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Trial registered on ANZCTR


Registration number
ACTRN12612000830897
Ethics application status
Approved
Date submitted
23/07/2012
Date registered
7/08/2012
Date last updated
23/03/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Mitochondrial agents in the treatment of bipolar disorder
Scientific title
A double blind, placebo controlled, randomised trial to evaluate the effect of mitochondrial agents, N-acetyl cysteine or placebo on the depressive phase of bipolar disorder
Secondary ID [1] 280896 0
NIL Known
Universal Trial Number (UTN)
NIL
Trial acronym
MITO-NAC BD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
bipolar depression 286968 0
Condition category
Condition code
Mental Health 287305 287305 0 0
Other mental health disorders
Mental Health 287336 287336 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ARM 1: N-acetyl cysteine (NAC)
Treatment for 16 weeks

NAC 500mg 2 capsules Twice a day (BID)
Placebo for cardionutrient, 1 capsule BID
Placebo for acetyl L carnitine, 1 capsule BID
Placebo for mitochondrial combination, 1 capsule BID

ARM 2: Mitochondrial combination + NAC
Treatment for 16 weeks

1 cardonutrient capsule BID containing
- alpha lipoic acid 75mg
-ubidecarenone 75mg
-magnesium 32mg
-aplha tocopherol 3.36mg

1 acetyl L carnitine (ALC) capsule BID 500mg

1 mitochondrial combination capsule BID containing:
- Thiamine 50mg
-Riboflavin 50mg
-Nicotinamide 100mg
- Vitamin B5 45mg
- Vitamin B6 41.1mg
- Floic acid 400ug
- Vitamin B12 400ug
- Vitamin E 16.8mg (25IU)
-Calcium ascorbate dihydrate 121mg
- Vitamin A 450ugRE (1500IU)
- Vitamin D3 6.25ug
- Vitamin B7 300ug
- Ubidecarenone 25mg
-2 NAC capsules BID

ARM 3: Placebo
Treatment for 16 weeks

There will be matching placebos for each of the following:
Mitochondrial combination, ALC, cardionutrient and NAC. All will be taken one capsule twice daily except NAC placebo which will be two taken twice daily.
Intervention code [1] 285327 0
Treatment: Drugs
Comparator / control treatment
placebo
Control group
Placebo

Outcomes
Primary outcome [1] 287584 0
The primary endpoint for this trial is mean change in depressive symptoms of bipolar disorder measured using MADRS.
Timepoint [1] 287584 0
The MADRS will be conducted at all trial visits ( every 4 weeks) including the 16 weeks of treatment and at the post-discontinuation visit at week 20.
Secondary outcome [1] 298448 0
The secondary outcomes will include changes in the following:
- Bipolar Depression rating Scale (BDRS)
Timepoint [1] 298448 0
Conducted at all trial visits- Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [2] 298449 0
changes in hamilton anxiety scale (HAM-A)
Timepoint [2] 298449 0
conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [3] 298450 0
Changes in Young Mania Rating Scale (YMRS)
Timepoint [3] 298450 0
conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [4] 298451 0
Changes in Longitudinal interval follow-up evaluation- Range of Impairement Functioning Tool
Timepoint [4] 298451 0
conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [5] 298452 0
changes in Social and occupational functioning Assessment Scale (SOFAS)
Timepoint [5] 298452 0
Conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [6] 298453 0
changes in Quality of Life Enjoyment and Satisfaction Questionnaire- Short Form (QLES-Q)
Timepoint [6] 298453 0
conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [7] 298454 0
changes in Clinical gobal Impressions Severity/ improvement (CGI BP & CGI Improvement)
Timepoint [7] 298454 0
Conducted at all trial visits-Baseline (week 0) and every four weeks after that (visit 2,3,4,5 and 6)
Secondary outcome [8] 298455 0
Changes in patient global impressions scale
Timepoint [8] 298455 0
conducted at all trial visits except baseline. Weeks 4, 8, 12,16 and 20
Secondary outcome [9] 298456 0
Changes in blood oxidative and inflammatory markers eg: IL-6, CRP, MDA, TNF-alpha, protein carbonylation
Timepoint [9] 298456 0
Blood samples collected from consenting participants at baseline and week 16.

Eligibility
Key inclusion criteria
1. Must be required to meet DSM-IV criteria for bipolar disorder (I, II or NOS)

2. Have a current episode of depressive illness with a MADRS score greater than or equal to 20

3. Have capacity to consent to the study and comply with study procedures

4. Using effective contraception if female, sexually active and of child bearing potential

5. Any form of therapy must be stable for the last month.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants with known or suspected active systemic medical disorder

2.Recent gastrointestinal ulcers

3. Individuals who are pregnant or lactating

4. Individuals with a diagnosis of epilepsy

5. Individuals currently taking >250mg of n-acetylcysteine; >250mg of acetyl l-carnitine; or >25mg of coenzyme Q10

6. Individuals taking over 200ug of selenium/ day

7. Individual requiring warfarin or phenytoin

8. Participants currently enrolled in another intervention study

9. Participants who are intolerant to or have had an anaphylactic reaction to any components in the preparation.

10. Participants who are unable to comply with requirements of informed consent or treatment protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Recruitment: Participants will be recruited through participants’ case clinicians, advertisement or via private clinicians (e.g. family physicians or specialists). Potential participants will be contacted, briefly screened and a preliminary interview will be scheduled. All participants will give written informed consent before enrollment.

