Primary Objectives-To evaluate if mitochondrial dysfunction can be induced in healthy, middle aged subjects, through the use of simvastatin, and whether it can be reversed by oral ubiquinol supplementation. -To validate the techniques NIRS, PpIX-…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
mitochondrial dysfunction
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-PCr recovery time (in seconds) 8 weeks after the start of simvastatin
administration.
-PCr recovery time (in seconds) after 4 weeks of simvastatin administration.
Secondary outcome
-mVO2 (in ml/min/100 ml) measured by NIRS.
-mitoPO2 (in mmHg) measured by PpIX-TSLT.
-MMP in WBCs (in ratio of aggregated and monomeric JC-1) measured by the JC-1
assay.
-Serum FGF-21 concentration (in pg/ml).
-Hand grip strength (in kg) measured by the Jamar dynamometer and the pinch
gauge.
-hand grip strength (in kg) measured by the POWERjar©.
-Serum creatine kinase concentration.
Background summary
Age related diseases pose a burden for both the elderly and society as a whole.
In recent years, evidence has shown that dysfunction of mitochondria plays an
important role in age related diseases, such as Alzheimer*s Disease, diabetes
mellitus type 2 and sarcopenia. The mitochondrion is therefore becoming
increasingly important as a drug target. As mitochondrial function is already
optimal in healthy subjects, there is no way to show drug induced enhancement
of mitochondrial function early in clinical drug development other than using
patients with a mitochondrial disease. There are, however, many disadvantages
of doing early phase drug studies in patients with a rare disease. In this
study we aim to set up and validate a model for statin-induced mitochondrial
dysfunction in healthy subjects, which can be used to evaluate the
pharmacological effects of drugs that potentially enhance mitochondrial
function.
Prolonged administration of statins to middle aged, otherwise healthy subjects
has previously been shown to cause reversible mitochondrial dysfunction, which
is thought to be mainly due to a depletion of coenzyme Q10, an electron carrier
in complex I of the electron transport chain. Concurrent replenishment of Q10,
in the form of ubiquinol, during statin therapy is therefore expected to
reverse the statin-induced mitochondrial dysfunction. It has been successfully
demonstrated using dynamic 31P-MRS, that statins can induce a slight, yet not
clinically relevant, mitochondrial dysfunction. Treatment with statins for a
period of 4 weeks led to a prolongation of the phosphocreatine (PCr) recovery
time after muscle exertion induced PCr depletion using MR spectroscopy of the
muscle. However, whether oral Q10 supplementation can successfully reverse the
statin-induced prolongation in PCr recovery time has not yet been demonstrated.
It is considered essential to establish this prior to the use of statin-induced
mitochondrial dysfunction in healthy subjects as a model that can be applied in
early phase clinical drug development.
In conjunction, four techniques to measure mitochondrial function will be
compared in this study: near infrared spectroscopy (NIRS, a cheap, non-invasive
and portable method to measure mitochondrial function via muscle oxygen
consumption (mVO2)), Protoporphyrin IX - Triplet State Lifetime Technique
(PpIX-TSLT, a novel method to locally measure mitochondrial function through
the skin) and the mitochondrial membrane potential (MMP) in white blood cells
(WBCs). These new techniques will be validated against dynamic phosphorous
Magnetic Resonance Spectroscopy (31P-MRS). Dynamic 31P-MRS is an established
method to measure mitochondrial function and can be considered to be the gold
standard for in vivo mitochondrial function measurement. The PpIX-TSLT method
can potentially be used in low dose toxicology studies and the MMP in WBCs for
ex vivo dose response studies.
Hand muscle strength measurements, using the Jamar dynamometer and pinch gauge
(both validated methods widely used in the clinical setting), will be performed
to measure muscular strength and to determine whether a decrease in
mitochondrial function is associated with a decline in muscle strength. These
hand strength measurements will be compared to the POWERjar©, a novel method to
measure hand strength by opening a jar-like device. This hand strength
measurement is expected to correlate better with ADL functioning.
A rise in serum creatine kinase (CK) can result from statin use, which is
hypothesized to be due to muscle damage caused by mitochondrial dysfunction of
muscle cells. Therefore, serum CK measurements will be used as a safety outcome
variable.
Fibroblast growth factor 21 (FGF-21) in plasma has recently been shown to
correlate with mitochondrial disease as a biomarker. We hypothesise that it
yields potential as a plasma biomarker for mitochondrial dysfunction as a
whole.
In the current study healthy subjects will use statins for 8 weeks to induce
mild mitochondrial dysfunction. After mild mitochondrial dysfunction has been
established, i.e. after a 4 week open-label treatment with simvastatin,
subjects will be randomized to receive either ubiquinol or placebo in a double
blind fashion. The three additional techniques that are used to quantify
mitochondrial dysfunction are non-invasive, cheaper to use, and less burdensome
for subjects than dynamic 31P-MRS. These techniques will be used in parallel
for comparison and validation to gold standard dynamic 31P-MRS. Healthy
subjects will be included to keep the variability as low as possible.
Study objective
Primary Objectives
-To evaluate if mitochondrial dysfunction can be induced in healthy, middle
aged subjects, through the use of simvastatin, and whether it can be reversed
by oral ubiquinol supplementation.
-To validate the techniques NIRS, PpIX-TSLT and MMP in WBCs to measure
mitochondrial function and compare to dynamic 31P-MRS of the muscle in the
statin-induced mitochondrial dysfunction model.
