Clinical trial NCT02668016
Conditions: Adverse Effects Cardiovascular Diseases Hyperlipidemias
Keywords: cardiovascular diseases hyperlipidemias
Sponsor: Imperial College London
Start date: 2016-03-01; Completion date: 2020-12-31
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Front-line clinicians cannot currently test for an individual participant whether symptoms experienced are the pharmacological result of a statin or due to other phenomena. In this trial, participants who have previously ceased statins due to side effects will be offered the opportunity to undergo twelve randomly ordered 1-month periods. There will be four periods of no medication, four periods of placebo and four periods of statin. The placebo and the statin pills will be identical in appearance. Participants will record on a daily basis side-effects experienced. At the end of the study, the one-month sessions are sorted into the order shown above. The participant can then observe directly how much of the increase in symptoms seen with statin is also seen with placebo.

1. Hypothesis 1: that \>30% of participants enrolling for the study will complete it.
2. Hypothesis 2: Overall \>50% of symptom burden is nocebo rather than pharmacological
3. The investigators will define the Nocebo proportion of side effects.
4. Hypothesis 3: that the majority of participants, at 6 months after completion, will either be taking statins or have declined statins for reasons other than perceived side effects.

Detailed description:
Participants: 50 participants will be recruited to the trial.

Method: At baseline each participant will have a detailed interview with the study doctor to assess past medical history and previous symptoms attributed to statins and assess if they are eligible to be enrolled. Eligible participants will be enrolled and allocated a random predefined order to take the study interventions in. These random codes will be generated by the trials unit statistician and supplied to the production pharmacy. The participant will be dispensed High Density Polyethylene (HDPE) containers which are in this pre-specified order. Each participant will receive 12 sets of HDPE containers pre-labelled. 4 sets of HDPE containers will contain no medication, 4 will contain 1-month supply of matched placebo and 4 will contain 1-month supply of atorvastatin 20mg. At the start of the next calendar month after the screening visit the participants will commence the trial intervention. The research nurse will call the participant to remind them to start on the 1st day of the next month after screening. Each day participants will rate their daily symptom on a phone application and will also complete 3 additional questionnaires on a monthly basis. The study nurse will call the participant at the end of each month to assess their progress in the trial. Each participant will return their boxes at dispensing visits (if applicable) and at the study end in order for a pill count to be undertaken to assess medication adherence. The placebo and atorvastatin pills will be visually identical.

The study enrols participants not intending to re-start clinical use of statins. Participants' other medications will continue to be managed as normal by their own physicians, with no restriction on starting, stopping or changing doses. For safety reasons the participant's own physician will be asked to consult the investigators prior to consideration of starting, or amending the dose of, any other lipid lowering medication.

For the trial, each participant will receive a smartphone, or if preferred, can have the application downloaded to their existing phone to allow real-time daily documentation of symptoms experienced on a visual analogue scale of 0-100. Participants will receive training on the simple touch-screen interface and a leaflet with further information will also be provided. Participants will rate symptoms every day, with the daily scores aggregated into a monthly score. This is preferable over scoring only once a month, because participants may struggle to remember and aggregate their symptom burden especially if it varies between days.

Each month participants will fill out two validated questionnaires on the impact of their side-effects on their quality of life. These are EuroQol (EQ-5D-3L), a well-validated measure of health related quality of life, and the Treatment Satisfaction Questionnaire for Medicine (TSQM) questionnaire, a validated treatment satisfaction questionnaire. EQ-5D-3L assesses five domains of health and overall self-rated health using a visual analogue scale. EQ-5D-3L is conventional for assessing efficacy of medication on quality of life but may not be sufficient for assessing side effects, therefore the TSQM questionnaire will also be used. Use of both a health related quality of life questionnaire and a treatment satisfaction questionnaire will allow assessment of participants' multiple health states, overall self-rated health status and treatment satisfaction, and provide a test of both convergent validity and measurement invariance for the monthly aggregate symptom burden score.

