Clinical trial NCT01568255
Conditions: Myopathic Symptoms
Keywords: myopathic symptoms
Sponsor: Cedars-Sinai Medical Center
Start date: 2012-03-01; Completion date: 2019-06-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Statins are a class of drugs that are highly effective at lowering cholesterol levels. However, compliance is often limited by symptoms of muscle pain. The investigators would like to study Vitamin-D deficient individuals who also have muscle pain due to statin use. About 1 billion people are estimated to have low or insufficient levels of vitamin D worldwide. Patients with low or insufficient levels of vitamin D may develop muscle disease. The purpose of this study is to identify if these symptoms are associated with vitamin D deficiency, and most importantly, if treatment of vitamin D deficiency can reduce muscle pain that is caused by statin treatment.

Detailed description:
Vitamin D2 (Ergocalciferol) is approved by the FDA to treat Vitamin D deficiency and will be given according to approved labeling. This drug has not been systematically studied to test the potential benefits of Vitamin D in patients who suffer from statin-induced muscle pain. Vitamin D2 is the current standard of care for treating vitamin D deficiency. Since the investigators are using Vitamin D2 therapy to treat vitamin D deficiency, and because our trial is a pilot study, the data will not be submitted to the FDA for consideration of changing the labeled indications for Vitamin D2 therapy.

This is a randomized, double-blinded, and placebo-controlled pilot study that will only be performed at CSMC. 40 females with moderate to severe myopathic pain while on Simvastatin will be enrolled in this study and will be randomized at a 1:1 ratio. Patients who will be approached are considering an alternative statin medication as part of their clinical care to address their muscle pain.

Participants will be recruited from the investigators' clinic patients. The study will be discussed with a patient during clinical visit by the treating doctor. Interested individuals will be provided with a copy of the consent form to take home for review with friends, family, and other physicians. The patient may then call the study staff to set a study appointment or enroll in the study during the clinical visit. A study investigator will discuss the study with the patient and ask the patient to read through the consent. The investigator will encourage the patient to ask any questions or discuss any concerns she might have.

If the consenting investigator is also the patient's treating doctor, the consenting investigator will request that the study coordinator approach the patient to determine the patient's interest in the study in order to avoid a conflict of interest. The coordinator will explicitly tell the patient that the patient's participation in the study is completely voluntary and that the patient's medical care will not be affected should she choose not to participate.

Participation in this study will be approximately 8 weeks. 20 participants will be randomized to the treatment group and 20 to the placebo group. The treatment group will receive Vitamin D2 therapy at 50,000 IU for 8 weeks (once per week) while the placebo group will receive a placebo pill (once per week) that is identical in nature. Participants have 2 study visits respectively at Week 0 and Week 8, and 1 phone follow-up visit at Week 1. In addition to the administration of Vitamin D2 or placebo mentioned above, other study procedures include informed consent, physical exam, questionnaires (brief pain assessment, and SF-12 to assess limitations on physical activity), review of medical records, medication and supplement review, blood draw, and phone followup. Subjects will be asked to stop any supplemental Vitamin D therapy to maintain an equal dose within patients in the Vitamin D2 and placebo group.

Prior to randomization, statin medication will be changed from Simvastatin to Atorvastatin and patients will be followed up by telephone at Week 1 for tolerability of the new statin medication. When a patient is intolerant to a particular statin, it is the standard of care to attempt another statin medication. Typically, many choose atorvastatin since a lower dose of the drug can be used to obtain the same target LDL/HDL, and lower doses reduce the risk of toxicity. This change in medication would be preformed regardless of the research protocol. Since the statin will be switched to a lower dose, it is possible that it will be a confounding factor, however, even the placebo group will be switched to the same alternate statin, reducing the differences between the two groups. In addition, Atorvastatin is also metabolized by the CYP3A4 enzyme, and because the presumed mechanism of association between vitamin D deficiency and statin-induced myopathic pain pivots on this enzyme, the investigators wanted to choose a statin that continues to utilize this enzyme. But, for reasons stated above, Atorvastatin has less myopathic symptoms due to lower doses used.

