Clinical Trials Register

Summary
EudraCT Number:	2015-000462-62
Sponsor's Protocol Code Number:	Statex1
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-12
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2015-000462-62

A.3

Full title of the trial

The effects of statins on skeletal muscle mitochondria: is exercise the medicine?

De effecten van statines op skeletspier mitochondria: is inspanning het medicijn?

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The influence of exercise on the energy generating capacity of the mitochondria: could exercise offer a solution?

de effecten van statine gebruik op het energie gebruik van de skeletspieren: biedt inspanning een oplossing?

A.3.2

Name or abbreviated title of the trial where available

statins, mitochondria, exercise

statines, mitochondria, inspanning

A.4.1

Sponsor's protocol code number

Statex1

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Radboud university medical centre
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Radboud university medical centre
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboud university medical centre
B.5.2	Functional name of contact point	dr. Silvie Timmers
B.5.3	Address:
B.5.3.1	Street Address	Philips van Leijdenlaan 15
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6525EX
B.5.3.4	Country	Netherlands
B.5.6	E-mail	silvie.timmers@radboudumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Atorvastatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Nederland BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Asymp and symp statin users will undergo baseline measurements of skeletal muscle mitochondrial function and muscle function after which they will be switched to a single-blind placebo intervention for 12 weeks. Then the same measurements will be repeated. Hereafter, only the symptomatic statin users will continue with the intervention en will be randomely allocated to: atorvastatin, atorvastin+exercise or placebo+exercise for another 12 weeks. Then the same measurements will be repeated again.

E.1.1.1

Medical condition in easily understood language

skeletal muscle side effects of statin use

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

•Do statins accumulate in muscle and cause inhibition of complex III activity of the mitochondrial respiratory chain ?

•Is the severity of the muscle function decline determined by the total statin concentration in muscle, as well as by the pharmacokinetic properties of the statin?

•Could aerobic exercise training on top of statin treatment offer protection against statin-associated muscle symptoms by positively influencing muscle metabolism?

E.2.2

Secondary objectives of the trial

• Can we identify clinically relevant predictive parameters that could facilitate the diagnosis of Statin-associated muscle symptoms in clinical practice (e.g. plasma markers, muscle function, muscle gene expression, whole body energy metabolism)?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

age: 18-70 years old
current statin users
mentally able/allowed to give informed consent

E.4

Principal exclusion criteria

familial hypercholesterolemia
impaired liver function
hereditary muscle defect
kidney insufficiency
unwillingness to abstain from grapefruit juice during the intervention

E.5 End points

E.5.1

Primary end point(s)

o Energy generating capacity of muscle mitochondria (in muscle biopsy)
(see ex vivo measurement in 8.3 study procedures for the detailed biochemical assays that will be carried out in the fresh muscle tissue).
o Muscle function (= muscle force, contractile speed, relaxation and
fatigability)
o Cardiorespiratory fitness (incremental cycling test)

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline (in both symptomatic and asymptomatic statin users);
at12 weeks: after a 12-week single-blind placebo intervention (in both symptomatic and asymptomatic statin users);
after 24 weeks: after a subsequent 12 weeks of double-blind randomized intervention with atorvastatin, atorvastatin+exercise or placebo+exercise in symptomatic statin users only

E.5.2

Secondary end point(s)

o Mitochondrial number (in muscle biopsy)
o Blood parameters: lipid profile (total cholesterol, HDL-, LDL-cholesterol,
triglycerides), liver enzymes (ASAT, ALAT, gamma-GT), kidney function (creatinin), creatine kinase, WBC count, pyruvate and lactate
o Statin concentrations in the muscle and blood
o Questionnaires on muscle complaints (Short-form McGill pain questionnaire
and Short-form Brief Pain Inventory)

E.5.2.1

Timepoint(s) of evaluation of this end point

Mitochondrial number: baseline, 12 weeks, 24 weeks
blood parameters, statin concentrations, questionnaires: every three weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

combination of single blind and double blind intervention

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-06-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-01-01

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