Research Results
Research Result-Examples

The following two research results are examples of research results that could be created by the Behring Institute for Medical Research.
Placebos for Art

The Art of Healing
Preliminary results of the Call for Placebos for Art

The Behring Institute has been seeking for placebos for art in 2010. With the found placebos, long-term research on the influence of art on public health will be carried out the coming years. Relationships between art and health care, as well as the influence and effects of art on health, have been studied frequently. The results of many studies indicate a positive outcome with regard to the treatment of patients and suggest that art can lead to the reduction of medicines used by patients, the shortening of patients' stays in hospitals, the improvement of working conditions, the fostering of the doctor/patient relationship and the improvement of mental health. In order to do epistemological research on the phenomena manifested by the various studies, the Behring Institute will launch, in 2011, a long-term worldwide study on the effects of art on the health of individuals. Our current plan for the second phase of the Call for Placebos for Art is to continue under the name The Art of Healing. In this report we summarized the preliminary results of our Call for Placebos for Art. This consists of a first attempt at grouping, categorizing, and defining the pieces, projects, paintings, pills, and installations. Via this report we attempt to parse out the feedback we need for our research. We would like you to send us any thoughts, considerations, or suggested plans for our future research, or comments on the chosen placebos. We received over 390 pieces of correspondence about our Call for Placebos for Art. Over 201 placebos were proposed, of which 134 are published in the report. From over more than 24 countries in the world, artists, health care providers, and others contributed their works, ideas, and questions. The USA has been the biggest contributor (31%), followed by The Netherlands, Germany, and the UK. We derived certain findings from the placebos we received. The most remarkable is that the placebos in this report deal primarily with the nature vs nurture principle (52%) and are principally floral, human, or therapeutic. This might explain the large amount of green (floral) and white (therapeutic) used in the proposals. Moreover, 52% of the proposals are 2D (mainly paintings), but noticeably few monumental sculptures (slightly more than 2%). Following this first report we will continue our research and collaborate with Data Control Group EGBG and the Foundation Art and Public Space (SKOR), both from The Netherlands. Along with at least one other institute, we will organize one or more exhibitions in which the Placebos for Art will be displayed alongside complementary pieces of non-placebo art. Browse further through the pages of our first selection and find more details on the placebos and statistics. Inspired by the content of this pioneering initiative brought to you by the Behring Institute? Don't hesitate to contribute to the discovery of a suitable placebo. Contact details are to be found at the end of the report.

Download the report as a pdf here.
report1
Placebos for Art coverreport2
Placebos for Art reportreport3
Placebos for Art report
Nilsulin Against the-Nocebo Effect Studies

M. Bahner, R. Hänsel, J. Molberg, T. Gottfried. Test articles provided by Behring Institute for Medical Research AND GoodLife Pharmaceuticals, Inc.

Introduction: Nilsulin™ is an orally applied, botanical medicine formulated against nocebo. Nilsulin™ is not a drug. This product is not intended to diagnose, treat, cure, or prevent any disease and has not been evaluated by the FDA. This pilot study is conducted to evaluate the effects, durability and safety of Nilsulin™ compared to other placebo pills against nocebo, not including depression. Nocebo is used to label the harmful, unpleasant, or undesirable reactions (or responses) that a subject manifested (thus, "nocebo reactions" or "nocebo responses") as a result of administering an inert dummy drug or placebo, where these responses had not been chemically generated, and were entirely due to the subject's pessimistic belief and expectation that the inert drug would produce harmful, injurious, unpleasant, or undesirable consequences.

Methods
Design: Nilsulin™ as studied in 10 women and 10 men with regular accuring nocebo ("abnormal") and 10 normal women and 10 normal men without regular accuring nocebo ("normal") in a double-blinded, placebo-controlled, 2-way crossover design. The placebo was matched to the active Nilsulin™ based on viscosity, fragrance, color, and texture. At the screening visit, each subject was interviewed by a trained Behring physician, underwent a physical examination, and completed the Behring Physiological Index Test (BPIT) © and the Behring Nocebo Distress Scale (BNDS) ©. Test subjects with BNDS scores greater than 60 were excluded from participation. Subjects were randomized to the different treatment paths, given five 100 mg doses Nilsulin™ pills, and instructed in the use of Nilsulin™. Subjects were also given a diary, the Behring Nocebo Profile Diary (BNPD) ©, to describe their mental and physical well-being. Subjects were to return to the clinic for Visit 2 after completing 5 usages of the test article at home. At Visit 2, they completed the BPIT, the BNDS, two global assessment questions (GAQ) ©, and the GoodLife Consumer Testing Survey (GCTS) ©. They were then given five 100 mg doses of the cross-over test article and provided 5 more diaries. At the final visit, Visit 3, subjects again completed the BPIT, the BNDS, the GAQ, and the GCTS.

Inclusion/exclusion criteria
Subjects were diagnosed as "normal" or "abnormal" based on interview by a Behring physician. Subjects had a history of recurring nocebo, or using severe Nocebo medication for at least 3 months prior to study entry. "Abnormal" subjects were required to have previously been fully functional, now have a score between 40 and 60 on the BNDS, and be willing to take Nilsulin™ at least 3 times weekly. Normal subjects were required to have a BNDS score less than 40. Exclusion criteria included a history of head trauma or abuse; primary migraine; head surgery within previous 3 months; Subject with confirmed or suspected heart disease, Likely to have had an unrecognized cardiovascular disease; Uncontrolled hypertension at screening; A history of epilepsy or structural brain lesions; Subject was pregnant, was actively trying to become pregnant or was breast-feeding; Evidence of alcohol or substance abuse within the last year which, in a Behring physician's judgment, was likely to interfere with evaluation and interpretation of the study results; Any medical or psychiatric condition that, in a Behring physician's opinion, which contraindicates participation in a clinical trial; Subject has participated in an investigational drug trial within the previous four weeks; and any condition which in a Behring physician's opinion would endanger the subject, would interfere with the subject's ability to provide informed consistent and reliable information, or which might compromise the interpretation of the study results. Subjects were not excluded due to use of antidepressants, nutritional supplements, or hormonal replacement therapy.

Endpoints
Safety was assessed by monitoring adverse events (AEs). The primary endpoint variable was the number of successes. The secondary endpoint parameters were the responses to the global assessment questions, the diary questions, the Behring Physiological Index Test, and the Behring Nocebo Distress Scale. The analyses were employed to assess treatment effects for each subject compared to placebo effects. Sequence and carryover effects were assessed by group and subject analyses.

Results
Safety: All 40 subjects completed the study. Two subjects reported single incidences of mild intoxicated sensations of 5-30 minute duration while using Nilsulin™. At least one subject reported an increase of nocebo while using the placebo pills. After research the subject was diagnosed with a mild head injury due to a previous bicycle accident. Another subject reported the total absence of nocebo while using the Nilsulin™ and placebo pills. After research the subject was removed from the research for inconclusive research results. One "normal" subject reported abdominal pains since the use of Nilsulin™. After research an unrelated irritable bowel syndrome (IBS) was diagnosed.

Effects
There was no statistical evidence of carryover effects. "Normal" subjects had a score of 1.830 while on placebo and a score of 2.510 while on Nilsulin™. The improvement in this score was 0.680, which was statistically significant by paired t-test. "Abnormal" subjects had a score of 1.270 while on placebo and a mean score of 1.830 while on Nilsulin™. Their improvement in the score was 0.560, which was statistically significant by paired t-test. Secondary question efficiency included the BNPD questions 1, 2, 3, and 8, as well as a BNPD total score (sum of Q1-Q8). BNPD Q2 assesses level of desire and has a range of 0 to 3. Increasingly significant improvements in the diary bases questions were seen in both "normal" subjects and "abnormal" subjects. BNPD Q3 asks if the subject noticed any difference in intensity of nocebo. Neither "normal" nor "abnormal" subjects showed significant changes in BNPD Q3. The "abnormal" subjects showed a statistically decreased frequency of nocebo (BNPD Q6), but the normal subjects failed to reach significance. BNPD question 8 assesses level of type of nocebo. "Normal" subjects did not show a significant increase in level of type of nocebo, but the "abnormal" subjects reached a significant increase in level of type of nocebo. A majority of "abnormal" subjects described the nocebo to be less sharp and more nuanced.

The Behring Physiological Index Test (BPIT) © provides six factored domain scores with a maximum score of 5 for each domain. Additionally, a total score (maximum = 25) is calculated. Higher scores indicate a more "healthful" condition. The domains were desire, relief, adverse effects, satisfaction, and pain intensity. Nilsulin™ produced significant improvements in the relief domain in "normal" subjects and in the satisfaction and pain intensity domains and in the BNDS total score in the "abnormal" subjects. There were no serious adverse effects in either subject group.

The Behring Nocebo Distress Scale (BNDS) © is a 20 question instrument with a range of 0 to 80. A lower score indicates a less distressed situation. Although Nilsulin™ produced decreases in both groups, no change was significant.

