Optimization of patient and site engagement in the SYNCHRONIZE™ phase 3 clinical trial program for survodutide in obesity through clinical trial simulation

Abstract

Introduction

Clinical trial simulations (CTSs) are an increasingly common way to incorporate site staff and participant feedback into clinical trial design. CTSs can help overcome the unique challenges presented in obesity trials. Here, a CTS was conducted for three trials from the SYNCHRONIZE™ phase 3 program of survodutide in obesity.

Methods

Individuals meeting the inclusion criteria of the SYNCHRONIZE trials (referred to as “participants”), and clinical trial professionals with experience in conducting obesity trials (“site staff”), were recruited. Trial designs were reviewed by participants and site staff, and participant-facing materials by participants. Both groups were interviewed about these aspects of the trials.

Results

Overall responses to the clinical trial designs were positive. Site staff were comfortable with the inclusion/exclusion criteria and thought recruitment would not be difficult. However, they indicated that pre-screening could help ensure participants' appropriateness for the trial. Additionally, they felt steps should be taken to encourage participant engagement throughout the trial. Participants’ concerns focused on optimizing training and educational materials, time commitments for the trial, and burden of data collection. Recommendations from the CTS led to changes in visit interval, increased virtual visit options, and changes in participant materials. Psychological support was identified as potentially helpful by both site staff and participants. However, understanding how to implement this in clinical trials remains to be elucidated.

Conclusions

These results suggest participant and site staff input from a CTS could help improve obesity clinical trial design, which may ultimately lead to more robust data and reliable clinical findings.

Highlights

• •Clinical trial simulation can improve design and implementation of obesity trials.
• •Participant and site staff recommendations can increase adherence and retention.
• •Participants want more flexibility and less trial burden.
• •Site staff want support with recruitment and engagement throughout the trial.

1. Introduction

Randomized clinical trials play a crucial role in developing new treatments. However, time limitations on site staff, lack of skilled personnel, complex regulatory requirements, communication difficulties, inadequate research experience and training, inefficient trial designs, and lack of support from the trial sponsor are all major obstacles for site staff running clinical trials [[1], [2], [3], [4], [5]]. Recruitment and retention of participants also pose a challenge [6,7]. The International Council for Harmonisation (ICH) guidance on statistical principles for clinical trials (adopted by the US Food and Drug Administration [FDA] and the European Medicines Agency [EMA]) encourages investigators to minimize the incidence of withdrawals and losses to follow-up, given their potential to induce bias in data analyses [8,9]. However, evidence suggests that dropout rates can be impacted by non-trial-related factors like participants’ work, education, or other time commitments, travel, family interactions, socioeconomic factors, and health status [[10], [11], [12], [13], [14], [15]]. Clinical trials in obesity pose their own unique challenges. Although participants may be highly motivated by the potential for weight loss and its related health and quality of life benefits, retention of participants can be difficult [6,7,16].

Involving participants and site staff in the process of clinical trial design is an increasingly common way to overcome some of the barriers to successful trials [[17], [18], [19], [20]]. US FDA guidance recommends the incorporation of patient experience data into clinical trial design [10]. By simulating critical components of a clinical trial through a role-playing process, researchers can obtain and implement feedback from participants and site staff prior to trial initiation. Clinical trial simulations (CTSs) have shown that input from participants and site staff provides valuable learnings to improve recruitment, retention, and robustness of data [[20], [21], [22], [23], [24]]. Here, we report a CTS of the SYNCHRONIZE™–1 and −2 (NCT06066515, NCT06066528) [25], as well as SYNCHRONIZE™–CVOT (NCT06077864) [25] trials from the phase 3 clinical development program of the glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide in obesity.

2. Methods

2.1. Participants

Individuals living with obesity who met the inclusion criteria for SYNCHRONIZE–1, SYNCHRONIZE–2 [24], and/or SYNCHRONIZE–CVOT [25] (“participants”), as well as clinical trial investigators, nurses, and site coordinators (“site staff”), were enrolled. Participants were enrolled who had a wide spectrum of professions and educational levels. Site staff were enrolled from a variety of specialties, had to have ≥2 years of clinical trial experience, and engaged in ≥1 prior therapeutic obesity clinical trial. The CTS was conducted in the US, Germany, Poland, Brazil, China, Japan, and Australia. Sample size determination was based on feasibility of recruiting participants and site staff to complete the CTS before starting the actual trial and calculated to provide a robust sample with similar demographics to the planned trial populations of the SYNCHRONIZE trials. The SYNCHRONIZE study protocols included a large proportion of participants in the United States, and this was reflected in the sample selected for the CTS.

2.2. The simulated trial

The SYNCHRONIZE clinical trial designs have been published elsewhere [25,26], but briefly, participants enrolled in the trials will be randomized to survodutide or placebo, in addition to lifestyle modification. Treatment will be administered once weekly via subcutaneous injection with a pre-filled syringe (PFS). Participants enrolled in the SYNCHRONIZE trials were to fill out questionnaires related to experiences on treatment, quality of life, and eating behavior at baseline and at various timepoints in the trials, as well as a daily “food diary” of all meals and snacks.

2.3. Procedures of the CTS

The CTS took place in 2 parts. During Part 1, participants and site staff completed 30 min of pre-work, involving review of a pre-read document explaining the trial (see Supplementary Appendix) and a simulation animation video providing an explanation of the trial drug and protocol. They were then interviewed for feedback on elements of the trial design. Interviews were limited to 60 min for site staff and 75 min for participants. Given the time constraints, some topics were not addressed by all participants.