At the conclusion of the study, those in the treatment group whose serum 25 OH D levels have reached \> 30ng/mL (therapeutic) may continue on maintenance doses on ergocalciferol (1,000 Units/day) if they are receiving clinical benefit. For those whose 25 OH D levels are \< 30ng/mL, regardless of whether they received clinical benefit or not from the treatment arm, they will be offered a repeated 8 week course of Ergocalciferol therapy at 50,000 Units/week under standard of care. It will be up to the patient to accept or decline the therapy.

Arms: arm 1: Vitamin D Treatment Group arm 2: Placebo at 50,000IU for 8 weeks
Interventions: intervention 1: Ergocalciferol intervention 2: Placebo
Intervention descriptions: intervention 1: Ergocalciferol therapy at 50,000IU for 8 weeks intervention 2: placebo at 50,000IU for 8 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
 
 
 
 
 
 
 Is Treatment of Vitamin D Deficiency Associated with Resolution of Statin-Induced 
Muscular Symptoms 
 
Sponsors: Cedars-Sinai Medical Center CTSI, National Lipid Foundation 
 
Study Investigators: Margo Minissian PhDc, NP, Chrisandra Shufelt, MD, Talya Waldman NP, 
Caroline Alexander, MD, Puja Mehta, MD FACC, Janet Wei, MD, C. Noel Bairey Merz, MD 
FACC FAHA 
 
IRB Protocol No.: 23187 
 
Last Updated: November 4, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Section 1.0 
 
General Information  
 
Title: Is Treatment of Vitamin D Deficiency Associated with Resolution of Statin-Induced 
Muscular Symptoms 
Sponsors: Cedars-Sinai Medical Center CTSI, National Lipid Foundation 
Study Investigators: Margo Minissian PhDc, NP, Chrisandra Shufelt, MD, Talya Waldman NP, , 
Puja Mehta, MD FACC, Janet Wei, MD, C. Noel Bairey Merz, MD FACC 
FAHA 
 
Section 2.0 
 
Background information 
Vitamin D can be found in plants, fortified foods, or be synthesized in the epidermis using 
ultraviolet B rays.1  Even with the multiple sources of vitamin D available, an estimated 1 billion 
people world-wide have deficient or insufficient levels of Vitamin D.2  The prevalence is higher 
in urban environments where modern culture res1ults in increased indoor activities and sunblock 
use as well as ethnic populations where darker skin pigmentation requires increased sunlight 
exposure to produce an equivalent amount of vitamin D as their lighter skin counterparts.3,4  
Vitamin D is most known for its role in calcium homeostasis.  As a patient becomes deficient in 
vitamin D their calcium stores are depleted and they develop osteomalacia.  In addition to bone 
abnormalities, patients with low vitamin D levels may also develop an osteomalacic myopathy.  
Low vitamin D stores in these patients are associated with increased body sway, decreased 
muscular strength, changes in gait, difficulties in rising from a chair, inability to ascend stairs 
and diffuse muscle pain.5,6  Longitudinal studies have shown increased risk of falls with 
increasing amount of musculoskeletal pain intensity and locations.7  These symptoms of 
musculoskeletal pain are similar in nature to the muscle pain, or myopathic events, associated 
with statin use.8  In fact, patients with statin-induced myopathic events had lower serum vitamin 
D levels than statin-treated patients without myopathic events.8  Treatment with vitamin D in 
both statin-induced myalgic patients and the elderly has shown to reduce the occurrence of 
myopathic symptoms and falls, respectively.8,9  Unfortunately, the study by Ahmed et al was a 
non-randomized trial with subjective patient reporting as the measurable outcome.  In addition, 
the lack of a control prevents assessment of whether these myalgic symptoms would have 
resolved independently with time.  Both these factors may have led to a falsely elevated 
improvement in statin-induced myalgia; therefore, further randomized control trials are indicated 
to assess the validity of these findings. 
 
