The study design was approved by the local ethics committee of Magdeburg University Hospital and by government authorities. HV, as defined below, were recruited for the study in accordance with the Declaration of Helsinki principles and recommendations of the ESGE-workshop on the ethics of gastrointestinal endoscopy-based research[6]. The recruitment of HV was performed through the distribution of brochures or information posters avoiding affiliation or dependency of HV to the investigators. The purpose, risks of the procedure and the drug-related side effects were fully explained to participants and included in the written informed consent (e.g. risk of bleeding due to platelet inhibitory drugs). HV were informed about the opportunity to revoke study consent and cancel participation at any time. At least 24 h consideration time was provided to the HV before all participants provided written informed consent. Due to the extensive study protocol, all HV were financially reimbursed for their time, effort and contribution to the research. Financial compensation was equal in all HV and was modestly calculated based on generally used factors including compensation for time (or possible income shortfall due to participation in the study), risk, discomfort and inconvenience.

Ten HV [8 men and 2 women, age 27.8 years (22-37) and body mass index 24.7 kg/m² (22.3-27.2)] were included in the study based on previously described inclusion/exclusion criteria[7]. Briefly, HV had no abnormality at physical examination or during routine laboratory examination, no history of relevant illnesses especially history of peptic ulceration, no pregnancy in women and were negative for H. pylori infection.

The study was conducted as a prospective double-blind, placebo-controlled study with cross-over design. The main aim of the trial was to study the influence of several frequently used drugs on the healing of gastroduodenal lesions (preliminary clinical results were reported elsewhere)[8]. In addition, we aimed to evaluate the impact of the endoscopy-based trial on QOL in HV. All volunteers were asked to fill out the questionnaires on the day of each endoscopy, describing the subjective symptoms and QOL. Rofecoxib, clopidogrel, prednisolone, esomeprazole or placebo were given alone and/or together with acetylsalicylic acid (ASA). The endoscopic procedures were performed on days 0, 7 and 14 (Figure 1). The volunteers received one of the test drugs for one week and the same drug together with ASA for another week. Total duration of the study was over 6 mo including a 4-wk washout period between 5 different drug phases.

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Figure 1 Flow chart of the study. The multiple drug study with cross-over design was divided into 5 phases with test drug alone and in combination with low-dose aspirin during the second week. On days 0, 7 and 14 of each study, ten HV were asked to complete the questionnaires. Upper GI-endoscopy was performed on the same days with a 4-wk wash out period between the different phases.

After overnight fasting, the endoscopic examination was performed by an experienced endoscopist (G.T.) using a standard endoscope (GIF 145, Olympus, Germany). All HV received topical lidocaine 2% for local anesthesia and 20 mg of butylscopolaminiumbromid intravenously (iv) to inhibit gastric and small bowel propagation. Additionally, midazolam 5 mg was given iv if requested by the participants. During the procedure, patients were monitored for heart rate and oxygen saturation. After a systematic examination of the stomach and duodenum, multiple biopsies (10 per region, a total of 30 per endoscopy) were taken using standard forceps (5 mm maximum open diameter) from the distal duodenal bulb, antrum and corpus.

To determine the QOL in HV, we used a validated German version of the SF-36 (short form) questionnaire which includes an 8-scale profile: physical functioning, role physical, bodily pain, general health, vitality, social functioning, emotional role and mental health. These scales further represent two distinct higher-ordered clusters due to physical and mental health variance. A lower score in SF-36 indicates a greater impairment and can range from 0 (worst health) to 100 (best health). To determine the abdominal symptoms of HV, we used a previously validated visual analog scale (VAS) based questionnaire[9] with the following dimensions of symptoms: abdominal pain, bloating, reflux, nausea, vomiting, diarrhea and loss of appetite. The summary symptom score (0-70) was calculated by adding up the values of the single scores. A single score value from 1-10 was defined as presence, and 0-1 as the absence of any symptoms. As shown in Figure 1, VAS questionnaires were filled out on days 0, 7 and 14 and the SF-36 questionnaires were filled out before and after each drug phase. The score parameters of HV were compared to a previously evaluated control population of 28 patients, who underwent a single endoscopic examination and in the absence of acid suppressive drugs no visible macroscopic or histological abnormalities were found[9].