In Part 2, a group of participants completed 15 min of pre-work, followed by a 60-min interview reviewing materials that would be used by participants in the trial. No site staff were interviewed in Part 2. The materials included a tri-fold leaflet containing trial information for participants, food diary for recording meals and snacks, side effect management tip card, Instructions for Use (IFU) leaflet for the PFS, and PFS packaging (all in the Supplementary Appendix). Participants read the IFU and used red and green pens to highlight areas that were clear and helpful (green) and areas that were unclear and required further explanation (red). Participants were also observed following the instructions to open the PFS packaging, owing to the potential risk of the device falling out if the package was opened incorrectly (upside down), which would in turn make it unusable. Two types of packaging were tested: one was blank with no colors or markings, and one had a colored perforated strip, numbers, and symbols to guide the user.

All interviews were carried out in the native language of each participant, at the equivalent of an 8th grade reading level, representative of the literacy level for all clinical trials. Animation audio was provided in English, with native language subtitles for each country.

2.4. Data collection and analysis

Structured open-ended interview questions were developed with input from independent patient advisors and site staff advisors (part of the author team of this article), about the clinical trial elements. All interview responses were recorded and analyzed using structured notes. These notes were reviewed by the patient and site staff advisors, as well as the sponsors, and were grouped into themes and quantified. Participant responses were grouped into the categories “positive,” “negative,” or “neutral.” Responses were subsequently reviewed by the authors (experienced clinical investigators and patient obesity advocates). Patient and site staff advisors (DMR and VdW) made recommendations for actioning responses into improvements to clinical trial design. Finally, improvements were agreed upon, and clinical trial designs and procedures were adjusted.

2.5. Ethical approval, consent, and compensation

All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committees. Informed consent was obtained from all participants in the study. Participants were compensated for their participation in the structured interviews at local fair market value as per statutory ethical guidance.

3. Results

3.1. Participant and site staff characteristics

In Part 1 (trial design), 38 participants were enrolled (Table 1). Average age was 48 years (range, 20–72), 68% were female, and 21.1% had a body mass index (BMI) ≥40 kg/m². Twenty-one percent had former clinical trial experience. Among US participants (n = 12), 8 (66.7%) were White, 4 (33.3%) were Black, and 58% reported they had a high-school level education or above (these data were collected in the US population only). Twenty-two participants were recruited to Part 2 (patient-facing materials) (Table 1). No site staff participated in Part 2. The average age of Part 2 participants was 49 years, 50% were female, 36.4% had BMI ≥40 kg/m², and 9.1% had former experience with clinical trials.

Table 1.

Participant characteristics in Parts 1 and 2 of the CTS.

	Part 1 participants, n = 38	Part 2 participants, n = 22
Country, n (%)
Australia	4 (10.5)	0
Brazil	6 (15.8)	0
China	6 (15.8)	7 (31.8)
Germany	3 (7.9)	7 (31.8)
Japan	4 (10.5)	0
Poland	3 (7.9)	0
US	12 (31.6)	8 (36.4)
Race/ethnicity (US only), n (%)	n = 12	n = 8
White	8 (66.7)	5 (62.5)
Black	4 (33.3)	3 (37.5)
Age, mean (range), years	48.2 (20–72)a	48.7 (21–72)
Female, n (%)	26 (68.4)	11 (50)
BMI, n (%)
<30	5 (13.2)	2 (9.1)
30–34	16 (42.1)	6 (27.3)
35–39	9 (23.7)	6 (27.3)
≥40	8 (21.1)	8 (36.4)
CT experience, n (%)
Naive	30 (78.9)	20 (90.9)
Experienced	8 (21.1)	2 (9.1)
Education level (US only), n (%)	n = 12	n = 8
Master's or above	2 (16.7)	0
Bachelor's	2 (16.7)	3 (37.5)
High school	3 (25)	4 (50)
Other	4 (33.3)	0
Unknown	1 (8.3)	1 (12.5)

BMI, body mass index; CT, clinical trial.

^aTwo participants did not have their exact age recorded, so were left out of this calculation. The predicted ranges of their ages were 18–24 years and 45–50 years, respectively.

Thirty-eight site staff were enrolled in Part 1 (Table 2). Over 70% had >10 years of experience conducting clinical trials, and on average, site staff were involved in 2 obesity clinical trials in the prior 12 months. Investigators made up 79% of the site staff, and 21% were nurses or coordinators. Specialties included endocrinology, cardiology, internal medicine, obesity (bariatrics), and diabetes.

Table 2.

Site staff characteristics (Part 1 only).

	Site staff, n = 38
Country, n (%)
Australia	4 (10.5)
Brazil	6 (15.8)
China	6 (15.8)
Germany	3 (7.9)
Japan	4 (10.5)
Poland	3 (7.9)
US	12 (31.6)
Obesity clinical trials in the last 12 months, n (%)
0	2 (5.3)
1	16 (42.1)
2	6 (15.8)
3	7 (18.4)
4	2 (5.3)
5	3 (7.9)
6	1 (2.6)
Unknown	1 (2.6)
Site staff position, n (%)
CT investigator	30 (78.9)
Nurse/coordinator	8 (21.1)
Site staff specialty, n (%)
Endocrinology	21 (55.3)
Cardiology	6 (15.8)
Internal medicine	6 (15.8)
Obesity (bariatrics)	3 (7.9)
Endocrinology/Diabetes	2 (5.3)
Setting, n (%)
University teaching hospital	15 (39.5)
Private hospital	5 (13.2)
3A hospital (China)	5 (13.2)
Private practice	3 (7.9)
Dedicated research facility	2 (5.3)
Othera	8 (21.1)

CT, clinical trial.

^a“Other” includes outpatient clinic, office based in an urban setting, hospital and district healthcare center, clinical hospital and private practice, network of facilities, specialty referral center, community hospital, and hospital.