Allocation: Pack number allocation to treatment arm will be randomly assigned using permutated block randomisation. The computer-generated randomisation plan will be developed by an independent researcher. Packs are identical so as to conceal treatment allocation and blinding. To facilitate the double-blinding process, the trial medications (the combination treatment, NAC only and placebo) will be dispensed by and independent pharmacist in identical numbers and capsule forms in sealed containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be enrolled sequentially and will be allocated to treatments based on the computer-generated number sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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)
NSW,VIC
Recruitment postcode(s) [1] 5550 0
3220
Recruitment postcode(s) [2] 5551 0
2065

Funding & Sponsors
Funding source category [1] 285687 0
Government body
Name [1] 285687 0
National Health and Medical research Council Project Grant
Address [1] 285687 0
Street: Level 1, 16 Marcus Clarke Street Canberra ACT 2601

Postal: PO Box 1421 Canberra ACT 2601
Country [1] 285687 0
Australia
Funding source category [2] 290425 0
Government body
Name [2] 290425 0
CRC for Mental Health
Address [2] 290425 0
Level 2, 161 Barry Street,
Carlton South,
Victoria, 3053
Country [2] 290425 0
Australia
Primary sponsor type
University
Name
Mental Health Research Institute- University of Melbourne
Address
University of Melbourne
Kenneth Myer Building
30 Royal parade (Corner Genetics Lane)
Parkville Victoria 3052
Country
Australia
Secondary sponsor category [1] 284516 0
None
Name [1] 284516 0
Address [1] 284516 0
Country [1] 284516 0
Other collaborator category [1] 276971 0
University
Name [1] 276971 0
The University of Sydney
Address [1] 276971 0
The University of Sydney
NSW 2006
Country [1] 276971 0
Australia
Other collaborator category [2] 276972 0
University
Name [2] 276972 0
Melbourne University
Address [2] 276972 0
The University of Melbourne
Victoria 3010
Country [2] 276972 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287672 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 287672 0
Research and Ethics Office
Geelong Hospital
PO BOX 281
Geelong Victoria 3220
Ethics committee country [1] 287672 0
Australia
Date submitted for ethics approval [1] 287672 0
11/05/2011
Approval date [1] 287672 0
19/05/2011
Ethics approval number [1] 287672 0
11/10
Ethics committee name [2] 287673 0
The Melbourne Clinic Research Ethics Committee
Ethics committee address [2] 287673 0
The Melbourne Clinic
130 Church Street
Richmond VIC 3121
Ethics committee country [2] 287673 0
Australia
Date submitted for ethics approval [2] 287673 0
09/02/2012
Approval date [2] 287673 0
11/04/2012
Ethics approval number [2] 287673 0
207
Ethics committee name [3] 287674 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [3] 287674 0
Research Office
Level 13, Kolling Building
Royal North SHore Hospital
St leonards NSW 2065
Ethics committee country [3] 287674 0
Australia
Date submitted for ethics approval [3] 287674 0
28/02/2012
Approval date [3] 287674 0
10/05/2012
Ethics approval number [3] 287674 0
1201-022M

Summary
Brief summary
There is a body of evidence supporting the presence of oxidative stress states in bipolar disorder. With high levels of oxidative stress comes mitochondrial dysfunction. There is accumulating evidence that demonstrates that those with mitochondrial disease have a higher prevalence of bipolar disorder. The aim of this trial is to develop novel therapies for the depressive phase of bipolar disorder targeting the pathways of oxidative stress and mitochondrial dysfunction. This 20 weeks, double blind ranodmised, placebo controlled trial will investigate a combination treatment to enhance mitochondrial function, as well as exploring N-acetyl cysteine alone. The study will include 16 weeks of treatment with a post-discontinuation visit 4 weeks later. Participants will be randomly and sequentially allocated to one of the three treatment arms, in addition to any usual treatment they may be taking. The primary outcomes will be changes in symptoms based on the Montgomery Asberg Depression Rating Scale. Secondary outcomes include changes in HAMA, YMRS, BDRS, PGI, CGI and blood biomarkers.We will also be collecting blood samples at baseline, and week 16 from consenting participants to investigate blood markers of oxidative stress, inflammation and mitochondrial function.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34474 0
Prof Professor Michael Berk
Address 34474 0
Mental Health
Swanston Centre
PO BOX 281
GEELONG VIC 3220
Country 34474 0
Australia
Phone 34474 0
+61 03 4215 3330
Fax 34474 0
+61 03 4215 3491
Email 34474 0
mikebe@barwonhealth.org.au
Contact person for public queries
Name 17721 0
Prof Professor Michael Berk
Address 17721 0
Mental Health, Swanston Centre
PO BOX 281
Geelong VIC 3220
Country 17721 0
Australia
Phone 17721 0
+61 03 4215 3330
Fax 17721 0
+61 03 4215 3491
Email 17721 0
mikebe@barwonhealth.org.au
Contact person for scientific queries
Name 8649 0
Prof Professor Michael Berk
Address 8649 0
Mental Health, Swanston Centre
PO BOX 281
Geelong VIC 3220
Country 8649 0
Australia
Phone 8649 0
+61 03 4215 3330
Fax 8649 0
+61 03 4215 3491
Email 8649 0
mikebe@barwonhealth.org.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