High phenolics-containing extra-virgin olive oil (EVOO) can be one of the potential
dietary supplements for the treatment of MD. There is growing evidence to suggest that
daily consumption of EVOO in Mediterranean diets have beneficial effects on preventing
neurodegeneration. Previous reports demonstrated that phenolics including oleuropein,
oleocanthal, hydroxytyrosol and tyrosol found in EVOO have strong antioxidant properties
against the oxidative stress in brain tissue and protective effect on both acute and
chronic neurodegenerative diseases by in vitro study and animal models. In addition to
improvement of arsenic-induced oxidative stress by oleuropein or hydroxytyrosol
treatment, hydroxytyrosol also showed a protective effect on mitochondria by restoring
mitochondrial enzymatic activities in rat brain. In vitro study also demonstrated the
stimulatory effect of hydroxytyrosol on mitochondrial function including in mouse 3T3-L1
adipocytes and human endothelial cells. A recent reported clinical study showed that
consumption of olive oil could increase mitochondrial membrane fluidity and ATPase
activity in patients with relapsing-remitting multiple sclerosis, a neurodegenerative
disease associated with mitochondrial dysfunction.
Mitochondrial diseases (MDs) are the commonest group of inborn errors with a minimal
prevalence of 12.5 per 100,000 and 4.7 per 100,000 adults and children respectively.
These diseases are resulted from primary dysfunction of mitochondrial respiratory chain
(MRC) which is mostly caused by both nuclear and mitochondrial DNA defects. They are
progressive, multisystem disorders that can affect many parts of the body including
brain, nerve, muscle, kidney, heart, liver, eyes, ears or pancreas and some are
devastating or even life threatening. Development of effective treatments for the
patients is an unmet need until now. Effective treatment strategies and clinical trials
are limited, and therapies are mostly palliative. Drug developments and clinical trials
for these diseases are scarce in Hong Kong when compared with other countries.
MDs are extremely heterogeneous phenotypically and genetically with the biochemical
dysfunction and pathogenic mechanisms being unique in each individual molecular defect.
With the advance in next generation sequencing, over 300 mitochondrial genes are
implicated to cause human diseases. This wide heterogeneity has been hindering the
development of new therapeutic strategies such as gene therapy which requires long term
evaluation and substantial manipulation to improve efficacy and reduce toxicity risk. It
is therefore not efficient nor realistic to develop unique therapy targeting at a
specific molecular defect.
The future pharmaceutical development for treating mitochondrial dysfunctions will focus
on boosting the residual mitochondrial function by non-specific bypassing the defective
components of MRC or improving the aberrant cellular consequences. Dietary supplements
were demonstrated to treat MD owing to their roles as metabolic cofactors to ameliorate
mitochondrial ATP production, bypass mitochondrial complex defects and remove toxic
metabolites. However, there are few randomized controlled trials to assess the
cause-effect relationship of these dietary supplements.
The present study is a feasibility clinical trial to explore the longitudinal effect of
receiving hydroxytyrosol (HT) as dietary supplements on primary and secondary outcomes
(clinical, biochemical and radiological parameters and quality of life) and tolerability
in MD patients in Hong Kong. The investigators aim to obtain relevant data to determine
the sample size and treatment duration for the next phase of the clinical trial on
hydroxytyrosol (HT) efficacy. Another aim of this study is to evaluate the applicability
of the outcome measures in the current study for future clinical trials on different
treatment strategies.
This pilot study will be a longitudinal, open label study. Twelve subjects will be
recruited, including MD patients with confirmed MD-associated nuclear DNA or mtDNA
mutations, from the Hong Kong Children's Hospital (HKCH). Subjects will receive
hydroxytyrosol (HT) daily as dietary supplements for 12 months. After that, patients will
be randomly assigned in 1:1 ratio to either continue on or withdraw from receiving
hydroxytyrosol (HT) as their dietary supplements for another 6 months.
Hydroxytyrosol (HT) dosage are based on the past clinical trials in humans and the NOAEL.
The willingness of the participants to stay in the trial in terms of the percentage of
participants completing the whole trial on hydroxytyrosol (HT) dietary supplement will be
assessed. The withdrawal rate in different study periods and the reasons of withdrawal
will be further studied.
Subjects will visit the trial site at different time points after the start of dietary
supplements for clinical follow up, functional assessment including questionnaire, blood
and urine sampling and neuroimaging as primary and secondary outcome measures. There will
be more frequent follow-up and monitoring after initiation and withdrawal of supplements.
Data of primary and secondary outcome measures (except radiological evaluation) will be
collected before the trial as baseline, 2 weeks, 6 weeks, 3, 6, 9, 12 months after the
commencement of the trial and 2 weeks, 6 weeks, 3 and 6 months after randomization. The
investigators will examine the feasibility of collecting data on the primary and
secondary outcome measures in a clinical trial condition. The amount of missing data, the
reason for the missing and difficulties on those data collection will be evaluated.
An open label trial is used for this proposed study because a matching placebo with the
same properties, such as taste, smell, colour, etc, as hydroxytyrosol (HT) to keep
blindness is not yet developed at this moment. Therefore, a withdrawal design will be
used even though this can be a limitation of this study because of the easy accessibility
of hydroxytyrosol (HT) by the patients who can continue to use EVOO on their own after
being assigned for withdrawal, which may potentially affect the outcome. Information on
any deviation from the study protocol on this issue can be collected from the patients by
questionnaires at the end of the study to guide the data analysis and interpretation.