The investigators will also ask participants to fill in a short questionnaire detailing any potentially their own physicians, with no restriction on starting, stopping or changing doses For safety reasons the participant's own physician will be asked to consult the investigators prior to consideration of starting, or amending the dose of, any other lipid lowering medication.

Arms: arm 1: Atorvastatin 20mg daily for 1 month arm 2: Placebo daily for 1 month arm 3: No Atorvastatin or placebo for 1 month
Interventions: intervention 1: Atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: Atorvastatin 20mg tablets taken orally once daily for one month. intervention 2: Placebo tablets taken orally once daily for one month

Protocol documents:
Prot_000.pdf: 
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SAP_001.pdf: 
CONFIDENTIAL 
Imperial College London 
Self-Assessment Method for Statin side effects Or Nocebo trial 
(SAMSON) 
Statistical Analysis Plan 
Version 1.0 
January 14, 2020 
Prepared by: 
Statistics Collaborative, Inc. 
© 2020 Statistics Collaborative, Inc. 
NCT02668016 




SAMSON – STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page i 
CONFIDENTIAL 
Contents 
 Introduction ....................................................................................................................................... 1 
 Investigational plan .......................................................................................................................... 1 
2.1. 
Study design ............................................................................................................................ 1 
2.2. 
Study objectives and outcome measures ............................................................................ 2 
2.3. 
Study hypotheses ................................................................................................................... 2 
2.4. 
Randomization ........................................................................................................................ 3 
 Study schedule .................................................................................................................................. 3 
3.1. 
Study days ............................................................................................................................... 3 
3.2. 
Unscheduled visits ................................................................................................................. 4 
 Sample size determination and power calculation ...................................................................... 4 
4.1. 
Sample size calculation – Hypothesis 2 ............................................................................... 4 
 Statistical analysis: general considerations and conventions ..................................................... 5 
 Efficacy analysis ................................................................................................................................ 5 
6.1. 
Primary outcome (Hypothesis 2) ......................................................................................... 5 
6.1.1. 
Missing and partial data for primary outcome ..................................................... 7 
6.2. 
Other efficacy outcomes ........................................................................................................ 8 
6.2.1. 
Hypothesis 1 .............................................................................................................. 8 
6.2.2. 
Hypothesis 3 .............................................................................................................. 8 
 Characteristics of the population .................................................................................................... 8 
7.1. 
Demographics and baseline characteristics ........................................................................ 8 
7.2. 
Concomitant medications...................................................................................................... 9 
7.3. 
Medical history ....................................................................................................................... 9 
 Protocol deviations ........................................................................................................................... 9 
 Adverse events .................................................................................................................................. 9 
 Quality of life measures and confounding life events ............................................................... 10 


SAMSON – STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page ii 
 
CONFIDENTIAL 
Exhibit 
Exhibit  
Visit schedule ....................................................................................................................... 4 
 
Abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
CI 
confidence interval 
CRF 
case report form 
EQ-5D-3L 
EuroQol 
ICH GCP 
International Conference on Harmonisation 
Good Clinical Practice  
ICTU 
Imperial Clinical Trials Unit 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
preferred term 
SAMSON 
self-assessment method for statin side effects 
or nocebo trial  
SAP 
Statistical analysis plan 
SCI 
Statistics Collaborative, Inc. 
SD 
standard deviation 
SOC 
system organ class 
TSQM 
Treatment Satisfaction Questionnaire for 
Medicine 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 1 
CONFIDENTIAL 
 
Introduction 
This statistical analysis plan (SAP), which is based on protocol Version 1.2 dated 
August 1, 2019, defines the methods and analyses that Imperial College London plans to use to 
analyze the data from the Self-Assessment Method for Statin side effects Or Nocebo trial 
(henceforth, SAMSON). This study adheres to the principles outlined in the Medicines for 
Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 
2006/1928), and the International Conference on Harmonisation Good Clinical Practice (ICH 
GCP) guidelines. It is being conducted in compliance with the protocol, the Data Protection 
Act, and other regulatory requirements as appropriate. If the protocol is subsequently 
amended, this SAP may be amended as well. Should the SAP and the protocol be inconsistent 
with respect to the planned analyses, the language of the SAP is governing.  
 