3.2. Part 1 (trial design)

Overall, reactions to the simulated clinical trial were positive (Table 3). Positive reactions were grouped into 3 major themes. The first included reactions to the novel mechanism of action. Site staff were intrigued by the dual-receptor modality of the trial drug, and participants were excited about the possibility of reducing feelings of hunger and increasing energy expenditure. The second theme was the large population with unmet need. Many participants stated they would be interested to enroll or find out more about the trial (on a scale of 1 to 7, where 1 was “not interested” and 7 was “extremely interested,” mean response was 5.44), and site staff reported they had many patients who could benefit. The final theme was the response to the frequent monitoring and diet and exercise counseling. Participants valued the time and support that would be given to them to focus on treating their obesity.

Table 3.

Participant and site staff qualitative feedback.

Topic	Feedback
Overall impression of phase 3 CT	“Like I said you guys seem like you monitor everything … very, very closely, and how, in the video, it said you had to come in and do the weight, and … like they do your measurements and all that, and I think that is pretty cool, a lot of people don't take the time to do that, and I think with somebody in the position, where I'm obese, it's great, I think it's awesome, I think it is motivating that people are paying attention to what I'm doing and I'm not just doing it alone.” – Participant, US “If this trial came to my desk, I would definitely be approaching my study team and I have a study team that is very versed in this. I would approach them and say, how can we make this study happen in our site? I have the patients. I have the patient criteria that you guys need and I have the study team and the facility for it.” – Site staff, US
Recruitment and retention	“While watching the video alone I considered 20–30 patients that I saw over the past 2 weeks that we would be able to recruit. The inclusion criteria are very simple and there are plenty of patients for this.” – Site staff, Brazil “I don't think it will be very difficult because I see many patients every day with a BMI of >30 or ≥27 with comorbidities. Especially the inclusion criteria of dyslipidemia. I would say that around 1 in 2 or 1 in 3 of my patients have dyslipidemia.” – Site staff, Germany “83 weeks is good, but ambitious – it's a long time and the trick will be to keep patients engaged.” – Site staff, Germany “The challenge will be ensuring that patients remain engaged and don't drop out after the 1.5–2-year mark.” – Site staff, Poland “My thoughts depend on the results, if your results are apparent during the trial, that would be an incentive to continue. This would be life changing. You would be less likely to continue if you're not seeing weight loss.” – Participant, US “You would need to be seeing some positive results within the first 6 months. If you weren't seeing positive results within the first 6 months you would be questioning why you are doing it. If you are doing diet and exercise with injections, people around you should be noticing that you look well, that you look like you dropped weight. If you were in a trial for 6 months and people weren't noticing you, you would be questioning is this really working? I would be thinking what am I getting out of this? Would go to counselor – I've followed the program diligently I am not getting the results.” – Participant, Australia
Schedule and time commitments	“I wondered what would happen if it didn't fit with my work schedule because my now is work first.” – Participant, Japan “It will be important for it to be flexible during the holidays and work commitments in case I am unable to come to appointments. It would not be feasible for me to plan 1.5 years ahead for specific dates and weeks. Having a choice would be important and I would like to make sure that moving a visit on a specific date would not kick me out of the trial.” – Participant, Poland “If someone's working and they're having to leave to go to the doctor to have those things done, not only from the patients' aspect depending on how far they have to drive for the doctor's visit, from the work aspect, their supervisors may not want them to be take off work a lot for that.” – Participant, US “I would say a major con is some patients don't like the study schedule … especially in the beginning and especially for a study like this where they come in a lot more often in the beginning. So, that kind of prevents certain people, like people who work for the most part. It's hard for them, so it kind of shifts the population.” – Site staff, US
Simulation animation	“The animation could be really useful, just because it is of such a high quality to reinforce some other topics I think they should be aware of. The study staff usually explain those but the video can do a great job too so I would think of a way to incorporate that in explaining the studies. Now I know that would need to be IRB approved material but perhaps there is a mechanism to do so.” – Site staff, US “The presentation video that was used before the interview. This would be good for patients as well because it explains really well what will happen, how, and why.” – Site staff, Germany “The video was very good with a lot of detail and very good descriptions of what to expect. The video picked up on all the questions that you may have, and the explanations were excellent indeed.” – Participant, Germany
Willingness to use PFS	“I think I will be able to do it, I should get over my fear of it … The first couple of weeks having someone to guide me through it would be helpful and reassuring.” – Participant, Australia “I'd be comfortable. The information in the video showed that it was easy to do and that the needles were only very small.” – Participant, Germany “I wouldn't self-inject. First of all, I have needle phobia, and second, I myself taking a needle to inject myself? No way, absolutely no way!” – Participant, BR “The training is managed by our nurses, and we even have placebo syringes with NaCl that patients can use to inject themselves. And after getting a demonstration of a first injection by the nurse, the patient is usually able to handle the second injection themselves.” – Site staff, Germany “Video could show all the prep, all the care, hygiene … how it's done, the angle, the application. A video would be very good, but in the first visit where the patient will actually learn, make it, and self-inject it, there must be support at their side to clear doubts. It's very easy, seeing the video, but when you get a needle to self-inject, your hand will shake, and you'll need support from the competent HCP by your side.” – Site staff, Brazil
PRO questionnaires	“[completing questionnaires] is a way of journaling and keeping tabs on what you're doing, what you're going through. I think that's a good idea.” – Participant, US “If the questionnaire is twenty questions or whatever, ten, 15 min, I don't see how that would be an issue for anybody. You can sit there during a commercial and answer them. That doesn't sound like that would be an inconvenience.” – Participant, US "I would find it awful. I just don't want to spend so much time writing all these things down. Because when I stick to something, then I don't need this kind of control. And when I have eaten something I shouldn't have, then I don't need to write that down. I already know that I ate something wrong.” – Participant, DE “When I first saw this diary, I thought there was too much information to record, and it seemed very complicated and burdensome … but I guess you get used to it over time, and this is also a good reminder and help you discipline your diet.” – Participant, CN
Psychological support	“I think what's most difficult with these kinds of things is when you hit a plateau. When you lose a bit of weight but then it comes to a standstill. And you try and try, and you may even end up gaining weight because you're gaining muscle as a result of the exercise. Which would be positive, but it's still a weight gain. In that moment, I would really need a lot of psychological support.” – Participant, Germany “I think I'd get depressed if I wasn't losing weight so it would calm me down that maybe the treatment isn't working quickly.” – Participant, Brazil “I have issues with self-discipline, going to a psychologist in these difficult moments would be advisable, to give me the power of believing I am capable.” – Participant, Germany “Going through any type of dietary change is quite significant and mentally challenging as you are testing yourself. The same goes for the physical changes that comes with the mental challenge.” – Participant, Australia “The trial's purpose was improvement in health and modification of lifestyle and for that you need motivation in order to maintain and encourage patients and to maintain the ongoing lifestyle modifications.” – Site staff, Poland “Psychological support is essential for any study looking to impact behavior.” – Site staff, Germany
Personal connection between site staff and participants	“Ideally they should be welcomed by the same time or someone who is very well familiarized with the project, another reason that bothers patients leading to drop-offs is that each time they show up they are seen by a different professional … this leaves the patient feeling abandoned and undermined.” – Site staff, Brazil “Patients like it when they talk to the same person – especially when they can report weight loss achievement.” – Site staff, Germany “That's really a lot of value in this study – the [participants] thinking they have a coach, they have somebody reviewing this information and that is a motivator to continue the changes they have made.” – Site staff, US “If I was on placebo and my weight measurements weren't moving, having someone to celebrate small differences and offer advice would be important.” – Participant, Australia “I am not talking about praise in the traditional sense but getting some sort of recognition for what you have achieved. In this sense the trial could boost your confidence … But also to get some negative feedback when required. Like when things are stalling, that you're asked to have another look at what you're doing and ensure you are doing everything as you should.” – Participant, Germany