All data were analyzed using the SPSS 10 (Chicago, IL, USA) and Graph Pad Prism 4.0 (San Diego, CA, USA). The differences between the groups were analyzed according to corresponding formula and rules, using where appropriate paired or unpaired t-test and Friedman’s test (FT) for non-normal distributed data. For all comparisons, a P-value (two-sided) of < 0.05 was regarded as significant.

All 10 HV completed all 5 phases of the study with 15 endoscopies per HV. With the exception of 2 individuals who either experienced a prolonged bleeding after biopsies had been taken or melena (due to the combination of ASA and clopidogrel) without development of anemia, there were no further drug- or endoscopy-related complications. The VAS and SF-36 questionnaires were completed and returned in 99.5% and in 88% of all cases/time points, respectively. In 91% of endoscopies, HV declined to receive midazolam for sedation and received only topical anesthesia with lidocaine 2%.

SF-36 questionnaires were analyzed in regard to different aspects, such as influence of study drugs, different time points, as well as long term changes in QOL. The physical, mental and total scores, determined by the short form SF-36 questionnaire ranged between 65.6 to 97.0, 65.3 to 96.0 and 75.6 to 97.1, respectively. We found no significant changes in physical, mental or total scores either between different medications or due to participation in each drug phase (data not shown). Overall changes in physical, mental and total scores are shown in Table 1. For the long-term impact of the intensive endoscopy-based trial on the QOL in HV, the SF-36 assessed data were compared between baseline (day 0 during the first phase) and the last time point of the last phase more than 6 mo later. Remarkably, physical (88.4 ± 6.0 vs 86.4 ± 6.7), mental (82.1 ± 8.1 vs 84.6 ± 7.4) and total scores (88.0 ± 5.7 vs 88.6 ± 6.1) showed no significant changes over the 6-mo period (Figure 2). Single score analysis revealed that only general health decreased from 84.4 ± 13.1 to 79.4 ± 15.4 (mean ± SD; paired t-test P = 0.023) and mental health increased from 80.0 ± 6.8 to 83.2 ± 7.5 (P = 0.022).

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Figure 2 Changes in different multiple dimensions and physical, mental and totals scores between baseline and end of study determined by SF-36. During the 6-mo study with cross-over design, 10 HV underwent a total of 150 endoscopic examinations and 4500 biopsies from the antrum, corpus and duodenal bulb. The results are expressed in mean ± SD. Dotted line shows the theoretical max score from 100. Significant changes were observed (^a) for general (84.4 ± 13.1 vs 79.4 ± 15.4, P = 0.023 paired t-test) and mental health (80.0 ± 6.8 vs 83.2 ± 7.5, P = 0.022 paired t-test). In the remaining dimensions, physical, mental and total scores P > 0.05.

Physical complaints were assessed for different symptoms with VAS and analyzed in a similar manner to the SF-36 questionnaires. As anticipated, subjective physical and emotional perception even at baseline differed from one person to another (high inter-individual variability, data not shown). Almost 60% of all complaints were due to abdominal pain and reflux, but these scores showed no significant changes when compared with baseline (Figure 3). The rarest complaints with < 10% of the maximal score were nausea and loss of appetite. To evaluate the global changes we constructed a summary score; values at baseline (3.2 ± 5.1) were comparable to scores at day 7 (2.6 ± 3.7) and day 14 (3.0 ± 3.4) and were less than 5% of the theoretical maximal score.

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Figure 3 Changes between different symptoms and summary scores due to the endoscopy-based study determined by visual analog scale (VAS) based questionnaires. Upper endoscopies were performed on days 0, 7 and 14 of each phase. During every medication phase, HV underwent 3 upper endoscopies with multiple biopsies from the antrum, corpus and duodenal bulb. Maximal complaint score for any symptom or summary scores are 10 and 70, respectively. The results are expressed as mean ± SE and analyzed using Friedman's test (P > 0.05 for physical, mental and total-scores).