Investigational plan 
2.1. 
Study design 
SAMSON is a randomized controlled trial evaluating in a cohort of participants the proportion 
of adverse symptoms truly due to the effect of statin rather than nocebo. The investigators 
plan to randomize participants to receive, in a random predefined order, the study 
interventions. Each participant will receive 12 sets of pre-labelled HDPE containers. Four sets 
of containers will contain no medication; four will contain a one-month supply of matched 
placebo; and four will contain a one-month supply of atorvastatin 20mg. At the start of the 
next calendar month after the screening visit, the participants will commence the trial 
intervention. The research nurse will call participants to remind them to start on the first day 
of the next month after screening; thereafter, the participants will receive a monthly reminder 
to switch to the next set of HDPE containers. Each day participants will rate their daily 
symptom on a phone application; they will complete three additional questionnaires each 
month. 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 2 
CONFIDENTIAL 
2.2. 
Study objectives and outcome measures 
Front-line clinicians cannot currently test whether symptoms an individual participant 
experiences are the pharmacological result of a statin or due to other phenomena (e.g., 
nocebo). The value of such a tool would be two fold: 
• 
The tool would allow individual participants to establish for themselves whether 
they truly suffered a side effect from the drug or are victims of nocebo – which may 
in fact be more common. 
• 
By separating the components, the tool would permit clinical researchers to explore 
the determinants of each, opening opportunities to obtain better clinical outcomes. 
The main objectives of this study are to the following: 
• 
To develop a method for determining for an individual participant what extent 
experienced symptoms are associated with the statin or merely reflect a nocebo 
effect. 
• 
In a cohort of participants who have stopped statins because of adverse symptoms, 
to evaluate in what proportion the symptoms are truly due to the statin.  
2.3. 
Study hypotheses 
The study aims to test the following hypotheses: 
• 
Hypothesis 1: More than 30% of participants enrolling into the study will complete it.  
• 
Hypothesis 2: Overall, more than 50% of symptom burden is nocebo rather than 
pharmacological.  
The effect of nocebo effect on side effects will be defined as: 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 (𝑃𝑃ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎+𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜) =
(𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)
(𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠−𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎)    
• 
Hypothesis 3: At six months after completion of the study, at least 50% of 
participants will either be taking statins or have declined statins for reasons other 
than perceived side effects. 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 3 
CONFIDENTIAL 
2.4. 
Randomization 
Eligible participants are enrolled on InForm, which allocates each participant a random 
predefined order during which to take the study interventions. The Imperial Clinical Trials 
Unit (ICTU) generates these random codes and supplies them to the production pharmacy. 
 
Study schedule 
3.1. 
Study days 
Potential participants attend a screening visit during which the study doctor receives written 
informed consent from those who decide to participate. The study doctor then assesses the 
participants’ eligibility for the study by evaluating their past medical history and previous 
statin intolerance. Participants’ blood pressure is measured. Participants who do not have a 
recent lipid profile recorded in the last 6-months are offered the option of having one 
undertaken as part of the screening visit. The study doctor determines if the participant is 
suitable to be enrolled in the study. Suitable participants are enrolled on InForm. 
Scheduled follow-up telephone calls are undertaken each month during the 12-month period 
of the trial. The study nurse monitors the participants’ scores. If the scores show severe 
discomfort or if participants are not scoring on their phone, the study nurse makes 
unscheduled telephone follow-up calls and, if required, arranges an unscheduled study visit to 
see the study doctor who performs unscheduled tests deemed necessary.  
The end of study will be defined to occur when the specified number of participants have been 
recruited, all participants have completed the 18-month phone interview, and the database is 
locked.  
The 12-month follow-up contact may be combined with the end of study visit; if so this would 
be a face-to-face visit at the study center.  If so, the month 12 visit must be completed before 
the scheduled unblinding. The end of study visit may take place up to 31 days after the 12-
month telephone follow-up. The Exhibit presents the study visit schedule 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 4 
CONFIDENTIAL 
Exhibit. Visit schedule 
 
 
D1  
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M18 
 
Screening and Enrolment 
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
Telephone follow-up  
End of Study Visit 
6-month Follow-up visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid profile 
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EuroQol 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSQM 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Confounding life 
events questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
3.2. 
Unscheduled visits 
Unscheduled assessments are not performed unless participants develop adverse events that 
the chief investigator considers ‘related’ to the trial procedure or to atorvastatin therapy. 
 