HCP, healthcare provider; PFS, pre-filled syringe; PRO, patient-reported outcome.

3.2.1. Trial recruitment

Of the 38 site staff, 33 (86.8%) thought the inclusion criteria were very simple, and 13 (34.2%) reported recruitment would not be challenging and were confident they could recruit their patients (Table 3). Eleven site staff (28.9%) commented that the inclusion criteria were broad, which would aid recruitment of a large pool of patients. Site staff also predicted participants would be motivated to participate because, in their experience, weight management trials are in popular demand and very few drugs regulating body mass are currently available on the market. However, 24 site staff (63.2%) brought up potential challenges, including finding patients who were not receiving glucagon-like peptide-1 receptor agonists for the past 3 months, and patients who met the mental health, glycated hemoglobin (HbA1c), comorbidity, calcitonin levels, kidney function, weight stability, and lack of previous metabolic surgery requirements. Eight (21.1%) site staff thought the mental health criteria would be a barrier to participation and 5 (13.2%) thought the HbA1c requirements were too restrictive [24,25]. One member of the site staff mentioned financial barriers may present a challenge to recruitment and participation. It was suggested that sites be supported in pre-screening participants, to help foster a personal connection between sites and participants.

Participants expected recruitment to come from their healthcare provider (23; 60.5%), the internet (18; 47.4%), a hospital (6; 15.8%), print advertisements (5; 13.2%), health and wellness experts (i.e., dieticians, sports coaches, and fitness instructors; 2; 5.3%), television commercials (2; 5.3%), and word of mouth (2; 5.3%).

3.2.2. Time commitments

The proposed time commitment required in the trial had a mixed reception, with 13 (34.2%) participants responding positively, 14 (36.8%) neutrally, and 11 (28.9%) negatively (Fig. 1A). Among participants, 16 (42.1%) had concerns about keeping appointments while working full-time jobs and scheduling around holidays and life events (Table 3). Participants and site staff mentioned that a visit window of 3–4 days was preferred to a 1–2-day window, as originally proposed. Participants also thought the clinical trial was long, and that they may have difficulty anticipating their whereabouts and ability to accommodate visits for a 1.5-year period. Some expressed that the length and requirements of the trial would be burdensome, especially if they were not seeing weight loss results. Those that responded favorably voiced that weight loss is a lifelong process and that a 1–2-year time frame is appropriate to ensure weight loss is maintained and to build long-term regimens.

Fig. 1.

Participant responses (positive, negative, or neutral) to aspects of the trial design (Part 1), and select reasons for responses.

Values in the charts reflect the number of participants in sentiment category (or who did not respond), while those next to statements are the number of responses received for a given statement.

PFS, pre-filled syringe; PRO, patient-reported outcomes.

Site staff also expressed concerns about the trial length. Fifteen (39.5%) thought the trial duration would present a challenge; however, 13 (34.2%) thought the duration would not be a problem and would enable the collection of long-term data. One member pointed out that the SYNCHRONIZE–CVOT trial may be a difficult commitment for patients, since it was designed to continue until a predefined number of events occurred. Site staff also mentioned diet and exercise counseling and engagement with participants throughout the trial would be particularly important for retention of those receiving the placebo, as they may not experience as much weight loss as participants receiving the trial drug.

3.2.3. Animations

Although questions about the animations were not specifically written into the discussion guides, both participants and site staff spontaneously gave feedback about the simulation animation videos (Table 3). Among participants, 8 (21.1%) responded positively, 3 (7.9%) neutrally, and 2 (5.3%) negatively (Fig. 1B). Participants felt the animation videos were comprehensive, thorough, informative, easy to understand, and engaging. However, one participant reported that the information was overwhelming. Site staff indicated that the animations were visually appealing, detailed, informative, clear, easy to digest, and would be useful for recruitment purposes. Twelve site staff (31.6%) responded positively to the animations, (2 [5.3%] had a neutral response, while 5 [13.2%] responses were negative). Some site staff, however, reported the videos were too long, could be simplified, and could include more diverse races.