To analyze the subjective endoscopy-related impairment in HV, we used VAS which allows the volunteers to score the procedure-oriented discomfort. In analogy to physical complains VAS, we observed high inter-individual variability with the overall range varying from absence to 80% of maximum possible impairment during the endoscopy. As demonstrated in Figure 4, there was no significant difference between self-assessed scores for complaints about endoscopic procedures (1.4 ± 2.0, 1.4 ± 1.1 and 1.35 ± 1.1 for day 0, 7 and 14, RM ANOVA, P > 0.05).

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Figure 4 Changes in compliance scores due to endoscopic procedures between different time points determined by visual analog scale (VAS) based questionnaire. Upper endoscopies were performed on days 0, 7 and 14 of each phase and 30 biopsies were taken during each procedure. Maximal complaint score is 10. The results are presented as scatter plots with means as the lines and were analyzed by ANOVA test (P > 0.05).

The VAS-scores from HV were compared with previously published VAS-scores from a control population[9]. The overall mean for summary symptom scores of HV and controls were comparable (HV 2.9 ± 4 and controls 2.7 ± 4.4, t-test: P > 0.05) and was lower than 5% of the theoretically possible value. We found significantly more complaints for abdominal pain (0.98 ± 1.37 vs 0.3 ± 0.8, P = 0.012) and vomiting (0.22 ± 0.5 vs 0.03 ± 0.2, P = 0.046) in the HV group (Figure 5), but due to the limited number of HV we could not perform age adjustment for the symptoms. The difference between both scores were below the defined cut-off value for the presence or absence of symptoms and were significantly lower than a symptomatic population as previously published[9].

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Figure 5 Different symptoms and summary scores due to the endoscopy-based study compared in HV and the control group determined by visual analog scale (VAS) based questionnaires. Every HV completed 5 medication phases with 15 endoscopic examinations. Control population (data previously published in[9], adopted with permission) underwent only one upper GI endoscopy without endoscopic or histological pathology. Maximal complaint score for any symptom or summary scores are 10 and 70, respectively. The absolute symptom value was below the cut-off for presence of the symptom.

Involvement of healthy volunteers (HV) is absolutely essential in gaining valuable knowledge in clinical and preclinical research. The involvement of HV (HV) has a long history, but many unresolved issues of ethical, methodological or even legal concerns in this regard still remain unanswered. The importance of this becomes even more pronounced when invasive procedures like GI endoscopy are undertaken. Existing ethical recommendations and guidelines on this topic are mostly based on the opinion of experts, but many of these questions have not been studied in a systematic manner.

Multiple studies have shown that the motivation of HV plays a key role in recruiting volunteers. Financial reward is one of the crucial motivating factors in HV. Participation in research studies might be associated with study-related risks, discomfort and inconvenience that might become even more relevant in endoscopy-based studies. Impairment in the quality of life in HV may play a crucial role in understanding these ethical concerns, however, so far no study has addressed the impact of endoscopy-based research on the quality of life of HV.

In this pilot study the authors evaluate the changes in quality of life in HV in a long-term endoscopy-based drug study. The study was conducted according to existing ethical recommendation and guidelines. Using the well-validated SF-36 and visual analog scale-based questionnaires, they show that endoscopy-based research has no significant impact on quality of life in HV even under rigorous conditions.

This study provides valuable and important information regarding the quality of life of HV who participate in endoscopy-based studies, and supports the existing recommendation and guidelines on this topic in Gastroenterology.

Healthy volunteer: is a person who voluntarily participates in a research study. Volunteer come from volunteering which means working, participating or being involved in something without being motivated by financial or material gain. The historical intention, such as to promote good, serve society and improve human quality of life show static movement in paid volunteerism. Endoscopy-based research: are studies or trials performed on individuals which involve endoscopic techniques. Short Form 36: is a well-validated and widely used short survey which includes 36 specific questions on health-related quality of life.

This study examines the impact of a demanding endoscopy protocol on gastrointestinal symptoms and quality of life in 10 human volunteers. The study involved 15 endoscopic procedures over a period of 6 mo.