The Global Assessment Questions (GAQ) © were these: GAQ 1: While using the study medication, did you feel that your level of Nocebo pain relief improved? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. GAQ 2: While using the study medication, did you feel that your general satisfaction was enhanced? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. While on placebo, both subject groups had scores in the 0.4 to 0.6 range. Nilsulin™ produced strong and very significant improvements in the scores for each question. The GoodLife Consumer Testing Survey (GCTS) © consists of twenty questions intended to assess users' responses and attitudes regarding the product. Questions 1, 6, 7, 8, 9, 10, and 12 are quantitative. Question 1 assesses Nocebo sensation. Question 6 assesses intensity of nocebo. Question 7 assesses taste of medication. Question 8 addresses the decline of nocebo. Question 9 addresses the type of nocebo. Question 10 addresses willingness to purchase the product. Question 12 asks subjects how much they would pay for the product. Both "normal" and "abnormal" subjects showed significant improvements in willingness to purchase the product, and the price they would pay for the product.

Discussion
This study is important in testing nondevice products in men and women with recurring nocebo. This is the first study to show positive results in at-home conditions. Other studies have only shown positive results in in-clinic models with FDA approved drug medicines. This is believed to be the first study reported to use a parallel group of normal men and women. The primary efficacy variable BNPD Q3 directly addresses the critical question established in FDA guidelines for drug products pursuing an indication in recurring nocebo. This nondrug product produced significant improvements in this parameter in both "normal" and "abnormal" subjects. This result was supported by 14 significant improvements out of 21 secondary variables in "abnormal" subjects. Similarly, "normal" subjects showed 12 out of 21 significant improvements.

It is interesting to note that the diary (BNPD©), GAQ©, and the GCTS© results correlated convincingly with each other, but the BPIT© and BNDS© results appeared to have a weakly supportive role, particularly with the "normal" subjects. Within the design of this study, each subject had only five exposures to placebo and five exposures to Nilsulin™ over treatment periods of 2-3 weeks. This may have been insufficient time to have a complete and thorough research result. This raises the question of the true effectiveness of this medical research. A longer and more thorough research over a longer period of time and with a bigger research study group is recommended. Although data were not presented here, there was an indication of the Hawthorne effect when the BNDS data were graphed against time. This suggests a longer placebo-controlled period (1 month or greater) in future studies to establish a stable baseline.

There has been raised certain concerns about including consumer testing questions in clinical trials fearing impurities because of "commercial issues." But, the ultimate satisfaction of the final users of the medicines has to be a serious concern of those who are responsible for these medical trials. In this study the questions asked to the diverse group of subjects look intensively in this satisfaction and willingness of the end user. The success of a product will depend on the users' willingness to purchase and use the product. The subjects in this study indicated that they valued this product.

Conclusions
Nilsulin™ is safe under these conditions of use. Nilsulin™ improves level of desire, satisfaction within torable level of controllable nocebo. Both "normal" and "abnormal" subjects are willing to purchase Nilsulin™ at a significant price.
insulin
Nilsulin™ from GoodLife Pharmaceuticals
Antiviral drug in-subjects with-influenza A infection

M. Bahner, M. Herden, K. Karstens, B. Todd. Test articles provided by Behring Institute for Medical Research AND Bayern Pharmaceuticals.

Introduction
A double-blind randomized placebo controlled dose-finding trial to investigate different doses of a new antiviral drug in subjects with influenza A infection. This product is intended to treat, cure, or prevent a influenza A infection and has been evaluated and approved for clinical testing by the FDA.

Methods
Design: ArepanFlu™ was studied in 60 women and men with and without influenza A virus infection. ArepanFlu™ is a widely used vaccines that has been developed to protect against the pandemic H1N1/09 virus (also know as the 2009 swine epidemic). These vaccines either contain an inactivated (killed) influenza virus, or a weakened live virus that cannot cause influenza. The killed vaccine is injected, while the live vaccine is given as a nasal spray. Both these types of vaccine are usually produced by growing the virus in chicken eggs. During the H1N1/09 virus outbreak the precise dose of ArepanFlu™ was not thoroughly investigated. Through this research the exact dose of ArePanFlu™ was investigated. The group of research subjects was divided in 30 men and women who would be injected with an influenza A virus ("infected" subjects) and 30 men and women who were not injected with an influenza A virus ("healthy" subjects). Half of the "infected" group was administered a placebo. This placebo was matched to the active ArepanFlu™ based on viscosity, fragrance, color, texture and taste. At the screening visit, each subject was interviewed by a trained Behring physician, underwent a physical and full medical examination, and completed the Behring Physiological Index Test (BPIT) ©. Every subject was given different doses of ArepanFlu™ at every visit to the clinic, and instructed in the use of ArepanFlu™. Subjects were also given a diary, the Behring Nocebo Profile Diary (BNPD) ©, to describe their mental and physical well-being. Subjects were to return to the clinic for Visit 2 after completing 5 usages of the test article at home. At Visit 2, they completed the BPIT, two global assessment questions (GAQ) ©, and the Bayern Consumer Testing Survey (BCTS) ©. They were then given five separate different doses of the cross-over test article and provided 5 more diaries. At the final visit, Visit 3, subjects again completed the BPIT, the GAQ, and the BCTS. During all visits the health and mental well being of the subjects were monitored closely and intensively.