3.2.4. Pre-filled syringes (PFS)

When asked about the PFS, the majority of participants were willing to use it, but expressed desires regarding training (Table 3). The majority (23; 60.5%) responded positively to the PFS, 5 of whom had no prior experience using a PFS (Fig. 1C). Most felt using a PFS would be a slight barrier or no barrier to participating. Still, several (4; 10.5%) reported they were uncomfortable about self-injection. For those viewing the PFS as a slight barrier, initial training and support would be “sufficient to overcome concerns.” Their wants included initial in-person training with first administration observed on-site, demonstration videos that could be re-watched off-site, hard copy instructions with lay language and illustrations, questionnaires to test participant understanding, and practice devices at the site. Site staff were confident patients would be willing and able to use a PFS and thought initial training and demonstrations should be given by a nurse, pharmacist, clinical trial staff, or medical assistant, followed by patient practice. The importance of training was emphasized by many of the site staff (n = 15, 39.5%), who suggested that a training video would help complement in-person training. Many site staff (15; 39.5%) suggested that participants should be given flexibility in injection site due to patient preference.

3.2.5. Patient-reported outcome (PRO) questionnaires

Twenty-four participants (63.2%) responded positively about PRO questionnaires (Fig. 1D). They expressed the PRO questionnaires would help track their progress and help improve the trial data so the treatment would be better understood. One participant felt the PRO questionnaire would help him feel “more looked after.” For participants, the ideal amount of time to complete all PRO questionnaires in the trial was 15–20 min, quarterly, and longer commitment was perceived as burdensome (Table 3). Participants favored digital data capture, although site staff felt that for some older participants, a paper-based method would be preferable. Two participants did not respond to the question because of time constraints. Overall, 12 (31.6%) site staff recommended an electronic PRO questionnaire, and 5 (13.2%) recommended paper based. Site staff indicated it would be best to complete PRO questionnaires on-site, and that the simpler the form, the more effective it would be. Seven (18.4%) site staff recommended a questionnaire length of ≤10 min, 3 (7.9%) recommended 10–15 min, and 7 (18.4%) recommended 20–30 min maximum. Site staff thought the questionnaires should ask about physical activity, weight, mental health, social measures, diet, treatment, and quality of life.

3.2.6. Psychological support

Both site staff and participants felt psychological support was a key factor in the design of obesity clinical trials (Table 4). Among those who had time during the interview to respond to the question (26; 68.4%), most participants responded positively to proposed psychological support (22; 57.9%); 4 (10.5%) participants responded negatively (Fig. 1E). Participants outlined scenarios that might induce negative feelings and where psychological support would be ideal, e.g., a weight loss plateau, needing support adhering to diet and exercise, pre-existing weight-related depression, and managing the impact of seeing their body change. Eight (21.1%) site staff mentioned it was important to provide psychological support. Some thought that any trial focusing on lifestyle modification should ideally incorporate psychological support. However, consistent implementation across regions and sites could be a challenge.

Table 4.

Actions taken in the phase 3 trial program based on the recommendations of the CTS.

Insight	Action
PFS training Self-injection is not a barrier for the majority of participants and concerns can be overcome with training and support. Optimal training for the PFS administration (as defined by site staff and participants): 1Initial in-person training to aid understanding and administration; first administration observed on-site. 2Demonstration videos provided to support training that are viewed on-site and can be re-watched off-site. 3Videos supplemented by ‘hard copy’ instructions in lay language with illustrations.	1Initial in-person training to aid PFS understanding and administration was included as part of the procedures in the trial design. 2Pre-filled syringe instruction video was made in 6 languages (English, French, Italian, German, Japanese, Chinese). 3IFU leaflet for injections with PFS was improved based on simulations with patients.
Pre-screening participants Site staff want support with the time, finances, and flexibility to pre-screen participants for recruitment in a way that works for them. Pre-screening that fosters a personal touch helps build a connection between participant and site staff and will result in greater long-term engagement. Also supports identification of more engaged candidates for long-term retention.	Pre-screening process was implemented where allowed (US) for a small number of sites. Fair compensation was provided to sites for additional activities.
Mock PFS devices during recruitment Besides training how to self-inject, it is essential that prototype devices are available to sites during the screening and recruitment process. With this, sites will be able to show the device to potential participants so they can make a true informed decision whether to participate or not. This will also reduce risk of patients dropping out early.	Two mock PFS kits were provided to each site before recruitment started (prior to initiation) for demonstration purposes.
Tokens of appreciation Participants should feel valued throughout the trial, to support retention. Provide tokens of appreciation: Items/gifts such as scales, thermos flasks (to encourage drinking water), gym memberships, education on food labels and obesity, etc.	Tokens of appreciation were provided during the course of the trial. Type of token depended on country regulations and country strategy of local BI team.
Visit flexibility Participants indicated they would like to have flexibility in the visit window and to choose the visit type that works best for them (in-clinic vs virtual).	Greater flexibility was built into the trial design. Firstly, the visit window was extended to ±3 days. Secondly, some visits were changed to allow for remote assessments during the maintenance phase. For these visits, participants had the option to choose to come for an in-clinic visit, if they preferred.
Recruitment materials Site staff requested a short, illustrated document in lay language describing the trial to support sites for effectively pre-screening people to identify those best equipped to enroll and remain in the trial.	Brochures were created to inform both the participant and their family and friends.
Clarity around time commitments Participants want as much clarity as possible on the time required for each study visit due to the length of the trial. This will help them make an informed decision about whether to participate. This can be as simple as a table outlining time commitments for different in-clinic and remote visits.	After the CTS, a time investment assessment was carried out by site staff advisory board members specifically for these trials. The resulting time investment required from patients per visit was included in the informed consent table of visits and assessments.
Clarity around visit schedules Participants and site staff would like a simple calculation of the visit schedules and flexibility within this to make long-term planning for visit dates (to plan around holidays, work-related activities, etc.).	Incorporated study visit scheduling and notifications to participants on upcoming in-clinic and remote visits into online platform used by site staff and participants.
Additional explanation of aspects of clinical trial requested. More clarity is needed on what is meant by “rescue medication.” Additionally, there was a perception that there might be a discrepancy between the investigators' and the sponsors' definition of chronic or acute pancreatitis and drug misuse, and it was requested that these terms be clearly defined. More clarity was needed around the exclusion criteria of “personal and family history of cancer”. Finally, the mental health exclusion criteria were worrying to some participants and site staff, causing them to fear side effects.	A dedicated section clarifying rescue medication for the site staff was added to trial design. Definitions of chronic and acute pancreatitis and drug misuse were added to the trial design. The exclusion criteria in the trial design were clarified. Phase 2 trial safety and efficacy data were shared with participants and investigators, and both parties were given more information about how to identify mental health issues early so they could feel reassured.
Visit reminders Reminders in the form of apps, fridge stickers, or diaries can aid participant memory for when to administer treatment dose.	Reminder alerts about administration of the treatment dose were included in the eDiary used to collect information about injections.
GI side effect management Participants and site staff view GI side effects as manageable, as long as they are short-lived and guidance on treatments are provided.	A brochure about the management of GI side effects was created and handed out to be discussed by site staff with the participant.
Mode of action explanation There is a need for a separate document/video explaining the mode of action of the trial medication in more detail, but still in laymen terms.	A mode of action video in laymen terms was created.
Empty packaging storage It can be a burden for patients to store the empty boxes for 3 months and then bring them back to the trial site. However, discarding empty boxes of trial medication at home is not allowed for compliance reasons.	Participants were provided with a cooler box to take the trial medication home. Once a box was used, they placed the empty packaging back in the provided cooler box and then returned the cooler box to the site. This placed no additional burden on the patient or their space since the cooler box had to be returned to the site anyway.
Patient-facing materials Valuable input was given on the patient-facing materials (patient information 3-fold, nausea management tip card and food diary) during Part 2 of the trial simulations.	The patient-facing materials were updated based on participant feedback, with special focus on lay language, non-stigmatizing language, and images. The side effect tip card was updated with food recommendations that aligned better with participants' expected dietary advice for weight loss. Language in the IFU about opening the PFS packaging was simplified. A daily food diary was made optional, whereas a 3-day food diary was mandatory.
PFS packaging Although participants considered opening of the trial medication packaging “easy,” it was not always completed correctly as per the instructions.	Colored box indicators were added on the trial medication packaging to help participants open them correctly.
Trial medication storage Storage of trial medication at participants' homes could become an issue because of temperature requirements and the high volume of boxes dispensed.	Small refrigerators were provided to participants if needed. ​Alternatively, medication shipments to patients' home in between visits were arranged.

BI, Boehringer Ingelheim; CTS, clinical trial simulation; GI, gastrointestinal; IFU, instructions for use; PFS, pre-filled syringe.

3.2.7. Site staff-participant relationships

Participants who had time to respond to the question (21; 55.3%) felt positively about fostering personal relationships with site staff during the trial (Fig. 1F). Eleven (28.9%) indicated they appreciated the support provided by professionals, and 5 (13.2%) mentioned they would like constant contact with physicians and nurses throughout the trial.

Site staff also felt fostering personal relationships with participants was important for driving long-term retention, and ensuring participants felt valued and were receiving value from the trial (Table 3). Additionally, courtesy, familiarity, and engagement with each participant's journey, can help build trust. Seven (18.4%) recommended that trial site staff be consistent, to help strengthen these relationships. Relationships could be fostered between participants via group sessions and activities (however, there was some concern that participants could compare and contrast trial results). Nine (23.7%) recommended trial data access to participants, and success celebration. Nineteen (50%) site staff recommended the provision of items and gifts such as scales, water bottles, and gym memberships to help support the weight loss journey, and meal vouchers, coverage for travel expenses, and parking validation as tokens of appreciation.

3.3. Part 2 (participant-facing materials)

In Part 2, a group of participants was asked for feedback on participant-facing trial materials, including an informational tri-fold leaflet, food diary, side effect management tip card, IFU leaflet for the PFS, and PFS packaging (Supplementary Appendix).

3.3.1. Tri-fold leaflet

The tri-fold leaflet was received positively by most participants (95.5%), although some desired clarity around the instruction to “weigh yourself regularly”. Participants were unclear whether “regularly” meant daily, weekly, or monthly. Participants appreciated the inclusion of empathetic language that recognized obesity as a medical condition, validated their experience, and reminded them of lifestyle changes that could drive positive health behavior, as well as information on how the treatment works, and side effects they could expect. However, 4 (18.2%) participants reported they had difficulty understanding the mechanism of action, and 8 (36.4%) found the references to side effects worrying. Recommendations for improvement included providing more information on incorporating a healthy lifestyle, counseling and emotional support, what side effects to expect, the PFS, and certain elements of the trial.

3.3.2. Food diary

While 15 (68.2%) participants responded positively to the food diary, many wished it was simpler. Seven (31.2%) felt they would be fatigued by the food diary, describing the requirement as “too much to record,” “complicated,” “time-consuming,” and “burdensome”. However, 10 (45.5%) thought it would be useful for tracking their diet and 6 (27.3%) reported it would help with dieting discipline. While 9 (40.9%) participants thought the diary should be digital, 10 (45.5%) reported preference for a paper-based version.

