Statin Adverse ReactionPhase 4MUSENCT03874156
MUscle Side-Effects of Atorvastatin in Coronary Patients
A Phase 4 study testing Atorvastatin 40mg in people with Statin Adverse Reaction, run by Vestre Viken Hospital Trust at 2 sites in Norway.
Trial summary
The study aims to estimate the effect of atorvastatin on muscular symptom intensity in coronary patients with subjective statin-associated muscle symptoms (SAMS) and to determine the association with blood levels of atorvastatin and its metabolites, to obtain an objective marker for true SAMS. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Statin Adverse Reaction
- What is being tested?
- Atorvastatin 40mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 77 participants
- Where
- 2 sitesNorway
- Study dates
- 5 Mar 2019to 12 Dec 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years or older
- First or recurrent diagnosis (myocardial infarction) or treatments (Percutaneous Coronary Intervention [PCI] or Coronary Artery Bypass Graft operation [CABG]) for a coronary heart disease (CHD) event at least 6 months prior to study start and prescribed atorvastatin (irrespective of dose)
- Reporting muscle complaints (i.e. pain, weakness, tenderness, stiffness or cramp) that they attribute to atorvastatin therapy or atorvastatin discontinuation due to muscle complains
- Signed informed consent and expected cooperation of the patient according to International Council for Harmonisation/Good Clinical Practice and national/local regulations
Who cannot join
- First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event the a) past 12 months prior to study start in high risk patients (i.e. at least one of following comorbid conditions: systolic heart failure, >1 previous myocardial infarction, kidney failure, diabetes, and smokers) and b) the past 6 months prior to study start in low risk patients without any of the co-morbid conditions mentioned above and in patients who are not taking a statin at all
- . Patients with symptomatic peripheral artery disease and patients with familial hypercholesterolemia
- Patient has any contraindications for atorvastatin listed in the Summary of Product Characteristics (i.e. known hypersensitivity to the ingredients, acute liver failure/ Alanine Aminotransferase > 3 times upper limit of the normal range in blood at study start, pregnancy and breastfeeding)
- History of previous rhabdomyolysis, myopathy or liver failure due to statin treatment with Creatine Kinase > 10 times upper limit of the normal range or Alanine Aminotransferase > 3 times upper limit of the normal range.
- Any condition (e.g. psychiatric illness, dementia) or situation, that in the investigator's opinion could put the subject at significant risk, confound the study results, interfere significantly with the subject participation in the study, or rendering informed consent unfeasible
- Short life expectancy (<12 months) due to other medical conditions
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- Not being able to understand Norwegian.
- Women of childbearing potential defined as all premenopausal female.
- Participation in another randomized clinical trial
Trial locations and contacts
2 sites in 1 country.
Norway2 sites
Vestre Viken Trust, Drammen Hospital
Drammen, Buskerud, 3004
Hospital of Vestfold Trust
Tønsberg, Vestfold, 3103
About this study
Official title: MUscle Side-Effects of Atorvastatin in Coronary Patients (MUSE) -a Randomized Controlled Trial
The study aims to estimate the effect of atorvastatin on muscular symptom intensity in coronary patients with subjective statin-associated muscle symptoms (SAMS) and to determine the association with blood levels of atorvastatin and its metabolites, to obtain an objective marker for true SAMS. A randomized study will include 80 coronary patients with SAMS during ongoing atorvastatin therapy or previous muscle symptoms that led to discontinuation of atorvastatin. Patients will be randomized to 7-weeks treatment with atorvastatin 40 mg/day in the first period and matched placebo in the second 7-weeks period, or placebo in the first period and atorvastatin in the second period. A control group (n=40) without muscle symptoms will have 7 weeks open treatment with atorvastatin 40 mg/day. Blood samples will be collected at baseline and after each treatment period, and muscular symptom intensities will be rated by the patients weekly. The primary outcome is the difference in aggregated mean Visual Analogue Scale (VAS) scores between the last three weeks of atorvastatin treatment and of placebo treatment. The main purpose is to develop an objective marker for true SAMS, by comparing SAMS associated with blinded atorvastatin treatment with blood concentrations of atorvastatin and its metabolites. Diagnostic and discrimination performance will be determined. The study provides new clinical knowledge on SAMS in coronary patients and may contribute to more personalized statin treatment and monitoring, fewer side-effects and consequently improved adherence and lipid management in future practice.
- Conditions
- Statin Adverse Reaction
- Being tested
- Atorvastatin 40mg, Placebo Oral Tablet
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Atorvastatin 40mgDrug
Oral tablet fabricated and labelled at Krageroe Tablettproduksjon AS
Placebo Oral TabletDrug
Oral tablet fabricated and labelled at KrageroeTablettproduksjon AS
| Study group | Role | What they receive |
|---|---|---|
| Intervention group | Active comparator | Atorvastatin 40 mg once daily Receives: Drug: Atorvastatin 40mg |
| Placebo group | Placebo comparator | Matched placebo tablet once daily Receives: Drug: Placebo Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Individual mean difference in muscular symptom intensity measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score between treatment periods with statin and placebo
Individual mean difference in muscular symptom (i.e. pain, aching, tenderness, stiffness, cramp and/or weakness) intensity between treatment periods with statin and placebo, reported by the patients over the last three weeks (i.e. week 4-7) measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score with aggregated data from each subscale
Measured: 16 weeks following randomization
Secondary outcomes (9)
The proportion of patients who report muscle symptoms on atorvastatin treatment and not on placebo (dichotomous Statin Associated Muscle Symptom classification)
Measured: 16 weeks following randomization
The correlation between individual muscular symptom intensity between treatment periods with statin and placebo over the last three weeks measured with 0 to 10 VAS score aggregated from each subscale, and levels of atorvastatin and metabolites
Measured: 16 weeks following randomization
Sensitivity, specificity, and area under the curve of blood concentrations of parent drug and the active metabolites of atorvastatin for the classification of true Statin Associated Muscle Symptoms (SAMS)
Measured: 16 weeks following randomization
Individual mean difference in likelihood of statin discontinuation between treatment periods with statin and placebo over the last three weeks (i.e. week 4-7) measured with 0 to 10 VAS score with aggregated data from each subscale.
Measured: 16 weeks following randomization
Statin adherence measured weekly with self-reported questionnaire methods during the study periods
Statin adherence measured with self-reported questionnaires (numeric scale: <4/7, 5/7, 6/7 or 7/7) weekly during the treatment periods. Low statin adherence will be defined by taking statins less than 42 of 49 days during the 7 weeks treatment period
Measured: 16 weeks following randomization
Statin adherence measured with pill counts of returned packages
Statin adherence measured with pill counts of returned packages. Low statin adherence will be defined by a total of >=8 returned pills during the treatment periods
Measured: 16 weeks following randomization
Statin adherence measured with direct liquid chromatography-tandem mass spectrometry methods
Statin adherence measured with direct liquid chromatography-tandem mass spectrometry methods. Low statin adherence defined by dose-normalized statin and metabolites concentrations < 0.10 (nmol/L)/mg
Measured: 16 weeks following randomization
Levels of atorvastatin and its metabolites in blood plasma and white blood cells at study end
Measured: 16 weeks following randomization
Number of patients with new-onset coronary heart disease symptoms, intolerable muscle symptoms leading to discontinuation from the treatment arm, and elevated levels of creatine kinase (CK) and/or Alanine Aminotransferase (ALT) in blood
Safety endpoints: i.New-onset coronary heart disease symptoms. ii Intolerable muscle symptoms leading to discontinuation from the treatment arm.iii elevated levels of creatine kinase (CK) and/or Alanine Aminotransferase (ALT) in blood
Measured: 16 weeks following randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Mar 2019
- Study start5 Mar 2019
- Primary completion12 Dec 2019
- Study completion12 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Statin Adverse ReactionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Prospective, randomized double-blinded placebo controlled cross-over phase 4 study.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vestre Viken Hospital Trust
- Sponsor type
- University, hospital or other
- Collaborators
- The Hospital of Vestfold, Oslo University Hospital, University of Oslo
- Responsible party
- Sponsor
- Investigators
- john munkhaugen, MD, PhD, Principal investigator, Vestre Viken Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03874156
- Sponsor's protocol ID
- REK 2018/2302
- Acronym
- MUSE
- Status last verified
- Jan 2020
- First submitted
- 5 Mar 2019
- Last updated
- 3 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual participant data will be made available for other researchers
Publications
Sverre E, Munkhaugen J, Kristiansen O, Weedon-Fekjaer H, Peersen K, Gjertsen E, Gullestad L, Bergan S, Husebye E, Vethe NT. Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease. Pharmacol Res Perspect. 2023 Jun;11(3):e01089. doi: 10.1002/prp2.1089.
PubMed 37186070
Study at a glance
From the registry record, last updated by the sponsor on 3 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- MUscle Side-Effects of Atorvastatin in Coronary Patients (MUSE) -a Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT03874156
- Acronym / sponsor ID
- MUSE / REK 2018/2302
- Conditions
- Statin Adverse Reaction
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- Vestre Viken Hospital TrustUniversity, hospital or other
- Collaborators
- The Hospital of Vestfold, Oslo University Hospital, University of Oslo
- Study start
- 5 Mar 2019 (actual)
- Primary completion
- 12 Dec 2019 (actual)
- Study completion
- 12 Dec 2019 (actual)
- First posted
- 14 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study aims to estimate the effect of atorvastatin on muscular symptom intensity in coronary patients with subjective statin-associated muscle symptoms (SAMS) and to determine the association with blood levels of atorvastatin and its metabolites, to obtain an objective marker for true SAMS. A randomized study will include 80 coronary patients with SAMS during ongoing atorvastatin therapy or previous muscle symptoms that led to discontinuation of atorvastatin. Patients will be randomized to 7-weeks treatment with atorvastatin 40 mg/day in the first period and matched placebo in the second 7-weeks period, or placebo in the first period and atorvastatin in the second period. A control group (n=40) without muscle symptoms will have 7 weeks open treatment with atorvastatin 40 mg/day. Blood samples will be collected at baseline and after each treatment period, and muscular symptom intensities will be rated by the patients weekly. The primary outcome is the difference in aggregated mean Visual Analogue Scale (VAS) scores between the last three weeks of atorvastatin treatment and of placebo treatment. The main purpose is to develop an objective marker for true SAMS, by comparing SAMS associated with blinded atorvastatin treatment with blood concentrations of atorvastatin and its metabolites. Diagnostic and discrimination performance will be determined. The study provides new clinical knowledge on SAMS in coronary patients and may contribute to more personalized statin treatment and monitoring, fewer side-effects and consequently improved adherence and lipid management in future practice.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Prospective, randomized double-blinded placebo controlled cross-over phase 4 study.
| Arm | Type | Receives |
|---|---|---|
| Intervention group | Active comparator | Drug: Atorvastatin 40mgAtorvastatin 40 mg once daily |
| Placebo group | Placebo comparator | Drug: Placebo Oral TabletMatched placebo tablet once daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 18 years or older
- First or recurrent diagnosis (myocardial infarction) or treatments (Percutaneous Coronary Intervention [PCI] or Coronary Artery Bypass Graft operation [CABG]) for a coronary heart disease (CHD) event at least 6 months prior to study start and prescribed atorvastatin (irrespective of dose)
- Reporting muscle complaints (i.e. pain, weakness, tenderness, stiffness or cramp) that they attribute to atorvastatin therapy or atorvastatin discontinuation due to muscle complains
- Signed informed consent and expected cooperation of the patient according to International Council for Harmonisation/Good Clinical Practice and national/local regulations
Key exclusion criteria (9 listed)
- First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event the a) past 12 months prior to study start in high risk patients (i.e. at least one of following comorbid conditions: systolic heart failure, >1 previous myocardial infarction, kidney failure, diabetes, and smokers) and b) the past 6 months prior to study start in low risk patients without any of the co-morbid conditions mentioned above and in patients who are not taking a statin at all
- . Patients with symptomatic peripheral artery disease and patients with familial hypercholesterolemia
- Patient has any contraindications for atorvastatin listed in the Summary of Product Characteristics (i.e. known hypersensitivity to the ingredients, acute liver failure/ Alanine Aminotransferase > 3 times upper limit of the normal range in blood at study start, pregnancy and breastfeeding)
- History of previous rhabdomyolysis, myopathy or liver failure due to statin treatment with Creatine Kinase > 10 times upper limit of the normal range or Alanine Aminotransferase > 3 times upper limit of the normal range.
- Any condition (e.g. psychiatric illness, dementia) or situation, that in the investigator's opinion could put the subject at significant risk, confound the study results, interfere significantly with the subject participation in the study, or rendering informed consent unfeasible
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Atorvastatin 40mgOral tablet fabricated and labelled at Krageroe Tablettproduksjon AS | Drug | Intervention group |
| Placebo Oral TabletOral tablet fabricated and labelled at KrageroeTablettproduksjon AS | Drug | Placebo group |
Primary outcome
Individual mean difference in muscular symptom intensity measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score between treatment periods with statin and placebo
Time frame: 16 weeks following randomization
Individual mean difference in muscular symptom (i.e. pain, aching, tenderness, stiffness, cramp and/or weakness) intensity between treatment periods with statin and placebo, reported by the patients over the last three weeks (i.e. week 4-7) measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score with aggregated data from each subscale
9 secondary outcomes
The proportion of patients who report muscle symptoms on atorvastatin treatment and not on placebo (dichotomous Statin Associated Muscle Symptom classification)
Time frame: 16 weeks following randomization
The correlation between individual muscular symptom intensity between treatment periods with statin and placebo over the last three weeks measured with 0 to 10 VAS score aggregated from each subscale, and levels of atorvastatin and metabolites
Time frame: 16 weeks following randomization
Sensitivity, specificity, and area under the curve of blood concentrations of parent drug and the active metabolites of atorvastatin for the classification of true Statin Associated Muscle Symptoms (SAMS)
Time frame: 16 weeks following randomization
Individual mean difference in likelihood of statin discontinuation between treatment periods with statin and placebo over the last three weeks (i.e. week 4-7) measured with 0 to 10 VAS score with aggregated data from each subscale.
Time frame: 16 weeks following randomization
Statin adherence measured weekly with self-reported questionnaire methods during the study periods
Time frame: 16 weeks following randomization
Statin adherence measured with pill counts of returned packages
Time frame: 16 weeks following randomization
Statin adherence measured with direct liquid chromatography-tandem mass spectrometry methods
Time frame: 16 weeks following randomization
Levels of atorvastatin and its metabolites in blood plasma and white blood cells at study end
Time frame: 16 weeks following randomization
Number of patients with new-onset coronary heart disease symptoms, intolerable muscle symptoms leading to discontinuation from the treatment arm, and elevated levels of creatine kinase (CK) and/or Alanine Aminotransferase (ALT) in blood
Time frame: 16 weeks following randomization
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jan 2020.
- Derived from this study: PubMed 37186070Sverre E, Munkhaugen J, Kristiansen O, Weedon-Fekjaer H, Peersen K, Gjertsen E, Gullestad L, Bergan S, Husebye E, Vethe NT. Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease. Pharmacol Res Perspect. 2023 Jun;11(3):e01089. doi: 10.1002/prp2.1089.
- Individual participant dataSharing planned: Yes. De-identified individual participant data will be made available for other researchers
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
john munkhaugen, MD, PhD principal investigator
Vestre Viken Trust
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Atorvastatin 40mg in people with Statin Adverse Reaction, run by Vestre Viken Hospital Trust at 2 sites in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Individual mean difference in muscular symptom intensity measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score between treatment periods with statin and placebo (time frame: 16 weeks following randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03874156, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jan 2020.