Early in vitro studies have shown the presence of vitamin D receptors (VDR) on muscle cells.10 
In fact VDRs on muscle cells have been shown to decrease with age;11 similarly, increasing age 
is a risk factor for developing statin-induced myalgias.12 Physiologically, vitamin D may directly 
bind to nuclear receptors in muscle tissue to improve muscle strength or directly increase 
intracellular phosphate concentrations resulting in increased ATP production and hence 
improved muscle functioning.11,13  An alternate theory involves competition of the cytochrome 
P-450 3A4 (CYP3A4) isozyme that is both responsible for statin metabolism and vitamin D 
activation.  It is theorized that in vitamin D deficient states, CYP3A4 preferentially hydroxylates 
25 OH D instead of metabolizing statins, leading to statin-induced toxicity.14  Statins that most 
commonly cause myopathic pain (simvastatin and atorvastatin) inhibit the CYP 3A4 system. 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Section 3.0 
 
Trial Purpose and Hypothesis 
Purpose: 
Statins are a highly effective therapeutic intervention for lipid optimization.  Compliance is often 
limited by myopathic pain symptoms.  The purpose of this study is to test if treatment with 
vitamin D can alleviate statin-induced myopathic pain in subjects with serum vitamin D levels < 
30ng/mL.  This could provide patients a low cost, low risk intervention that would enhance statin 
compliance. 
 
Hypothesis: 
We hypothesize that vitamin D therapy will improve statin-induced myopathic symptoms 
compared to placebo. 
 
 
Section 4.0 
 
Trial Design 
4.1 Participant Selection and Overall Trial Design 
Los Angeles based community physicians and the principal investigator’s patients will be 
recruited for the study.  This will serve to attract a primarily urban and ethnically diverse 
population of subjects. Only outpatients will be used for the study.    We will enroll patients with 
an indication for statin therapy that are experiencing benign, mild to moderate myopathic 
symptoms such as: myalgia, myositis and myopathy but not rhabdomyolysis but are still able to 
continue their current statin medication.  Rhabdomyolysis will be ruled out with a serum creatine 
kinase (CK) level < 10 x the upper limit of normal (ULN).  These definitions are based on the 
ACC/AHA/NHLBI guidelines as they are more clearly defined than FDA or NLA definitions for 
myopathic symptoms related to statin use (Appendix A).  Clinician interview will determine that 
source of pain is myopathic and that myopathic pain is related to statin use.  Other etiologies of 
myopathic pain will be ruled out such as; increased physical activity, hypothyroidism, trauma, 
falls, accidents, seizure, shaking chills, infections, carbon monoxide poisoning, polymyositis, 
dermatomyositis, alcohol abuse, and drug abuse (cocaine, amphetamines, heroin, or PCP).15  If 
serum vitamin 25 OH D levels are less than 30ng/mL, then the patient will be eligible for the 
study, as these patients are considered vitamin D deficient.  The patient will continue their 
current statin regimen and will be randomized to either the placebo arm or treatment arm, which 
is the Vitamin D arm (Appendix B).  All statin medications will be studied in this trial. 
 
4.2 The primary aims of our study include: 
1.  Assess if treatment of vitamin D deficiency improves statin-induced myopathic pain 
2.  Assess if treatment of vitamin D deficiency improves statin tolerance3.  Assess if treatment of 
vitamin D deficiency improves the quality of life in patients with statin-induced myopathic pain 
 
4.3 The primary outcomes of our study include: 
1.  Myopathic pain 
2.  Quality of life 
3.  Vitamin 25 OH D levels 
4.  Statin tolerability 
 
These will be measured used the brief pain inventory (Appendix C), the SF 12 survey (Appendix 
D), serum measurements, and pill counting, respectively.   


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
 
4.4 The secondary outcomes of our study include: 
1.  Parathyroid hormone (PTH) 
2.  Calcium 
3.  Lipid profile 
 
PTH and calcium levels are directly dependent on serum 25 OH D levels.  In addition, lipid 
profiles are affected by statin compliance.   
 
4.5 The modifiable variable in our study is: 
Number of medications patient is taking that is metabolized by the CYP3A4 enzyme 
 
One of the proposed mechanisms of action in statin-induced myalgia and vitamin D deficiency 
involve competition at the CYP3A4 enzyme.  Therefore, the total amount of CYP3A4 dependent 
medications each patient consumes will be tabulated to assess if it confounds outcomes at the 
end of the study.  This will be most relevant for those patients who entered the study with a statin 
that is metabolized utilizing the CYP3A4 enzyme (lovastatin, simvastatin, atorvastatin, 
rosuvastatin, fluvastatin).  Because 3 of these 5 statins are available in generic formulation, they 
will most likely be prescribed at a higher frequency in our urban dwelling population.  This will 
be done with a medication list review (Appendix E).  
 