3.3.3. Side effect tip card

The side effect tip card was well-received, and many participants were glad to have access to information that was less well known. However, some wanted food recommendations that accommodated diverse cuisines. Additionally, some of the food recommendations were not aligned with participants’ expected dietary advice for weight loss. For example, the card recommended avoiding certain fruits or vegetables, while recommending plain cookies and cake to avoid gastrointestinal side effects.

3.3.4. Food diary/side effect tip card imagery

There were mixed responses to the imagery used in the food diary and tip card. While participants in the US and Germany spontaneously mentioned that they felt positively about the image of the woman that was portrayed in these materials, half (n = 3) of the participants from China felt that the image was not in keeping with the medical and professional feel of the trial. Three participants (13.6%) responded negatively to the image of the woman on the food diary, stating she had an inappropriate facial expression or hair color, and expressing they expected an image of a slim, healthy person.

3.3.5. Instructions for use of PFS

Participants felt the IFU was clear and supportive, and appreciated the clarity of the language and the suitable imagery accompanying the text. However, three participants (13.6%) felt the instructions for opening the packaging were too detailed and confusing, and indicated a preference for simpler guidance. Participants also worried storage of the PFS would be difficult, as it required refrigeration, and that empty, used boxes needed to be stored and returned to the site.

3.3.6. PFS packaging

More participants responded positively to the packaging with colored markings (14; 63.6%) than the all-white packaging (11; 50%). Opening instructions were not always followed correctly for the all-white packaging. Many participants failed to orient the box correctly, blocking access to the plastic tray. Participants did not recognize they had opened the packaging incorrectly most of the time, but when shown the correct procedure, they reported this was easier. Participants felt the packaging labeled with colored markings was easier to open than the all-white packaging. Site staff suggested a need for better labeling of kits for easier identification, as it can be time-consuming for both the site staff and participants to find the right kits in the refrigerator, which in turn could lead to inadvertent temperature excursions. A recommendation was made for an additional label to be located on the side of the packaging.

4. Discussion

In this CTS, participants and site staff were asked to review trial designs and participant-facing materials for the SYNCHRONIZE phase 3 clinical development program of survodutide. Most participants and site staff responded positively to the trial designs. However, recommendations were provided on how the trial design and materials could be improved, and many were implemented. This input may be valuable for increasing participant recruitment and retention to obesity trials.

Several recommendations emerged from the interviews regarding the recruitment process. Site staff recommended that sites be given time and finances to pre-screen participants to help identify highly engaged participants, as well as to build connections between participants and site staff, with the goal of greater long-term engagement. Pre-screening was supported for some sites, though timing of implementation was a limiting factor. Based on suggestions for educational materials using different approaches, a document explaining the trial in lay language and videos explaining the clinical trial process and the mode of action of the trial drug were created. Both site staff and participants voiced the need for flexibility in scheduling and potential burden of time commitment required for clinical trials. Broader visit windows and the option for virtual visits were implemented, where appropriate for the trial design.

Two key aspects of the trial experience raised by both participants and staff were ongoing training/education and burden of implementation. Both site staff and participants desired PFS training, including on-site demonstrations, videos and pamphlets to accommodate different learning styles, and practice devices on-site. The majority of these suggestions were addressed. Treatment administration demonstration videos in support of initial in-person training were available to site staff both on and off-site. These were supplemented with illustrated hard copy instructions. Sites were supported to assist in the injections on a weekly basis if needed by participants. Participants suggested the tri-fold informational leaflet include more information about the trial, healthy lifestyles, emotional support, side effects, and the PFS. The side effect tip card was well-received, although some participants wanted culturally diverse food recommendations and inclusion of foods that were more appropriate for the treatment of obesity. Changes were made to the materials as suggested. Furthermore, colorful instructive markings were added to the PFS packaging as participants benefited from this during the CTS.

Participants perceived a study burden regarding answering questionnaires in the PROs, which are critical for obesity trials. Most respondents desired PRO questionnaires that took no longer than 20 min to complete, were administered electronically, with paper versions to be available if required. Participants desired a less cumbersome food diary requirement, and some wanted a digital food diary, whereas others desired a paper-based version, suggesting it may be important to be flexible to different tracking styles to achieve better adherence. It is also important for sponsors to recognize the data that are essential, and those that are “nice to have” but may become a burden to both site staff and participants and impact long-term engagement with the trial.

Participants expressed differing opinions regarding the marketing images, emphasizing that attention to the visuals used in clinical trial materials is important. Some participants were not in favor of the image showing the woman with obesity and suggested that marketing images be changed according to cultural preferences. Thus, several images with people from different cultural backgrounds were included in the materials, which were selected with the help of patient advisors following the CTS. Additionally, non-stigmatizing, culturally sensitive, patient-first language was drafted and reviewed by patient advisors in all clinical trial materials prior to finalization. These results reflect the importance of sensitivity to stigma associated with obesity in both visual and written materials, and the use of patient-first language.

Both site staff and participants felt strongly that psychological support should be available to participants throughout the trial, though site staff acknowledged implementation would be challenging across regions and sites. Fostering personal relationships between site staff and participants was favored by most respondents and may provide some desired psychological support. Participants should have face-to-face visits with site staff to help them feel reassured during monitoring. In addition, dietary and exercise support provided during face-to-face visits can keep engagement high throughout the trial as participants could see results regardless of being on the investigational drug or placebo. Site staff also suggested gifts such as scales, water bottles, gym memberships, meal vouchers, and funds for travel and parking be offered to encourage participants and increase long-term engagement.

