Statin Immune Study (ImmunoStat)

Impact of LILRB5 Genotype on Immune Response to Atorvastatin

Statins are widely used drugs to treat hypercholesterolaemia. In general, they are very safe drugs. However, up to one third of statin users can experience muscle symptoms, which are most commonly mild without any conventional laboratory signs of muscle damage. However, these muscle symptoms can often lead to poor compliance to the cholesterol-lowering therapy, reducing its effectiveness. Recent data has highlighted the potential role of immune system in development of statin-induced muscle pain. Variation in the LILRB5 gene has been associated with statin intolerance. We aim to investigate the impact of LILRB5 genetic variability in tolerability and immune response to atorvastatin in healthy volunteers.

The study is being undertaken at the Tayside Institute for Cardiovascular Research (TICR) in Ninewells Hospital, Dundee. We will recruit participants who have donated a sample to GoSHARE study. The participants will be healthy, and recruited according to their genotype of LILRB5 (information available from GoSHARE). The volunteers will then enter a randomised cross-over study with two treatment periods. During treatment period one, all participants will be commenced on atorvastatin or placebo (a dummy drug). Before and at the end of the treatment period, blood and urine samples will be taken and a muscle symptoms questionnaire will be completed to assess the tolerability and immune response to the study drug exposure. After four weeks, the study drug is stopped for a washout period of three weeks before cross-over commences. Thereafter, during treatment period two, the alternate study drug will be started, and tolerability will be assessed similar to that in period one. The study will last approximately 11 weeks. The volunteers have a total of 5 visits to the TICR.

Study Overview

• Status: Completed
• Conditions: Drug Intolerance
• Intervention / Treatment: Drug: Atorvastatin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • University of Dundee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 40-69 years
• Statin-naïve
• White European
• Healthy
• Acceptable laboratory test results

Exclusion Criteria:

• Significant disease
• Regular drug therapy
• Recent involvement (<30 days) in a CTIMP
• Inability/unwillingness to comply with the protocol
• Carry the rare variant of the CKM polymorphism rs11559024
• Unable to consent
• Woman of childbearing potential (i.e. premenopausal female capable of becoming pregnant)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atorvastatin; The participants will receive atorvastatin (80 mg) orally once daily for 28 days.	Drug: Atorvastatin; Atorvastatin 80 mg once daily for 28 days.
Placebo Comparator: Placebo; The participants will receive matched placebo orally once daily for 28 days.	Drug: Placebo; Placebo once daily for 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome will be the change in CK levels at the end of the treatment from baseline in both treatment periods.	Measured at baseline (day 0) and day 29 of both treatment periods.

Collaborators and Investigators

• Sponsor: University of Dundee
• Collaborators: NHS Tayside
• Investigators: Study Chair: Colin NA Palmer, PhD FSB FRSE, University of Dundee

Publications and helpful links

General Publications

• Dube MP, Zetler R, Barhdadi A, Brown AM, Mongrain I, Normand V, Laplante N, Asselin G, Zada YF, Provost S, Bergeron J, Kouz S, Dufour R, Diaz A, de Denus S, Turgeon J, Rheaume E, Phillips MS, Tardif JC. CKM and LILRB5 are associated with serum levels of creatine kinase. Circ Cardiovasc Genet. 2014 Dec;7(6):880-6. doi: 10.1161/CIRCGENETICS.113.000395. Epub 2014 Sep 11.
• Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, Carr DF, Bloch KM, Fahy J, Hanson A, Yue QY, Wadelius M, Maitland-van Der Zee AH, Voora D, Psaty BM, Palmer CN, Pirmohamed M. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014 Oct;96(4):470-6. doi: 10.1038/clpt.2014.121. Epub 2014 Jun 4.

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2017
• Primary Completion (Actual): November 3, 2017
• Study Completion (Actual): November 3, 2017

Study Registration Dates

• First Submitted: December 2, 2016
• First Submitted That Met QC Criteria: December 2, 2016
• First Posted (Estimate): December 6, 2016

Study Record Updates

• Last Update Posted (Actual): December 3, 2018
• Last Update Submitted That Met QC Criteria: November 29, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Atorvastatin; LILRB5; Statin intolerance
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 2016CV05; 16/ES/0128 (Other Identifier: East of Scotland Research Ethics Service)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: As per GoSHARE tissue bank protocol, the data derived from the existing samples will be returned to the tissue bank for research use.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No