Sample size determination and power calculation 
4.1. 
Sample size calculation – Hypothesis 2 
Each “effect of nocebo” will be a value which, for the sake of the calculation in the protocol, 
was assumed to be between 0 and 1. The study aims to report an average effect of nocebo for 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 5 
CONFIDENTIAL 
the population that has a 95% CI of ±10%. To achieve this, assuming a conservative scenario of 
individual-participant values scattered uniformly from 0 to 1 (i.e., SD = 1/√12 = 0.29), the 
number of participants to be studied will need to be ≥N where 0.29/√N ≤0.10/1.96( i.e., 
N>(1.96×0.29/0.10)2=36. The investigators planned to recruit 50 participants. In all a total of 62 
participants were screened and 60 were randomized.  
 
Statistical analysis: general considerations and conventions 
Descriptive and inferential statistics will be used to summarize results of the SAMSON study. 
Continuous variables will be summarized using the number of subjects (N), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Discrete variables will be 
summarized using counts and percentages.  
Summaries will be provided for demographics, medical history, concomitant medications, and 
adverse events. For summaries of medical history, concomitant medications, and AEs, the 
Medical Dictionary for Regulatory Activities (MedDRA®) and the World Health Organization 
Drug dictionaries, as appropriate, will be used. 
All data listings, summaries, and statistical analyses will be generated using SAS® Version 9.4 
(or higher) or other validated software. 
 
Efficacy analysis  
As described in Section 2.3, the study has three hypotheses.  
6.1. 
Primary outcome (Hypothesis 2) 
Hypothesis 2: Overall >50% of symptom burden is nocebo rather than pharmacological.  
For the trial, all participants receive a smartphone or, if they prefer, the application can be 
downloaded to their existing phone. Access to the phone will allow them to record real-time 
daily documentation of symptoms experienced on a visual analogue scale of 0-100. 
Participants will rate symptoms every day, with the daily scores averaged into a monthly 
score.  


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 6 
CONFIDENTIAL 
Each participant receives four months (4 × 28 days) each of no medication, placebo, and active 
medication (i.e, statin). We represent the individual participant’s symptom score data as 
follows:  
𝑥𝑥01
𝑥𝑥𝑝𝑝1
𝑥𝑥𝑠𝑠1
𝑥𝑥02
𝑥𝑥𝑝𝑝2
𝑥𝑥𝑠𝑠2
𝑥𝑥03
𝑥𝑥04
𝑥𝑥𝑝𝑝3
𝑥𝑥𝑝𝑝4
𝑥𝑥𝑠𝑠3
𝑥𝑥𝑠𝑠4
 
𝒙𝒙ഥ𝟎𝟎=
∑
𝑥𝑥0𝑗𝑗
4
𝑗𝑗=1
4
=
∑
ቀ(∑
𝑥𝑥0𝑖𝑖)
28
𝑖𝑖=1
/28ቁ
4
𝑗𝑗=1
4
 , 𝒙𝒙ഥ𝒑𝒑=
∑
𝑥𝑥𝑝𝑝𝑗𝑗
4
𝑗𝑗=1
4
=
∑
ቀ(∑
𝑥𝑥𝑝𝑝𝑖𝑖
28
𝑖𝑖=1
)/28ቁ
4
𝑗𝑗=1
4
, 𝒙𝒙ഥ𝒔𝒔=
∑
𝑥𝑥𝑠𝑠𝑗𝑗
4
𝑗𝑗=1
4
=
∑
ቀ(∑
𝑥𝑥𝑠𝑠𝑖𝑖
28
𝑖𝑖=1
)/28ቁ
4
𝑗𝑗=1
4
   