4.6 Study population 
Recruitment of patients will occur during outpatient clinic visits and through outpatient referrals 
from Los Angeles-based community physicians.  Community physicians will not be sharing 
detailed study information with patients.  Our study population will consist of 40 male and 
female urban dwelling patients of varied ethnic origin.  Although women are preferentially 
affected by osteoporosis and the phenomenon under study may be similar to osteomalacic 
myopathy, we will include men in the study for inclusiveness All women of child bearing age 
included in the study must be using an effective form of contraception because statin therapy can 
be harmful to a growing fetus. These women are all already on statin therapy so they cannot be 
pregnant as per clinical care. However, to ensure patient safety, all women will undergo urine 
pregnancy testing at the beginning of the study.  Lactating women, however, can transmit statins 
to children through breast milk; therefore, they will be excluded from our study. 
 
4.7 Safety 
In order to assess if patients meet all inclusion and exclusion criteria, the patient will have to be 
interviewed, their chart reviewed, blood pressure measured, and have a urine pregnancy test 
(child bearing women).  To ensure it is safe for the patient to begin the study, the chart will be 
reviewed to ensure baseline laboratory values within the last 6 months are within normal limits: 
creatinine (Cr), calcium (Ca), aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), albumin (alb).  Serum thyroid-stimulating hormone (TSH) values need to be within 
normal limits within the last 12 months.  If these labs are not current, they will be re-drawn at the 
beginning of the study.  Blood pressure will be measured prior to initiation of study since some 
research suggests that vitamin D therapy can lower blood pressure.16  Finally, the patient will 
have to be interviewed to assess if they meet all inclusion and exclusion criteria.   
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
4.8 Course of Experiment 
During the patients routinely scheduled clinical care visit or at time of referral, the patient will be 
screened for study eligibility.  Patients on any statin will be included.  Patient must have 
clinically documented vitamin D level <30ng/mL within 6 months of study entry during screen.  
It will be determined during the screen that patients’ myalgia symptoms are due to statin therapy 
and that patient is able to continue their current statin medication.  Once all the 
inclusion/exclusion criteria are met, the patient is recruited into the study and scheduled for their 
first research visit. At research visit #1, patients will be consented for the study, have lab work 
drawn for safety and laboratory outcome measurements (primary and secondary outcomes), 
complete study surveys (SF-12 and BPI), medical history, and medication review documents. 
They will also undergo a physical exam where blood pressure, height, weight, vital signs, 
abdominal and hip circumference measurements will be taken. The patient will then be 
randomized to either a treatment or placebo group and given the study drug. The study will be 
double-blinded. The treatment group will receive Ergocalciferol therapy at 50,000IU for 8 weeks 
while the placebo group will receive a placebo pill that is identical in nature.  Patients will be 
asked to continue their current statin. Once serum creatinine, calcium, urine pregnancy (child 
bearing women) if indicated and creatine kinase levels return, likely within the same day, patient 
will be given a phone call and asked to start study drug or placebo for the next 8 weeks. Patients 
will then be called by study investigators and/or coordinator in 1-2 weeks for a phone follow-up 
where tolerability of study drug will be discussed as well as discussion and documentation of any 
adverse events (AEs).  During this phone call an exit appointment will be scheduled after 
completion of 8 week course of study drug vs placebo.  If patient is unable to tolerate protocol an 
earlier exit visit will be scheduled.   During the exit visit patient will undergo a repeat physical 
exam, complete surveys and medication review, and phlebotomy that will measure the primary 
outcomes, secondary outcomes, modifiable variables, and safety measurements:  creatinine, 
calcium, and creatine kinase levels.  For a temporal summary, please refer to Appendix G. 
 
Section 5.0. 
 
Selection and Withdrawal of Subjects 
Patients experiencing myopathic pain while consuming any statin medication will be approached 
by one of the study investigators regarding their participation. The study will be explained to 
them and if they would like to participate in the study the patient will be given a consent form to 
review.  The patient will be given the opportunity to ask any questions.  After all questions have 
been answered and the patient appears to fully understand the study, they will be offered 
additional time to think about participation and go over the study material. The patient will be 
given the contact information for the study investigator in order to ask additional questions.  
After all questions are answered, and the patient has fully reviewed the consent and decides to 
participate, the patient will be scheduled for her first research visit at which time written consent 
will be obtained.     
 