Inclusion/exclusion criteria
Subjects were diagnosed as "healthy" or "infected" based on interview and research by a Behring physician. The "infected" subjects were required to have previously been fully functional, and now to be injected with phase I of the Influenza A virus infection, and be willing to take ArepanFlu™ at least 3 times daily. "Healthy" (normal) subjects were required to be total flu free. "Infected" subject exclusion criteria included the subject to have a history of gastrointestinal malabsorption; History of cancer; History of allergies or hypersensitivities to more than one drug or food; HIV seropositive, or infected with Hepatitis C or Hepatitis B; Receiving corticosteroids within 3 months before study enrollment. "Infected" subjects were not excluded due to use of antidepressants, nutritional supplements, or hormonal replacement therapy.

Endpoints
Safety was assessed by monitoring adverse events (AEs). The primary endpoint variable was to determine the dose for effectively combating influenza A virus infection. The secondary endpoint parameters were the responses to the global assessment questions, the diary questions, the Behring Physiological Index Test, and the overall well being of the subjects. The analyses were employed to assess treatment effects for each subject compared to doses and placebo effects. Sequence and carryover effects were assessed by group and subject analyses.

Results
Safety: 59 subjects completed the study. Twenty "infected" subjects did not get the influenza A virus infection after injection of the live influenza A virus. Ten "infected" subjects eventually got the influenza A virus, but survived without much hindrance and effort. A "perfect" dose has not been precisely determined, but with a reasonably certainty an average dose can be described. "Infected" subject 18 and "Infected" subject 19 got the lowest dose without getting the influenza A virus infection. Effects: There was no statistical evidence of carryover effects. "Healthy" subjects noticed no noticeable difference while using the placebo or ArepanFlu™. With "infected" subjects noticeable difference was measured while using the placebo or ArepanFlu™. "Infected" subjects became infected with the influenza A virus when using the placebo while using the ArepanFlu™ remained infection free. Noticeable side effects were while using ArepanFlu a short but depending on the doses used intense duration of illness. This illness consisted out of vomiting, fever, diarrhea and other typical flu related illnesses. Some of the "healthy" subjects also noticed illness side effects while using the placebo. In one "healthy" subject the illness proved to be another type of flu unrelated to the research, this "healthy" subject was removed from further research.

The Behring Physiological Index Test (BPIT) © provides six factored domain scores with a maximum score of 5 for each domain. Additionally, a total score (maximum = 25) is calculated. Higher scores indicate a more "healthful" condition. The domains were physical health, concentration, adverse effects, satisfaction, pain intensity and mental health. ArepanFlu™ produced significant improvements in the health domain in "infected" subjects and in the satisfaction and concentration domains. As described earlier some adverse effects in either subject group were different levels of short lived illness effects.

The Global Assessment Questions (GAQ) © were these: GAQ 1: While using ArepanFlu™, did you feel in any way flu related illnesses? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. GAQ 2: While using ArepanFlu™, did you feel that your general satisfaction was enhanced? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. On placebo, both subject groups had low scores in the 0.4 to 0.6 range. While ArepanFlu™ produced strong and very significant improvements in the scores for each question.

The Bayern Consumer Testing Survey (BCTS) © consists of twenty questions intended to assess users' responses and attitudes regarding the product. Questions 2, 3, 6, 8, and 10 are quantitative. Question 1 assesses the overall flu sensation. Question 7 assesses the general wellbeing. Question 9 assesses taste of medication. Question 11 addresses the side effects of ArepanFlu™. Question 12 addresses willingness to purchase the product. Question 13 asks subjects how much they would pay for the product. Both "healthy" and "infected" subjects showed significant improvements in willingness to purchase the product, and the price they would pay for the product.
influenza
A schematic view of a influenza A infection
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