𝑥𝑥̅- mean symptom score for no medication, placebo, statin, i-day 1 to 28 of treatment month, j – 
treatment month 1 to 4  
We assume no carry-over effect. Thus, the estimated mean of the effect of nocebo is calculated 
as follows:  
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= ෍ቆ𝑥𝑥̅𝑝𝑝𝑛𝑛−𝑥𝑥̅0𝑛𝑛
𝑥𝑥̅𝑠𝑠𝑛𝑛−𝑥𝑥̅0𝑛𝑛
ቇ/𝑁𝑁
𝑁𝑁
𝑛𝑛=1
 
N= number of study participants 
Because the study participants are independent of each other, the variance of the estimated 
mean can be calculated as the as the sum of variances of the individual participants:  
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 𝒔𝒔𝟐𝟐= ෍𝑠𝑠𝑛𝑛2
𝑁𝑁
𝑛𝑛=1
= ෍𝑉𝑉𝑉𝑉𝑉𝑉
𝑁𝑁
𝑛𝑛=1
ቆ𝑥𝑥̅𝑝𝑝𝑛𝑛−𝑥𝑥̅0𝑛𝑛
𝑥𝑥̅𝑠𝑠𝑛𝑛−𝑥𝑥̅0𝑛𝑛
ቇ 
To calculate the variance of the estimate, we use a Taylor series approximation, which is a 
function of the variance of the numerator, variance of the denominator, and the covariance of 
the two:  
1) 𝑉𝑉𝑉𝑉𝑉𝑉(𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛) = 𝑉𝑉𝑉𝑉𝑉𝑉 ൫𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0൯= 𝑠𝑠𝑝𝑝2 + 𝑠𝑠02 −2𝑟𝑟𝑠𝑠𝑝𝑝,𝑠𝑠0𝑠𝑠𝑝𝑝𝑠𝑠0  
2) 𝑉𝑉𝑉𝑉𝑉𝑉(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) = 𝑉𝑉𝑉𝑉𝑉𝑉 (𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0) = 𝑠𝑠𝑠𝑠2 + 𝑠𝑠02 −2𝑟𝑟𝑠𝑠𝑠𝑠,𝑠𝑠0𝑠𝑠𝑠𝑠𝑠𝑠0 


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 7 
CONFIDENTIAL 
3) 𝐶𝐶𝐶𝐶𝐶𝐶(𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛, 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) = 𝑐𝑐𝑐𝑐𝑐𝑐൫𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0 , 𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0) = 𝑐𝑐𝑐𝑐𝑐𝑐 ൫𝑥𝑥̅𝑝𝑝, 𝑥𝑥̅𝑠𝑠) −𝑐𝑐𝑐𝑐𝑐𝑐 ൫𝑥𝑥̅𝑝𝑝, 𝑥𝑥̅0) −
𝑐𝑐𝑐𝑐𝑐𝑐 (𝑥𝑥̅0, 𝑥𝑥̅𝑠𝑠) + 𝑐𝑐𝑐𝑐𝑐𝑐 (𝑥𝑥̅0, 𝑥𝑥̅0) =  𝑐𝑐𝑐𝑐𝑐𝑐 ൫𝑥𝑥̅𝑝𝑝, 𝑥𝑥̅𝑠𝑠) −𝑐𝑐𝑐𝑐𝑐𝑐 ൫𝑥𝑥̅𝑝𝑝, 𝑥𝑥̅0) −𝑐𝑐𝑐𝑐𝑐𝑐 (𝑥𝑥̅0, 𝑥𝑥̅𝑠𝑠) + 𝑠𝑠02 
𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒, 𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,
𝑐𝑐𝑐𝑐𝑐𝑐൫𝑥𝑥̅𝑝𝑝, 𝑥𝑥̅𝑠𝑠൯=
∑
(𝑥𝑥𝑝𝑝𝑗𝑗−𝑥𝑥̅𝑝𝑝)(𝑥𝑥𝑠𝑠𝑗𝑗−𝑥𝑥̅𝑠𝑠)
4
𝑗𝑗=1
4 −1
 
