risk of failure and/or rectal cancer. There are also patient preferences which must be considered.The IRA is easier to perform and does not require pelvic dissection, but instead the preserved rectum demands continuous topical medication and the risk for rectal cancer remains [Early complications generally refers to complications within 30 days of surgery and they are most often graded according to the Clavien-Dindo scale [Considering late complications, pouchitis for IPAA is reported in between 36–48% of cases [Regarding bowel function, the main issues are continence, number of bowel movements, need to evacuate the bowel during nighttime and urgency to evacuate the bowel. For IRA, between three and six bowel movements per 24 h have been reported [The pelvic dissection associated with IPAA constitutes a risk for impaired sexual function and impaired fecundity. Sexual function is described and compared in different ways in IPAA studies and the results are difficult to compare [In reconstructive surgery, the goal is to improve quality of life (QoL). Still, it is not obvious how to assess and compare QoL in surgery for UC [Failure, defined as excisions or permanent deviation, is reported in between 4–9% of IPAA cases at 5 years and 7–19% at 10 years [The obvious limitation with our study design is the lack of randomization. As mentioned in the introduction we have made an attempt to randomize between IRA and IPAA but after receiving detailed information, patients decline randomization and insist on choosing a reconstructive method themselves, with similar numbers opting for IRA and IPAA. We do not consider it a risk, but a fact, that some degree of selection bias will occur as some patients are more concerned regarding pelvic surgery, and its possible consequences, while others are more concerned by the need of anti-inflammatory medication, endoscopic surveillance and the risk of rectal cancer. We aim to minimize such effects with the provision of standardized information whenever possible. Because this is a multicenter study the same consultant cannot present the oral information to every patient. Instead, all patients will be shown the same information video by the consultant IBD Surgeon.We do, however, see an upside to the lack of randomization. It is of interest to see what patients choose when presented with standardized information and if there are any demographic patterns in the choice of reconstructive method. Furthermore, we do not think that IRA will necessarily be a better choice than IPAA but rather it will be equally good in the selected cohorts eligible for either restorative procedure. Patient involvement may also increase the chance of a favorable outcome.Another question that we hope to address is if there are any differences in the outcome of IPAA between the patients that were eligible for both IRA and IPAA and the patients that had IPAA as their only restorative option, i.e. will the level of proctitis affect the outcome of IPAA.The multinational setting of the study will also allow for detection of possible differences in the attitude towards functional outcomes and complication patterns between the Swedish and English UC population. It will also improve the external validity of our study. | PMC10122388 |
Conclusion | Because we have failed to enroll patients in an RCT we believe this is the best available way to compare the outcomes between IRA and IPAA. This design will also provide a good overview of the entire UC population that required colectomy. | PMC10122388 |
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Trial status | As of September 28, 2022, we have enrolled 37 IRA patients and 11 IPAA patients in the study arms and 23 IPAA and 18 ileostomy patients in the control arms. | PMC10122388 |
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Acknowledgements | Mr Guy Worley made considerable contributions in the start-up of the study in the UK. | PMC10122388 |
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Authors’ contributions | Guarantor: Mr Risto had full access to all of the data in the study and takes responsibility for the integrity study. Study concept and design: All co-authors. Interpretation of results: All co-authors. Drafting of the manuscript: Risto. Figures and tables: Risto and Nordenvall. Critical revision of the manuscript for important intellectual content: All co-authors. Final approval of the version to be submitted: All co-authors. | PMC10122388 |
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Funding | Open access funding provided by Linköping University. The study was financed by grants from: The Swedish state under the agreement between the Swedish government and the county councils (the ALF-agreement), The Bengt Ihre research fund and the “Magtarmfonden” research fund. None of the funders have had any role in the current study. | PMC10122388 |
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Availability of data and materials | Not applicable, no data, only protocol. | PMC10122388 |
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Declarations | PMC10122388 |
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Ethics approval and consent to participate | The study was approved by the regional ethics review board in Stockholm, Sweden (Dnr: 2017/124–31/2, 2018/2224–32) and The London Brent Research Ethics Committee (REC), UK (18/LO/1190). Written consent is/will be signed by all participating patients. | PMC10122388 |
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Consent for publication | Not applicable, no individual data. | PMC10122388 |
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