Although many recommendations from the CTS (listed in Table 4 and summarized in Fig. 2) were implemented successfully into the trial, it was not possible to implement others. For instance, psychological support was not provided because of the complexity in implementing this across regions and sites. Future studies should investigate what types of psychological support would benefit patients most, and how these can be feasibly incorporated into obesity clinical trials. Additionally, short animation videos to support pre-screening were only implemented in the US via a local amendment and a separate informed consent form. Pre-screening videos were not implemented globally owing to permission differences across participating countries. Finally, patients were offered injection site flexibility in a sub-study of SYNCHRONIZE–1.

Fig. 2.

Actions taken in response to CTS results.

CTS, clinical trial simulations.

These results highlighted a number of takeaways that may improve the development of future CTSs. First, although the CTS helped identify important observations from both participants and site staff that could improve the trial, potential impediments to implementing these changes were identified, including financial constraints, sponsor commitment, communication of the changes, importance of site relationships, and the need for training to implement the changes. Future simulations should anticipate potential implementation barriers, and consequently, which actions are feasible. Thus, recommendations from the CTS should be reviewed in a meeting between both study advisors and study sponsors. Secondly, it is critical to allow enough time to complete the CTS, analyze the results, and then implement potential changes. This CTS was started in April 2022, and feedback was finalized in August 2022, while the trial protocols were finalized in August 2023, providing enough time to implement changes based on CTS feedback. A CTS should be planned carefully to allow for enough time to implement solutions. Additionally, while this CTS focused mostly on recruitment, retention, and the early parts of the trial, it would be useful for CTSs to also assess the long-term impact of the trial, including learnings obtained from the experience of site staff. While electronic systems are increasingly used for collecting data, this can create an extra burden on the sites when technical difficulties arise. It could be beneficial to test any electronic systems involved in the trial, so participants and site staff can give feedback on difficulties they had using the systems, before a system is chosen for the trial. Finally, it is important to ensure that any change made following the CTS is applied uniformly across regions and sites.

Limitations of this CTS included the lack of involvement of the site staff in the evaluation of the participant-facing materials (Part 2). Their perspective would have been helpful given their experience in using this content in the context of a clinical trial. An additional limitation was that a greater number of study coordinators should have been included in the CTS. Site coordinators are the primary interface of the trial and have abundant firsthand knowledge about the trial operations and what areas need improvement. Their input was invaluable to the improvement of the SYNCHRONIZE trials, and future CTSs should strive to involve more site coordinators in evaluating clinical trials. A final limitation was that there was no built-in assessment of the outcomes of the changes made following the CTS.

The results of this study suggest that participant and site staff input from a CTS may be a valuable way to improve clinical trial design. Any changes that ease the burden and make a trial more attractive to participants and site staff can help increase recruitment and retention, which may ultimately lead to more robust data and more reliable clinical findings.

CRediT authorship contribution statement

Domenica M. Rubino: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Investigation, Formal analysis, Data curation, Conceptualization. Vicki Mooney: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Viviënne van de Walle: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Investigation, Data curation, Conceptualization. David Baanstra: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Investigation, Data curation, Conceptualization. Wouter Daniëls: Writing – review & editing, Writing – original draft, Visualization, Supervision, Project administration, Methodology, Investigation, Conceptualization. Christopher Recaldin: Writing – review & editing, Writing – original draft, Visualization, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation. Joe Nadglowski: Writing – review & editing, Writing – original draft, Visualization, Validation, Resources, Methodology, Investigation, Data curation, Conceptualization.

Data statement

All relevant data are presented in the manuscript.

Funding sources

The study was supported and funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Survodutide is licensed to Boehringer Ingelheim from Zealand Pharma, with Boehringer solely responsible for development and commercialization globally.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D. M. Rubino is currently a clinical investigator for Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Terns; received consulting/advisory board fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Cytoki, Eli Lilly, Neurocrine Biosciences, NodThera, Novo Nordisk, Pfizer, Regeneron, and Shionogi; payment or honoraria for participating as a speaker from Novo Nordisk; Honoraria from ADA, Clinical Care Options, Endocrine Society, Medscape, Peer View, and Prime Education; travel support for speaking/presenting from ADA, Boehringer Ingelheim, Endocrine Society, Lilly, Medscape, Novo Nordisk, Peer View, and Prime Inc.; support for meeting registration from ADA and Endocrine Society; and medical writing support from Boehringer Ingelheim and Novo Nordisk. V. Mooney is the Executive Director of the European Coalition for People Living with Obesity (ECPO) and Chairwoman of the Board of Irish Coalition for People Living with Obesity (ICPO). She reports consultancy fees from Boehringer Ingelheim, speaker fees from Ethicon and Novo Nordisk, and grants (paid to the European Coalition for People Living with Obesity) from Boehringer Ingelheim, Medtronic, Novo Nordisk, and Pfizer.V. van de Walle is currently a clinical investigator for Boehringer Ingelheim, Chiesi, Eli Lilly, and ImmunXperts. She received paid consulting fees from Boehringer Ingelheim, Danone, and Ermium, as well as travel support for speaking/presenting at Veeva and Medidata conferences.D. Baanstra and W. Daniëls are employees of Boehringer Ingelheim.C. Recaldin is an employee of Branding Science.J. Nadglowski is an employee of the Obesity Action Coalition.

Glossary

BI

Boehringer Ingelheim

BMI

body mass index

CT

clinical trial

CTS

clinical trial simulation

EMA

European Medicines Agency

FDA

Food and Drug Administration

GI

gastrointestinal

GLP-1

glucagon-like peptide-1

HbA1c

glycated hemoglobin

HCP

healthcare provider

ICH

International Council for Harmonisation

IFU

Instructions for Use

PFS

pre-filled syringe

PRO

patient-reported outcome

Appendix A. Supplementary data

The following is the Supplementary data to this article.

Data availability

Data will be made available on request.