4) 𝑠𝑠𝑛𝑛
2 = 𝑉𝑉𝑉𝑉𝑉𝑉ቀ
𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0
𝑥𝑥𝑠𝑠
തതത−𝑥𝑥̅0ቁ= ቀ
𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0
𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0ቁ
2
൬
𝑉𝑉𝑉𝑉𝑉𝑉 ൫𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0൯
(𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0)2
+
𝑉𝑉𝑉𝑉𝑉𝑉 (𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0)
(𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0)2 −2
𝑐𝑐𝑐𝑐𝑐𝑐൫𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0 ,𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0)
൫𝑥𝑥̅𝑝𝑝−𝑥𝑥̅0) ( 𝑥𝑥̅𝑠𝑠−𝑥𝑥̅0) ൰ 
s = standard deviation, s2= variance, r = correlation 
The Taylor’s series approximation is based on asymptotic theory. Should the data not allow 
stable estimates of the components of the variance, we will use a bootstrapped estimate of the 
variance. 
To calculate the 95% CI for the mean nocebo effect, the test statistic is 𝑡𝑡= √𝑁𝑁(𝜇𝜇−𝜇𝜇0)/√𝑠𝑠2  
The null hypothesis is rejected if 𝑡𝑡> 𝑡𝑡𝛼𝛼,𝑁𝑁−1 where, in SAS, 𝑡𝑡𝛼𝛼,𝑁𝑁−1 is TINV(1-α, N-1); 
In SAS, the p value associated with the test statistic T is PVAL=1-probt(abs(T), N-1) or 
PVAL=cdf('T', T, N-1). 
The 95% confidence interval is 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒± 𝑡𝑡𝛼𝛼/2,𝑁𝑁−1 √𝑠𝑠2 /√𝑁𝑁 
6.1.1. 
Missing and partial data for primary outcome 
For the calculation of mean symptom score for particular treatment (statin, placebo, no 
medication) missing scores (i < 28) will be handled by only using study months that have at 
least 10 of daily symptom scores non-missing. We will perform sensitivity analyses using 
different thresholds for non-missing scores (such as 14 and 16 non-missing scores) and 
compare the percentage of missing symptoms scores during the ‘pill’ months (statin or 
placebo) versus ‘no pill’ months. We will assess the temporal pattern of missing symptom 
scores by comparing the percentage of missing scores at the beginning of the study to the 
percentages at later study months.  


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
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The nocebo effect for an individual participant will be calculated only if he or she has non-
missing symptom scores for at least one month of each treatment (j ≥ 1). If the participant has 
not recorded any symptom score for one of the three treatments (j=0 for statin, placebo, or no 
pill) the nocebo effect cannot be calculated, and the primary endpoint analysis will exclude 
that participant. 
6.2. 
Other efficacy outcomes 
6.2.1. 
Hypothesis 1 
Hypothesis 1: More than 30% of enrolled participants will complete the study.  
1) Point estimate 𝑝𝑝̂ = 𝑥𝑥/𝑁𝑁  where x is the number of participants who completed the study 
and N is the number of enrolled participants  
2) Hypotheses: 𝐻𝐻0 : 𝑝𝑝̂ = 𝑝𝑝0  𝑎𝑎𝑎𝑎𝑎𝑎   𝐻𝐻𝐴𝐴 = 𝑝𝑝̂ > 𝑝𝑝0        𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝑝𝑝0 = 0.3  
3) Test statistic 𝑧𝑧=
𝑝𝑝ො−𝑝𝑝0
ඥ𝑝𝑝0(1−𝑝𝑝0)/𝑁𝑁 
4) Reject null hypothesis if 𝑧𝑧> 𝑧𝑧𝛼𝛼, 𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒  𝑧𝑧0.05 = 1.645 
5) 95% confidence interval:𝑝𝑝̂ ± 𝑧𝑧𝑎𝑎/2ඥ𝑝𝑝ෝ(1 −𝑝𝑝ෝ)/𝑁𝑁= 𝑝𝑝̂ ± 1.96ඥ𝑝𝑝ෝ(1 −𝑝𝑝ෝ)/𝑁𝑁   
6.2.2. 
Hypothesis 3 
Hypothesis 3: At six months after completion of the study, at least 50% of the participants will 
either be taking statins or have declined statins for reasons other than perceived side effects. 
This hypothesis will be tested in the same way as Hypothesis 1 above but setting 𝑝𝑝0 = 0.5.  
 
