Clinical trial NCT01568255: Is Treatment of Vitamin D Deficiency Associated With Resolution of Statin-Induced Muscular Symptoms
Official title: Is Treatment of Vitamin D Deficiency Associated With Resolution of Statin-Induced Muscular Symptoms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Myopathic Symptoms
Keywords: myopathic symptoms
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
First posted: 2012-04-02
Enrollment: 11
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study was prospective, randomized, and double blinded pilot Ergocalciferol 50,000 IU once weekly for 8 weeks compared to Placebo in statin myalgic women. Subjects screened for eligibility underwent baseline and exit visits. For baseline and exit visits, subjects had safety labs drawn for lipid and vitamin D levels, completed Brief Pain Inventory (BPI) severity and interference questionnaires, as well as a Short Form (SF-12) questionnaire and medical history.Additionally, subjects underwent physical exams for baseline visits. After physical exams, subjects were then randomized to Placebo or Ergocalciferol treatment.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Female gender (refer to section 4)
2. Age \> 18, using an effective form of contraception (refer to section 4)
3. An indication to be on statin therapy
4. Moderate to severe myopathic pain while on Simvastatin
5. Serum CK level \< 10 x ULN
6. Vitamin 25 OH D level \< 30 ng/mL (as secondary hyperparathyroidism is triggered below this level)1
7. English speaking patients only
8. Myopathic pain that cannot be attributed to other medical conditions
9. Continue a statin within the CYP3A4 family
10. Competent to give informed consent

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 \< 100 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

Primary outcomes:
measure: Number of Participants With Reduction in Myopathic Pain
timeFrame: 8 weeks
measure: Brief Pain Inventory (BPI) Severity at Exit
timeFrame: 8 weeks
measure: Vitamin 25 OH D Levels
timeFrame: 8 weeks
measure: Brief Pain Inventory (BPI) Interference at Exit
timeFrame: 8 weeks
Secondary outcomes:
measure: Lipid Profile - Total Cholesterol Levels
timeFrame: 8 weeks
measure: Lipid Profile - LDL Cholesterol Levels
timeFrame: 8 weeks
measure: Lipid Profile - HDL Cholesterol Levels
timeFrame: 8 weeks
measure: Lipid Profile - Triglycerides Levels
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Margo B. Minissian, PhD
role: PRINCIPAL_INVESTIGATOR
References: