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Trial registered on ANZCTR


Registration number
ACTRN12616000567426
Ethics application status
Approved
Date submitted
29/04/2016
Date registered
3/05/2016
Date last updated
10/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Mitochondrial agents in the treatment of chronic fatigue syndrome: a 20-week, open-label, intervention trial
Scientific title
Mitochondrial agents in the treatment of chronic fatigue syndrome: a 20-week, open-label, intervention trial
Secondary ID [1] 289109 0
Nil Known
Universal Trial Number (UTN)
U1111-1182-4482
Trial acronym
INVIGOR8
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Fatigue Syndrome 298571 0
Condition category
Condition code
Other 298651 298651 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study aims to examine the efficacy of a novel, tolerable, and practical adjunctive intervention by examining a combination of agents acting on mitochondrial targets.

The trial will assess the efficacy and tolerability of twice daily dosing for 20-weeks of purpose-designed combination capsules taken orally providing a daily amount of: N-acetylcysteine (NAC) 2000 mg; Acetyl L-carnitine (ALC) 1000mg; ubiquinone (Co Q10) 200 mg; magnesium (as orotate 500mg) 64mg; calcium ascorbate dehydrate (equiv ascorbic acid 200mg) 242mg; cholecalciferol (equiv vitamin D3 250IU) 12.5micrograms; a-tocopherol (equiv natural vitamin E 50IU) 60IU; alpha lipoic acid 150mg; Retinyl palmitate (equiv vitamin A 3000IU) 900ugREIU; and vitamin B co-factors: biotin (vitamin H) (600micrograms), thiamin hydrochloride (100mg), riboflavin (100mg), nicotinamide (200mg), calcium pantothenate (100mg), pyridoxine hydrocholoride (100mg), folic acid (800micrograms), cyanocobalamin (vitamin B12) (800micrograms) in people diagnosed with CFS.

A capsule count will be done to determine compliance.
Intervention code [1] 294612 0
Treatment: Drugs
Comparator / control treatment
No control group. Open Label.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298147 0
Chalder Fatigue Scale (CFQ 11)
Timepoint [1] 298147 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [1] 323272 0
Montgomery–Asberg Depression Rating Scale (MADRS).
Timepoint [1] 323272 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [2] 323273 0
Short Form-12 Health Survey
Timepoint [2] 323273 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [3] 323274 0
Insomnia Severity Scale (ISI)
Timepoint [3] 323274 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [4] 323275 0
Work and Social Adjustment Scale (WSAS)
Timepoint [4] 323275 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [5] 323276 0
International Physical Activity Questionnaire (IPAQ) – Short Form
Timepoint [5] 323276 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [6] 323277 0
Clinical Global Scale – Severity
Timepoint [6] 323277 0
Baseline, Week 4, Week 8, Week 12, Week 16 and Week 20
Secondary outcome [7] 323318 0
Clinical Global Scale – Improvement
Timepoint [7] 323318 0
Week 4, Week 8, Week 12, Week 16 and Week 20

Eligibility
Key inclusion criteria
a. Male and female patients aged 18 to 65 years,
b. Diagnosed with chronic fatigue syndrome by an independent physician (a letter or referral will be preferred to confirm diagnosis),
c. Fulfil criteria for CFS as per the US Centres for Disease Control and Prevention (CDC), which requires persistent, unexplained fatigue for at least 6 months, concurrent with at least four of the following, 1) Impaired memory/concentration, 2) Sore throat, new headaches, 3) Unfreshreshing sleep, muscle pain, 4) Multi-joint pain 5)Tender lymph nodes
6) Post-exertional malaise
d. Have capacity to consent to the study and comply with study procedures,
e. Be using effective contraception if female, sexually active and of childbearing age,
f. Participants currently under any form of therapy will need to have been on that therapy for at least four (4) weeks prior to enrolment.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Patients with known or suspected active and unstable systemic medical disorder,
b. Patients who have a major depressive episode in the two years preceding the diagnosis of CFS,
c. Acute suicidality as indicated by a score of 5 or 6 on Item 10 of the MADRS (or at the discretion of Principal Investigator)
d. Patients with current diagnosis of a psychotic disorder, bipolar disorder, substance abuse/dependence, eating disorder, significant personality disorder,
e. Recent gastrointestinal ulcers or renal stones,
f. Individuals who are pregnant or lactating,
g. Individuals with a diagnosis of epilepsy,
h. Those who are currently taking any of the study preparations (a 2-week washout period will be required if participants currently taking the study preparations would like to take part) or over 200micrograms of selenium/day,
i. Individuals currently enrolled in any other intervention study,
j. Individuals needing warfarin or phenytoin,
k. Individuals who are intolerant to or have had an anaphylactic reaction to any components of the preparation,
l. Inability to comply with either the requirements of informed consent or the treatment protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Open label study, Not randomised. Participants allocated to intervention sequentially.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
20-week open-label intervention study of a combination therapy for patients with chronic fatigue syndrome. Participants will receive 20 weeks of daily treatment, adjunctive to treatment as usual, with assessment visits at baseline, W4, W8, W12, W16, and W20.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data analysis, including descriptive statistics, t-tests, multiple regression, logistic regression, chi-square test, and ANOVA will be conducted using SPSS. Analysis of all outcome measures will be performed at each time point. Repeated measures linear mixed models analysis will be used to test the effect on rate of change on primary and secondary outcome measures over time. Tests of significance will use a level of a = 0.05.

No formal sample size calculation was performed as the study is a pilot, open-label and exploratory in nature. As with most pilot studies, the sample size will be a sample of convenience as the study is unfunded and limited by resourcing.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5704 0
The Melbourne Clinic - Richmond
Recruitment postcode(s) [1] 13192 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 293477 0
Self funded/Unfunded
Name [1] 293477 0
N/A
Address [1] 293477 0
N/A
Country [1] 293477 0
Primary sponsor type
University
Name
The University of Melbourne
Address
Grattan st
Parkville 3052 VIC
Country
Australia
Secondary sponsor category [1] 292301 0
None
Name [1] 292301 0
Address [1] 292301 0
Country [1] 292301 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294919 0
The Melbourne Clinic Ethics Committee
Ethics committee address [1] 294919 0
2 Salisbury St
Richmond 3121 VIC
Ethics committee country [1] 294919 0
Australia
Date submitted for ethics approval [1] 294919 0
27/01/2016
Approval date [1] 294919 0
17/02/2016
Ethics approval number [1] 294919 0
270

Summary
Brief summary
Chronic fatigue syndrome (CFS) is a prolonged multisystem illness, characterised by very poor stamina, delayed post-exertional fatigue, which adversely affects one’s functioning across numerous physical and mental domains. Current treatments for CFS include pharmacological (e.g. fluoxetine, rintatolimod, galantamine), psychological (e.g. cognitive behaviour therapy (CBT), adaptive pacing therapy), and lifestyle interventions. For many who remain in treatment, they continue to experience significant social, occupational, and functional impairment. Thus new treatment approaches are urgently needed.
While significant fatigue remains a common complaint across numerous disorders, it is posited that CFS is related to metabolic dysfunction, mitochondrial dysfunction and impaired biogenesis, in turn related to oxidative stress and systemic inflammation. Mitochondria are structures within cells primarily responsible for energy generation, and are particularly active in oxygen-rich and highly energy dependent tissues, such as the brain. Recent research suggests that patients suffering from CFS may improve with the supplementation of mitochondrial nutrients and antioxidants. This supplementation may be associated with the reduction to mitochondrial membranes, restoring mitochondrial energy production, protecting cellular structures and enzymes from oxidative damage, and decreasing fatigue. Given that CFS is largely a heterogeneous illness associated with a complex and multifactorial aetiology, combined with the present state of available treatments, it is plausible that the introduction of a combination of metabolic therapies may have positive effects on mitochondrial dysfunction and lead to symptom improvement for CFS sufferers.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 65498 0
Dr Ranjit Menon
Address 65498 0
The Melbourne Clinic Professorial Unit & The University of Melbourne
2 Salisbury St
Richmond
VIC 3121
Country 65498 0
Australia
Phone 65498 0
+61394874748
Fax 65498 0
Email 65498 0
drmenon@gmail.com
Contact person for public queries
Name 65499 0
Dr Jenifer Murphy
Address 65499 0
The Melbourne Clinic Professorial Unit & The University of Melbourne
2 Salisbury St
Richmond
VIC 3121
Country 65499 0
Australia
Phone 65499 0
+61394874748
Fax 65499 0
Email 65499 0
jenifer.murphy@unimelb.edu.au
Contact person for scientific queries
Name 65500 0
Dr Jenifer Murphy
Address 65500 0
The Melbourne Clinic Professorial Unit & The University of Melbourne
2 Salisbury St
Richmond
VIC 3121
Country 65500 0
Australia
Phone 65500 0
+61394874748
Fax 65500 0
Email 65500 0
jenifer.murphy@unimelb.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary