Patient Involvement to Inform the Design of a Clinical Trial in Postbariatric Hypoglycemia


 Background: Bariatric surgery may lead to symptomatic postprandial hypoglycemia as a major side effect without established therapy so far. We aimed to develop an evidence-based study design of a clinical trial that tests treatment options and can provide useful patient-relevant evidence.Methods: We searched systematically for guidance of core outcome sets to determine the most relevant types of outcomes and duration of such a trial. Our search comprised literature databases, a database of core outcome sets and self-help organizations. We then developed a simple online questionnaire based on interviews with German-speaking patients with postprandial hypoglycemia after bariatric surgery. We recruited participants by reaching out to all German speaking endocrinologists in Switzerland and large Swiss bariatric centers. We asked for preferences regarding outcome types and acceptable duration of being included in a corresponding clinical trial.Results: The systematic search did not identify evidence-based guidance for informing our study design. Experience of clinical and research routine as well as patient interviews helped in identifying potential outcomes and the design of an online questionnaire. Therein, a total of 29 persons started the questionnaire and 22 answered questions related to the primary outcome. Of these, 17 (77.3%) deemed quality of life more relevant as primary outcome than the rate of hypoglycemic episodes. A trial length of four weeks or longer was regarded as acceptable for 19 of 21 respondents to this question (91.4 %) and of six months or longer for 12 respondents (56 %). Conclusions: In situations with no other guidance, a simple questionnaire may help to inform trial design decisions. This study identifies a patient preference for “quality of life” as a primary outcome and supports the evidence-based conception of a patient-centered clinical trial in postbariatric hypoglycemia.


Background
Bariatric surgery is one of the most effective interventions to achieve long-term weight loss in patients with severe obesity, but frequently leads to serious side effects (1)(2)(3). One of them is postprandial hypoglycemia (PBH), previously referred to as late-dumping, affecting in standardized test settings about 50% of patients with a gastric bypass (4)(5)(6) although it is frequently undiagnosed (7). This may lead to a reduced quality of life (8), secondary weight gain (9,10) and may even be associated with an increased mortality (11)(12)(13). Serious hypoglycemia requiring assistance of third parties and/or hospitalization for hypoglycemia affects around 1% (8,14). Although some patients are able to effectively control hypoglycemic episodes with dietary modi cation, there is no established treatment for severely affected patients with frequent postprandial hypoglycemia (5).
A recent exploratory trial with 12 patients after gastric bypass indicated that both the SGLT2-inhibitor empagli ozin and the IL-1 receptor antagonist anakinra may reduce postprandial insulin release and prevents hypoglycemia (15). These ndings call for further evaluation in a larger randomized clinical trial.
We aimed to develop an evidence-based study design for such a trial that tests these treatment options and can provide useful patient-relevant evidence on their merits. However, selecting a primary outcome that appropriately re ects the needs of patients turned out to be a major challenge. Ideally, such a trial would explore patient-relevant outcomes but also improve the understanding of the underlying metabolic effects of the tested treatments that would mediate potential patient-centered bene ts (such as glucose levels).
Clear frameworks such as those established for assessment of anti-diabetic treatments that may help to utilize hypoglycemia as trial outcome in non-diabetic persons are lacking. Extrapolation of such frameworks to nondiabetic patients may be inappropriate and would require strong assumptions as changing glucose levels in diabetic and nondiabetic persons may correspond to different symptoms and health effects.
For postprandial hypoglycemia, no core outcome set (COS), as "an agreed standard set of outcomes that should be measured and reported, as a minimum, in all clinical trials in speci c areas of health or healthcare" (16) has been published. In 2016, the BARIAtric and metabolic surgery Clinical Trials (BARIACT) project de ned COS for patients undergoing bariatric surgery based on patient and healthcare provider perspectives. However, postprandial hypoglycemia was not among the list of candidate outcomes includeed in the delphi processes (17).
We systematically searched in September 2019 for clinical trials speci cally including patients with symptomatic postprandial hypoglycemia and found only small trials using biomarkers (e. g. time of glucose levels below a speci c threshold) (18,19) or clinical scoring systems (e. g. Edinburgh Hypoglycemia Scale) mostly within standardized mixed meal test-settings(20-22) which do not re ect real-life circumstances and provide no patient-relevant information. Only one trial that we identi ed reported effects on quality of life as a secondary outcome (23).
The measurement of hypoglycemic episodes by continuous glucose measurement systems appears to accurately depict real-life glucose level variation and may give an objective measurement of the metabolic effects of an intervention aiming to alleviate symptomatic metabolic disorders (24). However, it is unclear how relevant it is for patients with symptomatic hypoglycemic episodes to measure merely metabolic changes, since some hypoglycemic episodes may not be recognized (7,25,26) and have varying symptomatic presentation, especially when occurring frequently or during the night (7). Measuring the frequency of hypoglycemic episodes alone without consideration of their severity and patient-reported symptoms seem inadequate to re ect patients' needs. Furthermore, using the classical Whipple's triad (i.e. appearance of typical symptoms, low plasma glucose, and relief of symptoms following glucose administration) would be unfeasible in a real-life evaluation. We, therefore, sought to identify the outcome parameter that is most relevant for patients and their subjective wellbeing.

Methods
The aim of this project was to develop an evidence-based study design of a clinical trial that tests treatment options and can provide useful patient-relevant evidence.
First, we searched published articles that might address outcomes for clinical trials on postbariatric hypoglycemia to identify outcome domains and to obtain a list of potential core outcome domains (27) with searches on PubMed using terms related to bariatric surgery and hypoglycemia (we searched rst in September 2019 and searched again in July 2020; the detailed search strategy is in the webappendix). as well as COMET initiative database (http://www.comet-initiative.org/studies/), and Google scholar using the terms "patient-relevant outcome" or "patient-centered outcome" combined with "bariatric surgery", "gastric bypass", "sleeve gastrectomy","late-dumping" or "postprandial hypoglycemia" excluding articles with the term "diabetes".
Second, we set out to identify speci c self-help organizations for patients with postbariatric hypoglycemia in Switzerland using a google and facebook search with the German terms for "self-help organization" and "bariatric surgery" or "bypass" and "late-dumping" or "hypoglycemia".
Third, we approached the patients in our clinic and the Hypo-BEAR trial participants (15) to collect in unstructured discussions with individual patients any potential patient-relevant outcome measures which we then presented to two of the most severely affected patients in our clinic with postprandial hypoglycemia (s. supplements, preliminary questionnaire) who agreed to support us for this project with their patient feedback. We expected that quality of life and hypoglycemia would be the most relevant outcome domains.
With this approach we aimed to prioritize the outcome candiates according to patient's preferences and values and then determine the study duration and follow-up. The questionnaire contained a brief outline of the nature of the study, that persons with con rmed postprandial hypoglycemia after bariatric surgery can participate and that it is entirely voluntary. The data items and corresponding questions are listed in Tables 2 and 3. On 25 October 2019, the questionnaire was sent via email to all German speaking endocrinologists by the Swiss Society of Endocrinology and Diabetes as well as directly by the study team to large bariatric centers in the German-speaking part of Switzerland (Clarunis Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital, Basel; Cantonal Hospital Aarau; Cantonal Hospital Solothurn Site Olten and Site Solothurn; Center of Bariatric Surgery, Bern). The healthcare providers then asked their patients to ll out an online version of the questionnaire. Where this was not possible we provided them with a printed version, that could be lled out by hand and was later digitized by our study team.

Statistical analysis
All analyses were descriptive. We calculated medians and interquartile ranges unless stated otherwise.

Ethics and transparency
The study was conducted in compliance with the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 as well as national legal and regulatory requirements and approved by the local ethics committee (EKNZ Req-2019-00933). All data and material are available online in the Open Science Framework under https://doi.org/10.17605/OSF.IO/49RDE.

Results
The search in PubMed yielded 521 hits, none of them were deemed relevant after screening titles and abstracts ( Table 1). The free-text search in Google Scholar and the search on the COMET database also retrieved no pertinent information. We identi ed two main organizations dealing with bariatric patientsthe Swiss Obesity Foundation(29) and the Swiss Bariatric Surgery Self-help Network (30). Both online plattforms offered contact details to various self-help organizations within Switzerland. None spe cally addressed a subgroup for postbariatric hypoglycemia. Also the internet forum of the Swiss bariatric surgery self-help network did not yield results for "late-dumping" or "hypoglycemia" nor was it possible to identify a spokesperson for respective patients. s. Table 2 and Table 3 The two severely affected patients directly providing feedback on the list of outcomes resulting from discussions with other patients valued almost all outcome parameters as important. These data con rmed our expectation that more global outcome domains would be preferable. Similar to trials in oncology (31) and as part of the COS of the BARIACT project(17), we selected "quality of life" as one patient-relevant outcome parameter that would encompass multiple identi ed items. As our second potential outcome, we chose a reduced rate of hypoglycemic episodes. Both reliably measurable by validated instruments such as questionnaires (8) or continuous glucose monitoring systems respectively (24).
The online questionnaire was active from 8 October 2019 to 26 February 2020. 29 persons accessed the online questionnaire website, 22 responded to the question related to the primary outcome and 20 provided all requested information.
The majority (17 of 21 respondents, 89%) were female and median age was 40.5 years (IQR 31-51.5). Most responders (n = 18) underwent Roux-Y gastric bypass surgery, one participant sleeve gastrectomy and another one both ( Table 2). The median postoperative interval was ve years (IQR 2.8-7). Ten respondents (50%) reported several hypoglycemic episodes per week, ve (25%) reported daily episodes, and ve (25%) stated to have hypoglycemic episodes at least once a month. Nine (45%) reported to have a drug therapy for their postprandial hypoglycemia of which six respondents speci ed their therapy ( Table 2). One patient received a triple therapy.
Of all responding participants, 17 (77.3%) deemed quality of life more relevant as primary outcome than the rate of hypoglycemic episodes (5 participants; 22.7%; Table 3). Of 21 responders, 19 (91.4%) found taking a study medication for a period of four weeks acceptable, 15 (71.3%) would accept three months, while only 12 (52.1%) found six months or longer acceptable. Six patients (28.5%) voted for a trial length of nine months or more (one free text answer opted for 18 months, s. Table 3).

Discussion
We used an evidence-based approach to design a clinical trial to test a novel treatment in patients with postprandial hypoglycemia after bariatric surgery. This informed our decision to focus on quality of life as primary outcome, measured between four weeks and six months after randomization.
Neither our literature search in several databases, nor search for patient organizations provided us with the required information. Since we did not want to rely only on our perspectives as clinicians and clincial researchers we aimed to inform our decisons by involving patients, fully acknowledging that this simple approach cannot replace an su ciently large and broad endeavour aiming to create a core outcome set, which would be most desireable. Instead, we used a pragmatic approach where we sought to involve patients as early as possible in the conception of our trial. We collected potential outcome candidates during clinical routine and research visits with affected patients.
We developed an online questionnaire that was easy to follow and quick to ll out. From a technical perspective the rate of hypoglycemic episodes might be a most preferred primary outcome because of the objective and reliable measurement by continuous glucose monitoring, providing a clean measurement of physiological effects. However, this would disregard patient-relevant aspects such as inconveniences to take a drug, side effects and be not really patient important as it would not well re ect how patients "feel and function". Our study showed a clear patient preference of "quality of life" over a "reduced rate of hypoglycemic episodes".
Most of the patients expressed a preference for a active trial length (i.e. intake of study medication) of four weeks or even longer, possibly indicating high feasibility and a high willingness of participants to adhere to a longer study period that might be required to show sustained effects of a treatment. Most of the respondents (75%) are strongly affected with hypoglycemic episodes occurring either daily or several times per week, indicating an urgent need for treatment options. The number of patients that already receive an off-label drug therapy (45%) and still notice a high frequency of hypoglycemic episodes indicates not only the need for an effective treatment but also highlights problems related to off-label prescribing, such as reimbursement aspects.
Several limitations need to be considered. First, our sample of patients was small and included only German-speaking participants from Switzerland, potentially limiting the generalizability of results. However, the sociodemographic and medical characteristices of the respondents of the questionnaire are very similar to the expected spectrum of patients with postbariatric hypoglycemia with a female preponderance, younger age, bariatric surgery, and a typical postoperative interval (5,6,32). Second, our preselection of outcome parameters may have excluded other relevant outcomes which more extensive approaches (such as discrete choice experiments or Delphi rounds (33)(34)(35)) may reveal. Third, selection bias may have affected our ndings. Strongly affected patients may have more likely responded and completed the questionnaire due to a higher motivation for nding an effective treatment. Fourth, our questionaire was online which may have introduced barriers to participate for certain patients.

Conclusions
Quality of life seems to be the most important outcome for patients with postprandial hypoglycemia after bariatric surgery. Using quality of life instead of rate of hypoglycemia as primary outcome in randomized clincal trials that test treatments for patients with this condition may provide more useful and patientrelevant evidence to guide health care decisions. This study was approved (EKNZ Req-2019-00933) by the local ethics committee "Ethikkommission Nordwest-und Zentralschweiz", Basel, Switzerland. Participants were invited by email or directly in the outpatient clinic during routine visits to participate in the anonymous online questionnaire which at the beginning outlined the nature of the project, and described that participation was entirely voluntary. Consent to participate in the questionnaire was implied by its completion. No formal completion was required due to national regulations since participants were answering anonymously and no tracking was done.

Consent for publication
Not applicable.
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on request.