Secondary Objectives
-To determine the safety of the statin-induced mitochondrial dysfunction model
in healthy, middle aged subjects.
-To determine the correlation between various states of mitochondrial function
and serum CK concentration.
-To determine the correlation between various states of mitochondrial function
and serum FGF-21 concentration.
-To determine the correlation between mitochondrial function and muscle
strength using the hand grip strength test (Jamar dynamometer) and pinch
strength test (pinch gauge).
-To determine the correlation in hand strength between Jamar dynamometry test
and pinch gauge test and the POWERjar© test.
Study design
The study consists of a screening (maximal 28 days before start of study
period), a statin part of 8 weeks, in which the subject will be asked to
self-administer simvastatin 40 mg orally once daily and an ubiquinol or placebo
part of 4 weeks, in which the subject will be asked to take solubilised
ubiquinol (Q10) 300 mg orally once daily or placebo orally once daily in
parallel to the statins. The ubiquinol or placebo part starts after 4 weeks of
simvastatin administration. Measurements (dynamic 31P-MRS, NIRS, PpIX-TSLT and
MMP) and blood sampling (mitochondrial function biomarker) will be done 4 times
in a period of 8 weeks: once before the start of the statin part (baseline),
once after 2 weeks of statin administration, once before the ubiquinol or
placebo part (baseline ubiquinol) and after the both parts (end of study). One
follow-up telephone call is scheduled no longer than 10 days after the last
occasion.
Study burden and risks
Simvastatin is a registered drug, which is widely used in the clinic as
cholesterol lowering drug. The safety profile of this compound is well known.
The risk of myopathy/rhabdomyolysis of daily administration of simvastatin 40
mg is 0,08% and simvastatin 80 mg is 0.61%. However, to induce mild
mitochondrial dysfunction the dose of simvastatin needs to be high enough. The
risk of taking ubiquinol 300 mg is excpected to be minimal. The use of the
5-aminolevulinic acid patch is needed to validate the PpIX-TSLT and local
adverse events in the skin are reported. The most common side effects (seen in
more than 1 patient in 10) are reactions at the site of application, including
irritation, erythema (reddening of the skin), pain, pruritus (itching), oedema
(swelling), exfoliation (skin peeling), scab formation and induration
(hardening of the skin) The benefit of this measurement is the later use as a
cheap and non-invasive device to measure mitochondrial function. The main
benefit is to find a model for mitochondrial dysfunction in healthy volunteers,
so that early drug research does not hasve to be performed in patients with
mitochondrial dysfunction and to validate cheap and non-invasive to do this.
There is no direct benefit in participating for the subject, but there might be
a beneficial effect on the cardiovascular system due to simvastatin.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.;2. Males or females aged 40-70 years (inclusive).;3. BMI between: 18-32 kg/m2, minimal weight 50 kg.;4. Expected compliance to the protocol especially with respect to administering simvastatin 40 mg orally once daily for 56 days and ubiquinol 300 mg orally once daily for 28 days.;5. Having a normal day and night rhythm.
Exclusion criteria
1. Clinically relevant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, rheumatic/joint, psychiatric, renal, and/or other major disease.;2. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In case of uncertain or questionable results, tests performed during screening may be repeated before the first occasion to confirm eligibility or judged to be clinically irrelevant.;3. Creatine Kinase (CK) > 145 U/L (females) or > 170 U/L (males) in laboratory test results.;4. Presence of any contraindication to have MRI scans performed (e.g. pacemaker, intracranial clips etc.).;5. Having diabetes mellitus or lower extremity peripheral vascular disease, as these conditions may interfere with interpretation of the dynamic 31P-MRS and NIRS of the lower extremity.;6. Recent (within 14 days) or current use of interfering medications: paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), statins and gluco- and/or mineralocorticoid drugs with exception of contraceptives. Usage of other medications will have to be reviewed for interference with the study by the study physician.;7. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.;8. Positive test for drugs of abuse at screening or pre-dose.;9. If female, pregnancy (defined as a positive bHCG urine test) or breast-feeding.;10. A history (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). ;11. History or symptoms of any significant disease including (but not limited to) neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder.;12. History or symptoms of any myopathy.;13. A history or presence of porphyria or any other skin disease that is caused by exposure to light. ;14. A history or presence of allergy to 5-aminolevulinic acid or porphyrins.;15. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.;16. Donation of blood or loss of over 500 mL within 3 months prior to screening.;17. Unwillingness or inability to refrain from consuming aldosterone increasing food or supplements during the study period: bananas, liquorice, glucosamine and palm oil. ;18. Unwillingness or inability to refrain from consuming grapefruit or grapefruit juice.;19. Unwillingness or inability to refrain from consuming alcohol within 48 hours before each visit until the end of that visit.;20. Unwillingness or inability to refrain from tobacco usage within 12 hours before each visit until the end of that visit.;21. Unwillingness or inability to refrain from moderate to strenuous physical activity (e.g. fitness classes, weight lifting, marathon-running etc.) from the screening until the last study visit. ;22. Having a type of lifestyle with no physical activity.;23. Unwillingness or inability to refrain from consuming xanthine containing beverages and foods within 12 hours before each visit and during the study visits.;24. Unwillingness or inability to use contraception if female with child bearing potential.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001289-91-NL |
| CCMO | NL48758.058.14 |