Supplementary Material Open-label placebo vs double-blind placebo for irritable bowel syndrome: A randomized clinical trial Table of Contents

Supplementary Material

Open-label placebo vs double-blind placebo for irritable bowel syndrome:

A randomized clinical trial Table of Contents

1. Multiple imputation analysis rationale and description page 2 2. Table S1: Comparison of demographics and baseline variables page 3 3. Table S2: Pooled estimates of outcomes at 6-weeks page 4 4. References for multiple imputation analysis page 5 5. Figure S1: Percent of participants who reported adverse events page 6 6. Semi-scripted information for participants pages 7 - 9 7. Table S3: Outcomes at 3-week Midpoint page 10

Multiple Imputation Analysis

As specified in the study design paper¹, if a substantial proportion of randomized participants did not complete post-treatment outcome measures, a sensitivity analysis utilizing multiple imputation² was to be conducted. Of the 262 participants randomized, 51 (19.5%) did not complete the final visit 3 evaluations. Table S1 presents a comparison of baseline

characteristics between participants who completed post-treatment outcome measures and those who did not. For most of the baseline measures evaluated, the participants with missing outcome data were similar to those with complete data. However, the participants with missing data had more severe IBS symptoms at baseline as measured by IBS-SSS, whether treated as a continuous measure or as a binary measure (using the cutoff of 300 as used to stratify the randomization). This finding suggests that the data are not missing completely at random (MCAR), but may be missing at random (MAR). The implication is that an analysis conducted only on the cases with complete data may provide a biased result and that an analysis based on multiple imputation may provide a valid result under the assumption that data are MAR³.

We used multiple imputation by chained equations (MICE)⁴ to generate 25 complete datasets. The multiple imputation models included baseline characteristics including

demographics (age, sex, race, ethnicity, education, employment status, marital status), psychological measures (PHQ-8, GAD-7, neuroticism, extraversion, openness, agreeableness, conscientiousness, pain catastrophizing, social support), IBS history (type of IBS, number of physicians seen, prior use of mint), previous participation in clinical research studies, and participant expectancy of improvement if treated in each of the study conditions and

preference among the study conditions. The models also included baseline and visit 2 measures of the clinical outcome measures (IBS-SSS, IBS-GIS, IBS-AR), the clinician seen at baseline and visit 2, severity of adverse events at baseline and at visit 2. The randomly-assigned study condition was also included in the model. Generation of the complete datasets was done using Stata software (version 16).

We used SAS statistical software (version 9.4) to fit regression models in each of the complete datasets and to pool the results using the methods proposed by Rubin². The models fit for each outcome were identical to those described in the main paper. Table S2 presents the results of the multiple imputation analysis for the primary and secondary clinical outcomes.

Table S1: Comparison of Demographics and Baseline Characteristics

Note: Values are means (standard deviations) unless otherwise specified. IBS-SSS = IBS-Severity

Characteristic Visit 3 Data

Available (n = 211)

Visit 3 Data Missing

(n = 51) p-value

Age 42.4 (18.1) 40.3 (17.8) 0.45

% Female 73.5 70.6 0.68

Race 0.58

% African American 3.3 5.9

% Asian 6.2 5.9

% Caucasian 84.8 78.4

% Multi/Other 5.7 9.8

No. Doctors Seen for IBS 2.6 (1.8) 2.4 (2.0) 0.51

Baseline Severity (IBS-SSS) 276.6 (64.8) 305.0 (73.4) 0.007

% Severe (SSS ≥ 300) 33.1 51.0 0.02

IBS Type 0.17

% IBS-Constipation 22.8 23.5

% IBS-Diarrhea 42.7 39.2

% IBS-Mixed 32.7 29.4

% IBS-Undefined 1.9 7.8

PHQ-8 5.1 (5.0) 5.7 (4.2) 0.42

GAD 4.7 (4.8) 4.7 (4.7) 0.96

Treatment Group 0.45

% Open-Label Placebo 32.2 41.2

% Double-Blind Placebo 33.6 31.4

% No Pill Control 34.1 27.5

Table S2: Pooled Estimates of Outcomes at 6-week Endpoint.

Primary Outcome

Mean improvement in Symptom Severity Score (IBS-SSS) p-values Open-label

Placebo (n=89)

Double-Blind Placebo

(n=87)

No Pill Control

(n=86)

Global test (2 df)

OLP vs.

NPC

DBP vs.

NPC

OLP vs.

Week-6 DBP change

score, mean 79.1 95.0 49.7 0.03 0.09 0.007 0.33

Secondary Outcomes

Percent reporting 50 or 150 point improvement in IBS-SSS 50 point

reduction * 63.6% 68.0% 53.1%

150 point

reduction * 27.2% 29.3% 13.0%

Global Improvement in Symptoms (IBS-GIS) p-values

Week-6

Endpoint 4.33 4.50 3.94 0.02 0.049 0.004 0.44

Slight, Moderate or

Substantial * 39.2% 45.5% 23.9%

Moderate or

Substantial * 19.8% 21.5% 6.5%

Adequate Relief (IBS-AR) Week-6

Endpoint 40.1% 43.4% 31.3% 0.25

*post-hoc analyses

Note: IBS-SSS = IBS Severity Scoring System. IBS-GIS = IBS Global Improvement Scale. IBS-AR = IBS Adequate Relief.