5.1 Inclusion Criteria: 
Only patients meeting all the listed criteria below will be asked to participate 
 
2.  Age > 18, using an effective form of contraception (refer to section 4)  
3.  An indication to be on statin therapy 
4.  Mild to moderate myopathic pain while on a statin  
5.  Pt able to continue current statin 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
6.  Serum CK level < 10 x ULN 
7.  Vitamin 25 OH D level <30 ng/mL (as secondary hyperparathyroidism is triggered below this 
level)2 
8.  English speaking patients only 
9.  Myopathic pain that cannot be attributed to other medical conditions 
10.  Continue a statin within the CYP3A4 family 
11. Competent to give informed consent 
12. Vitamin D Level <30ng/mL 
13. (+)Myalgia symptoms on a statin medication  
14. Negative pregnancy test 
 
 
5.2 Exclusion Criteria: 
1.  Clinical diagnosis of overt vitamin D deficiency: osteomalacia, rickets, hypocalcemia, 
hypophosphatemia 
2.  Already taking Vitamin D supplements >1000 IU/day 
3.  Serum creatinine> 2.2 mg/dL within last 6 months 
4.  AST/ALT > 3 x ULN of the local reference range 
5.  Serum CK level > 10 x ULN 
6.  Systolic blood pressure <90 mmHg 
7.  Albumin adjusted calcium >2.55 mmol/L or <2.20 mmol/L 
8.  Renal osteodystrophy 
9.  Malabsorption syndrome 
10.  Metastatic malignancy 
11.  Transplant recipients 
12.  A co-existent diagnosis of renal calculi within the previous 6 months  
13.  A co-existent diagnosis of primary hyperparathyroidism within the previous 6 months 
14.  Recent therapy with corticosteroids within the previous 6 months 
15.  Currently consuming Digoxin, as usage increases risk of hypercalcemia 
16. Lactating women (refer to section 4) 
 
5.3 Withdrawal Criteria 
Patients who are severely intolerant to their current statin therapy, meaning hydration and rest do 
not improve symptoms, will be asked to exit the protocol.  Patients will be brought back for their 
exit visits outlined in Appendix G and data regarding all measurable outcomes will be taken.  In 
addition, remainder study drug will be collected.  Patient will then be referred to primary care 
physician for further management of vitamin D deficiency, if persistent.  In regards to statin 
management, patients will be withdrawn from their current statin and asked to follow up with 
their cardiologist or primary care physician for further statin therapy management.   
 
Section   6.0  
Treatment of Subjects 
Study Drug  
The intervention under study in this trial will be ergocalciferol, vitamin D2.  Of the 40 patients 
selected for the study, 20 will be randomized to the treatment group while the other 20 will be 
randomized to a placebo group.  During this time they will also be encouraged to continue taking 
their current medication regimen and supplemental regimen as long as the cumulative Vitamin D 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
dose is <1000 IU/day.  Vitamin D is currently not a standard medical intervention in the 
treatment of myopathic pain.  Vitamin D, in this study, is being used to treat patients with low 
serum 25 OH D levels.  In addition, assessing for vitamin D deficiency is not routine and there is 
no consensus on who should be offered therapy; therefore, since the study extends for a short 
period of time, it is safe for deficient patients to be randomized to the placebo arm.  Furthermore, 
upon completion of the study, patients who were vitamin D deficient and randomized to the 
placebo arm will be offered therapeutic doses of vitamin D. 
 
Currently, there is no consensus on an optimal serum 25 OH-D level in asymptomatic 
insufficient patients.  Optimal serum goals are set based on overt symptoms of deficiency which 
typically occur at levels <15 ng/mL.  Therefore, the current standard of care is to treat patients 
with high dose ergocalciferol to keep levels at least >20ng/mL but ideally >30ng/mL as 
secondary hyperparathyroidism is prevented at these serum concentrations.  Since we are testing 
whether vitamin D supplementation will improve statin-related myalgias in subjects with low 
serum vitamin D levels, we have planned our study feasibility based on a 30ng/mL threshold.  
Ergocalciferol is the current standard of care for treating vitamin D deficiency. Since we are 
using ergocalciferol therapy to treat vitamin D deficiency, and because our trial is a pilot study, 
the data will not be submitted to the FDA for consideration of changing the labeled indications 
for ergocalciferol therapy. 
 
Section 8.0    
Assessment of Safety 
When the vitamin D system is overstimulated, hypercalcemia results because of increased 
intestinal calcium absorption and by the induction of bone re-absorption.  In regards to vitamin 
D, hypercalcemia is the criterion for harm, because it is the agent that causes symptoms.17  These 
symptoms include nausea, dehydration, lethargy, weakness, excessive thirst, anorexia, headache, 
constipation, weight loss, kidney stones, arterial calcium deposits and decreased or altered urine 
output.  However, toxicity is a rare concern with vitamin D, especially since UVB rays degrade 
excess vitamin D.2  Serum 25 OH vitamin D levels are measured approximately 2 months after 
initiation of high dose ergocalciferol therapy to monitor efficacy as well as toxicity.  This time 
period is consistent with the termination of our study, where we will obtain serum calcium and 
25 OH-D levels to monitor efficacy and toxicity.  Furthermore, the first signs of toxicity 
typically do not occur until a serum 25 OH D concentration of 100-140 ng/mL (>250nmol/L),18 
which is unlikely to be obtained at high doses prior to the 3 month monitoring period that is 
currently the standard of care.19 
 
Statins, although rare, can cause rhabdomyolysis.  This is the main concern when patients 
develop myopathic pain.  If serum CK levels are > 10 x ULN then the patient is toxic from statin 
therapy, and further therapy with statins should be discontinued.  Prior to study initiation, serum 
CK levels will be checked to screen out patients with rhabdomyolysis in whom continuation of 
statins is unsafe.   
 
Section 9.0. 
     Statistics 
Our goal sample size of enrolled patients is 40, with 20 patients in each arm.  We approximate 
10% of patients that we approach regarding the study will actually meet all inclusion and 
exclusion criteria as well as agree to the study; therefore, we estimate that we will have to 
approach approximately 400 patients. 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
 
9.1  DataAnalysis for Baseline Comparability. To establish comparability between the groups 
at baseline, all subjects randomized will be compared with respect to the baseline variables, 
including the primary and secondary outcome variables, demographics, reproductive history, risk 
factors, medical history, current medications, and physical exam variables.  Comparisons 
between treatment groups will be performed using two sample t-test for normally-distributed 
continuous variables, Wilcoxan rank-sum test for non-normal or ordinal data, and Chi-square test 
for categorical variables.  To evaluate whether a variable follows a normal distribution, we will 
use the Q-Q plot and Kolmogorov-Smirnov test.  
 
9.2. Data analysis to assess group difference at exit. If there is no systematic group difference 
in the primary and secondary outcome variables at baseline, comparisons of these variables 
between the groups will be conducted using measurements taken at study exit. Two sample t-test 
will be used for normally-distributed variables, Wilcoxon rank-sum test for non-normal or 
ordinal data, and Chi-square test for categorical variables. For variables that show group 
differences at baseline, change scores will be used in the above analysis. Change scores will be 
calculated as the difference between study exit and baseline. Secondary analysis to assess group 
difference will be carried out using regression models to adjust for baseline covariates/factors 
that show group difference in 9.1. The outcomes in the regression analysis are the measurements 
at exit or change scores. We will use linear regression for continuous outcome variables (may be 
subject to transformation), logistic regression for binary variables, and proportional odds models 
for ordinal data.  
 
 
9.3 Study Power.  This is a pilot study, so a formal sample size calculation for statistical power 
is not included.  Estimates of between-group difference and data variability will be used to 
conduct a more definitive sample size calculation for a larger study. 
 
Section 11.0   
Ethical considerations relating to the trial 
All participation is voluntary.  Patients will have the study explained to them in detail and be 
allowed to ask questions to allow for informed consent.  Patient charts will be reviewed and all 
information regarding the patient will be kept confidential. Since the study extends for a short 
period of time, it is safe for deficient patients to be randomized to the placebo arm. Upon 
completion of the study, patients who were vitamin D deficient and randomized to the 
placebo arm will be offered therapeutic doses of vitamin D. Risk of side effects is extremely 
low and benefits of therapy are high, favoring the risk benefit ratio towards treatment with 
vitamin D.  There are no potential conflicts of interest.   
 