Characteristics of the population  
7.1. 
Demographics and baseline characteristics 
Quantitative variables will be summarized using the number of subjects (N), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Qualitative variables will be 
summarized using counts and percentages.  


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
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The following demographic and baseline characteristics will be summarized: age, gender, 
height, weight, ethnicity, and past use of statin. Blood pressure and selected biochemistry 
laboratory measurements reported as well.  
Age in years will be calculated as the integer portion of the following: 
[(Date of randomization- Date of birth) + 1] / 365.25. 
Unless otherwise stated, percentages will be calculated relative to the number of subjects 
randomized.  
7.2. 
Concomitant medications 
Information on concomitant medication may be summarized by generic name as reported on 
the concomitant medication CRF. The number and percentage of subjects who took at least one 
drug within each generic type will be presented. Subjects will be counted only once if they 
take the same generic medication more than once. 
7.3. 
Medical history 
Medical history will be coded using the MedDRA and summarized by system organ class 
(SOC) and preferred term (PT). Medical history may be sorted by descending overall 
frequency, by SOC and PT, in the summary tables.  
 
Protocol deviations 
Important protocol deviations will be summarized by the category reported on the CRF form 
and sorted by descending overall frequency 
 
Adverse events 
Adverse events (AEs) are monitored throughout the study and documented on the 
appropriate AE form. They are coded using the MedDRA dictionary by system organ class 
(SOC) and preferred term (PT); they will be classified by seriousness, severity, and relation to 
study medications.  


SAMSON STATISTICAL ANALYSIS PLAN 
January 14, 2020 
Page 10 
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AEs will be summarized by subject, not event. AE data will be also presented in listings.  
 
Quality of life measures and confounding life events 
Each month participants fill out the following two validated questionnaires related to the 
impact of their side-effects on their quality of life: EuroQol (EQ-5D-3L) and the side effects 
domain of the Treatment Satisfaction Questionnaire for Medicine (TSQM) questionnaire. 
Participants will also fill in a short questionnaire detailing any potentially confounding life 
events they experienced over the previous month (e.g., change of daily routine, holidays, 
bereavement). At the end of study visit participants will have an exit interview exploring the 
nature of symptoms occurring during the study in case they may differ from those described 
in the baseline interview.  
The daily quality of life scores will have their distribution described by the mean and standard 
deviation or, if not normally distributed, by the median and interquartile range. These scores 
will then be aggregated to monthly average scores. The correlation within group and intraclass 
correlation will be used to assess within-subject agreement and group mean reliability. To 
establish the measurement properties (i.e., convergent validity and measurement invariance) 
of the new measure we will examine the correlations between the month averages and each of 
the two monthly validated scoring systems (EQ-5D-3L and TQSM). A strong correlation (r>0.4) 
will reflect satisfactory convergent validity. The stability of the correlations across the 12 
months will reflect the degree of measurement invariance. We will test this formally by a pair 
of path analysis models using Mplus: one model in which the within-time correlations between 
the monthly aggregate of the new measure and the validated measure (i.e. EQ-5D-3L and 
TQSM) are fixed across time, and another where they are allowed to differ. If the latter model 
does not offer a significant improvement in model fit (assessed by chi-squared and fit indices), 
this suggests measurement invariance.  
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