References

1. Ballou S, Kaptchuk TJ, Hirsch W, et al. Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial.

Trials. 2017;18(1):234. doi:10.1186/s13063-017-1964-x

2. Rubin DB. Inference and missing data. Biometrika 1976; 63:581-592.

3. Little RJ, D'Agostino R, Cohen ML, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med 2012; 367:1355-1360.

4. Raghunathan TW, Lepkowski JM, Van Hoewyk J, Solenberger P. A multivariate

technique for multiply imputing missing values using a sequence of regression models.

Survey Methodology 2001;27:85-95.

Figure S1: Percent of participants who reported adverse events.

Note: Error bars show standard errors.

Semi-Scripted Information for Participants

The three pages below provide the semi-scripted information that physicians used to inform participants about the experimental condition to which they had been randomized. Please note that prior to randomization, all participants were informed of the various experimental conditions to which they could be assigned, and they were provided with similar information about each condition. Finally, this information was delivered verbally to participants. They were not given written information.

Open-Label Placebo

Placebo Effect/Expectancy Building

•

You have been assigned to open-label placebo pills. Open-label means that we both know what treatment you are receiving.

•

A placebo is a pill with no active ingredient, like a sugar pill.

•

Placebo effects are powerful. We know that placebo pills can be as effective as

medications in clinical trials. It was previously thought that placebos only worked if you didn’t know you were taking them. Our team and others have shown that open-label placebos can be very helpful for IBS.

How it works. Chemicals. Brain-gut. Conditioning etc.

• The body can respond automatically to placebo pills naturally by releasing chemicals like endorphins and dopamine to relieve pain and IBS symptoms.

• The brain-gut axis is important in IBS. Placebo and taking pills is a form of mind/body treatment which is effective in IBS.

• Sort of like Pavlov’s dogs when they heard a bell. Responding doesn’t mean, “it is all in your head.”

Realistic and Comfortable Attitude Towards Belief/Disbelief

• Being open and having a positive attitude is helpful but you don’t have to believe it will work.

Importance of Taking Pills

• Studies have shown that people tend to do better the more often they take the placebo pills. Even if you think it’s not going to help, please take the pills.

Double-Blind

Like any double-blind trial (i.e. this is a peppermint oil trial)

What is Double-Blind?

•

You have randomly been assigned to the double-blind group which means you will receive either placebo pills or peppermint oil.

•

Neither you nor I will know whether you will be receiving the placebo pills or peppermint oil.

Why?

• We don’t want your or my expectations to influence the outcome.

• We want to study what the medication does without being influenced by either positive or negative expectations.

Peppermint Oil

• Is often used to treat IBS symptoms.

• It has been shown to reduce spasms in the GI tract which may help improve IBS symptoms.

• Although other anti-spasmodics are available, they have side effects.

• Peppermint oil as a treatment for IBS has been studied in Europe. We would like to retest this in the US.

Side Effects of Peppermint Oil

• Side effects have not been reported in peppermint oil studies.

No Additional Treatment

No Additional Treatment: Most importantly scientifically

•

You have randomly been assigned to the no additional treatment group.

•

This group is extremely important because it tells us what happens when you do not take the other treatments in the study.

Why?

• IBS symptoms often vary depending on the day or week. This group allows us to tell whether any changes in the placebo or peppermint oil groups are more than what would have happened with no treatment at all.

Importance of Visits

• This group is very important because studies rarely look at the natural course of IBS. By looking at your symptoms without additional treatment, it will help me get to know you and your IBS symptoms which will help me make individual suggestions at the end of the study.

What You Will Receive During the Study and Afterwards

•

After observing you carefully and you complete the study, we will make some individual suggestions for your IBS.

• Please don’t change anything you are currently doing to help your IBS. Wait until the end of the study and we can discuss together.

Table S3: Outcomes at 3-week Midpoint.

Primary Outcome

IBS-SSS Improvement from Baseline to 3-week Endpoint p-values Open-Label

Placebo (n=69)

Double-Blind Placebo

(n=72)

No-Pill Control

(n=72)

Global test

OLP vs.

NPC

DBP vs.

NPC

OLP vs.

Mean (SD) DBP

95% CI 67.8 (77.1)

49.2 – 86.3 64.5 (88.6)

43.7 – 85.4 49.7 (86.1)

29.4 – 69.9 0.508 -- -- --

Note: IBS-SSS = IBS Severity Scoring System. IBS-GIS = IBS Global Improvement Scale. IBS-AR = IBS Adequate Relief.

Secondary Outcomes

Global Improvement (IBS-GIS) at 3-Week Midpoint p-values Open-Label

Placebo Double-Blind

Placebo No-Pill

Control Global test

OLP vs.

NPC

DBP vs.

NPC

OLP vs.

Mean (SD) 4.39 4.32 4.19 0.509 -- -- DBP --

Adequate Relief (IBS-AR) at 3-Week Midpoint p-values Open-Label

Placebo Double-Blind

Placebo No-Pill

Control Global test

OLP vs.

NPC

DBP vs.

NPC

OLP vs.

Percent 31.9% 43.2% 44.6% 0.231 -- -- DBP --