Section 12.0. 
Data Handling and Recordkeeping 
All personal identifiable information will be kept confidential.  All data collected will be handled 
by the study investigators only and kept confidential.  No personal information regarding patients 
will be stored on personal computers. 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Section 13.0. 
 Financing and Insurance 
The patient will not incur any additional costs by participating in this study.  All interventions 
initiated by this research protocol will be covered by the study investigators source of funding, 
which currently remains to be determined. 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix A 
 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
 
Currently Taking ANY 
Statin 
Mild to Moderate 
Myopathic Pain on Statin 
but able to continue same 
Statin 
Vitamin 25 OH D < 30ng/mL 
Placebo 
Ergocalciferol 
Excluded from 
Study 
No 
No 
Yes 
Yes 
Randomized 
Appendix B- Study Design 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix C 
 
Appendix A. Brief Pain Inventory: measures pain from chronic diseases to assess the severity 
and impact of pain on daily life.  The short form survey has a Cronbach alpha reliability ranging 
from 0.77 to 0.91.  This survey takes approximately 5 minutes to fill out


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix D 
 
SF-12® Patient Questionnaire (Page 1 of 3) 
 
This information will help your doctors keep track of how you feel and how well you are able to 
do your usual activities. Answer every question by placing a check mark on the line in front of 
the appropriate answer. It is not specific for arthritis. If you are unsure about how to answer a 
question, please give the best answer you can and make a written comment beside your answer. 
 
1. In general, would you say your health is: 
 
_____ Excellent (1) 
_____ Very Good (2) 
_____ Good (3) 
_____ Fair (4) 
_____ Poor (5) 
 
The following two questions are about activities you might do during a typical day. Does YOUR 
HEALTH NOW LIMIT YOU in these activities? If so, how much? 
 
2. MODERATE ACTIVITIES, such as moving a table, pushing a vacuum cleaner, bowling, or 
playinggolf: 
_____ Yes, Limited ALot (1) 
_____ Yes, Limited A Little (2) 
_____ No, Not Limited At All (3) 
 
3. Climbing SEVERAL flights of stairs: 
_____ Yes, Limited ALot (1) 
_____ Yes, Limited A Little (2) 
_____ No, Not Limited At All (3) 
 
During the PAST 4 WEEKS have you had any of the following problems with your work or 
other regular activities AS A RESULT OF YOUR PHYSICAL HEALTH? 
 
4. ACCOMPLISHED LESS than you would like: 
_____ Yes (1) 
_____ No (2) 
5. Were limited in the KIND of work or other activities: 
_____ Yes (1) 
_____ No (2) 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
SF-12® Page 2 of 3 
 
During the PAST 4 WEEKS, were you limited in the kind of work you do or other regular 
activities AS A RESULT OF ANY EMOTIONAL PROBLEMS (such as feeling depressed or 
anxious)? 
 
6. ACCOMPLISHED LESS than you would like: 
_____ Yes (1) 
_____ No (2) 
 
7. Didn’t do work or other activities as CAREFULLY as usual: 
_____ Yes (1) 
_____ No (2) 
 
8. During the PAST 4 WEEKS, how much did PAIN interfere with your normal work (including 
both work outside the home and housework)? 
_____ Not At All (1) 
_____ A Little Bit (2) 
_____ Moderately (3) 
_____ Quite A Bit (4) 
_____ Extremely (5) 
 
The next three questions are about how you feel and how things have been DURING THE PAST 
4 WEEKS. For each question, please give the one answer that comes closest to the way you have 
been feeling. How much of the time during the PAST 4 WEEKS – 
 
9. Have you felt calm and peaceful? 
_____ All of the Time (1) 
_____ Most of the Time (2) 
_____ A Good Bit of the Time (3) 
_____ Some of the Time (4) 
_____ A Little of the Time (5) 
_____ None of the Time (6) 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
SF-12® Page 3 of 3 
 
10. Did you have a lot of energy? 
_____ All of the Time (1) 
_____ Most of the Time (2) 
_____ A Good Bit of the Time (3) 
_____ Some of the Time (4) 
_____ A Little of the Time (5) 
_____ None of the Time (6) 
 
11. Have you felt downhearted and blue? 
_____ All of the Time (1) 
_____ Most of the Time (2) 
_____ A Good Bit of the Time (3) 
_____ Some of the Time (4) 
_____ A Little of the Time (5) 
_____ None of the Time (6) 
 
12. During the PAST 4 WEEKS, how much of the time has your PHYSICAL HEALTH OR 
EMOTIONAL PROBLEMS interfered with your social activities (like visiting with friends, 
relatives, etc.)? 
_____ All of the Time (1) 
_____ Most of the Time (2) 
_____ A Good Bit of the Time (3) 
_____ Some of the Time (4) 
_____ A Little of the Time (5) 
_____ None of the Time (6) 
 
SF-12® Health Survey © 1994, 2002 by Medical Outcomes Trust and QualityMetric 
Incorporated. All Rights Reserved 
SF-12® is a registered trademark of Medical Outcomes Trust 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix E CYP3A4 Medication List 
 
CYP3A4 Medicine 
Study 
Onset 
Study 
Completion 
Amiodarone 
 
 
Amlodipine 
 
 
Carbamazepine 
 
 
Clopidogrel 
 
 
Diltiazem 
 
 
Fluconazole 
 
 
Fluoxetine 
 
 
Esomeprazole 
 
 
Gemfibrozil 
 
 
Nifedipine 
 
 
Phenytoin 
 
 
Rifampin 
 
 
Verapamil 
 
 
Mibefradil (posicor) 
 
 
Ezetimibe 
 
 
Niacin 
 
 
Sildenafil 
 
 
Quinidine 
 
 
Clarithromycin 
 
 
Erythromycin 
 
 
Ketoconazole 
 
 
Itraconoazole 
 
 
Terbinafine 
 
 
Protease Inhibitors 
 
 
Cyclosporine 
 
 
Nefazodone 
 
 
Midazolam 
 
 
Supplement w/Vitamin D 
and corresponding dose 
 
 
Total 
 
 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix G:  
FLOWCHART 
OFPROCEDURES  
 
Screen 
Visit 
Initial 
Research 
Visit #1 
Week 0 
Visit #2 
Phone 
Follow-up 
Week 1-2 
Visit #3 
(Week 8) 
Standard of Care Procedures: Procedures that are part of regular care and 
would be done even if you did not take part in this research study 
 Confirm myopathic pain from 
statin 
X 
 
 
 
Medical record review, labs: 
ast/alt/alb/ca/cr/tsh, vital signs 
X 
 
 
 
Chart review vitamin 25 OH D < 
30ng/mL 
X 
 
 
 
Research Related Procedures: Procedures, drugs, devices, evaluations or other 
services done only because of your participation in this research. 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
Consent 
 
X 
 
 
Physical Exam: including vital 
signs, height, weight, abdominal 
and hip circumference 
 
X 
 
X 
 
Safety Measurements 
Phlebotomy: 
 
Creatine kinase (ck) 
Creatinine (cr)Calcium (Ca) 
       
      Urine Pregnancy (U-Bhcg) 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
X 
        
 
X 
X 
Primary and Secondary 
Measurements w/Phlebotomy: 
intact PTH, Ca, vitamin 25 OH 
D, total cholesterol, LDL, HDL 
 
X 
 
X 
Primary outcomes survey 
measurements: 
SF-12, Brief Pain Inventory  
 
X 
 
X 
Modifiable Variables 
Measurements: 
Medication Review: CYP3A4 
medications, Supplement review 
 
X 
 
X 
Initiation of Medication: 
     Ergocalciferol vs Placebo 
 
 
X 
 
 
 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Phone Follow-up: discuss 
tolerability of medications and 
evidence of any adverse events 
 
 
X 
 
 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
Appendix H Characterization of Vitamin D levels  
 
25-OH D Level 
ng/mL (=microg/L) 
(used in USA) 
nmol/L 
(used internationally) 
Deficient 
<10 
<25 
Insufficient 
10-20 
25-50 
Hypovitaminosis 
>20-32/40 
>50-100 
Adequate 
>40-100 
>100-250 
Toxic 
>100/140 
>250 
 
*These values are used merely for definition.  There is limited consensus on the definition of 
varying serum 25 OH D levels.20  Internationally, 25 OH D is reported in nmol/L.  In the US, it is 
reported in ng/mL (or microg/L).  To convert ng/mL to nmol/L, multiply by the conversion 
factor 2.496.  To convert from nmol/L to ng/mL divide by the conversion factor 2.496. 
 


 
CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
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CSMC Office of Research Compliance 
Reference:  ICH E6: Good Clinical Practice: Consolidated Guidance 
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