Condition category
Mental and Behavioural Disorders
Date applied
27/10/2009
Date assigned
21/12/2009
Last edited
05/01/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims.
The purpose of this study is to test a drug called Metyrapone, in patients with moderate to severe depression, as an add-on to current antidepressant treatment. The short title of the study is the ADD Study. Depression is a common disorder, affecting approximately 10% of the population. The effects can be long-lasting and may recur frequently. Depression has a negative impact on people's quality of life, not only for those who are diagnosed with the condition, but also for their carers. Research has shown that many people with depression also produce more cortisol than is usual. This may stop antidepressant drugs from working properly. We would like to learn whether giving a drug named Metyrapone, in addition to a standard antidepressant for a short space of time (three weeks) produces benefits that are meaningful to patients with depression. Previous research on the drug Metyrapone has shown that it can block the production of the stress hormone cortisol produced in the body. The ADD study is also designed to see whether any postive effects of Metyrapone last beyond the three weeks during which it is given.

Who can participate?
Patients will be selected from those living in the community and visiting clinics on a regular basis for monitoring of their depression. We will identify 190 patients with moderate to severe depression at three centres in the United Kingdom. Your symptoms will be assessed by one of the researchers, using a scale that measures severity, to confirm whether this is the case. This will be done on two occasions, two weeks apart, before you enter the study and take the study medication.

What does the study involve?
Some patients will be given Metyrapone and some patients will be given an identical-looking capsule that does not contain any active medicine (a placebo or dummy pill). They will continue with their current antidepressant treatment at the same time. Participating in the study involves taking two capsules twice a day, every day for three weeks. The capsules will be taken at 12 noon and at bedtime, with milk or after a meal. As this study is 'blinded' it will not be possible to tell, until the end of the study, which treatment group patients have been in. Not knowing whether patients were taking Metyrapone or placebo will not affect the treatment given at the end of the study. Once recruited into the study, medication will be posted to the patient's address of their choice. A prescription will be written which will be faxed to the Pharmacy based at the Northumberland, Tyne & Wear NHS Foundation Trust, where responsibility lies for dispensing of study medication. Local research teams will check participants' progress throughout this treatment period, and for a further 21 weeks afterwards. Mood, general health and social function will be assessed. This enables the research teams to understand how patients are feeling during the trial and ascertain whether any beneficial effects last over time. Blood samples will be taken for routine tests, as well as saliva samples to measure stress hormone levels. With additional permission, a sample will be taken for genetic (DNA) analysis. A number of genes have been identified that might be involved in depression. A comparison will be made to compare the variations in these genes with the stress hormone level and other tests carried out with how well the drug treatment works to try and understand the reasons for why people vary in their response to treatment. We will also compare the results with people who are not depressed (healthy volunteers) to better understand what happens in depression. A sub-group of patients will be invited to take part in extra sub-studies investigating the stress system in depression and how Metyrapone affects this. Patients may choose to participate in these extra tests which include: computerised tests of brain processes such as memory and attention; brain imaging (Magnetic Resonance Imaging; MRI); and electrical recording of brain activity (electroencephalogram; EEG). The aim is to understand more about how stress can cause depression, how treatments may be improved, and if a prediction can be made whether a patient will respond, before giving a particular treatment. A separate group of healthy volunteers will also be invited to participate in the sub-studies but will not receive Metyrapone or placebo treatments.

What are the possible benefits and risks of participating?
Metyrapone may improve the symptoms of depression. Participants who take part in clinical trials generally feel better more than participants who don't. This may be down to the more frequent follow-up of patients in clinical trials, compared to routine clinical practice. There may be no direct benefit, but participants will help in finding out whether Metyrapone is useful in depressed patients and help doctors understand more about the role of stress hormones in this disorder. There is no promise that the study will help current participants, but it may help future patients. There may be side effects of Metyrapone; these will be explained in detail by the medical team and included in the patient information sheet. There is a small risk of bruising or discomfort at the injection site when blood samples taken.

Where is the study run from?
Newcastle University Institute of Neuroscience

When is the study starting and how long is it expected to run for?
Recruitment commenced in February 2011 and has now closed as of 30 November 2012. Patient follow-ups will continue until June 2013.

Who is funding the study?
National Institute for Health Research Efficacy and Mechanism Evaluation (NIHR EME) Board

Who is the main contact?
Professor Nicol Ferrier
nicol.ferrier@ncl.ac.uk

Trial website

http://www.TheADDStudy.co.uk

Contact information

Type

Scientific

Primary contact

Prof Ian Nicol Ferrier

ORCID ID

Contact details

Academic Psychiatry
Campus for Ageing and Vitality
Westgate Road
Newcastle Upon Tyne
NE4 6BE
United Kingdom
+44 (0)191 2081390
nicol.ferrier@ncl.ac.uk

Additional identifiers

EudraCT number

2009-015165-31

ClinicalTrials.gov number

NCT01375920

Protocol/serial number

EME 08/43/39

Study information

Scientific title

Antiglucocorticoid augmentation of antiDepressants in Depression: a double-blind randomised placebo-controlled parallel group trial

Acronym

ADD

Study hypothesis

That a three week course of metyrapone (versus placebo) augmentation of antidepressants in depressed patients who have failed to respond to at least two courses of antidepressants, in primary care and psychiatric outpatient clinics in the UK will be lead to a reduction in symptoms of depression.

Link to EME project website: http://www.eme.ac.uk/projectfiles/084339info.pdf

On 16/06/2011 various updates were made to this trial and can be found under this date in the relevant fields below.
1. The overall trial start date was changed from 01/01/2010 to 01/02/2011.
2. The overall trial end date was changed from 31/12/2011 to 01/05/2013.

On 01/02/2013 the overall trial end date was changed from 01/05/2013 to 30/06/2013.

Ethics approval

Sunderland Research Ethics Committee, 22/04/2010, ref: 10/H0904/9

Study design

Double-blind randomised placebo-controlled parallel-group trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

GP practices

Trial type

Treatment

Patient information sheet

http://www.theaddstudy.co.uk/info.html

Condition

Major depression

Intervention

Metyrapone 500 mg twice a day or twice daily placebo for 21 days in addition to the patient's current ongoing psychotropic medication which will remain stable throughout the trial.

Intervention type

Drug

Phase

Not Applicable

Drug names

Metyrapone

Primary outcome measures

Change in clinical symptoms of depression from 0 to +5 weeks (i.e. two weeks after end of treatment), assessed by the Montgomery-Asberg Depression Research Scale (MADRS)

Secondary outcome measures

Current secondary outcome measures as of 28/06/2013:
1. Mood as measured by the MADRS, YMRS and BDI at time 0, +3, +5, +8, +16, +24 weeks
2. Anxiety as measured by the CAS and STAI at time 0, +3, +5, +8, +16, +24 weeks
3. Quality of life, assessed using the EQ-5D at weeks 0, +3, +5, +8, +16, +24
4. Tolerability assessed using the TSES and self-report at weeks 0, +3, +5, +8 (additional self-report at weeks +1, +2 and +4)
5. Suicide risk assessed at weeks 0, +1, +3, +5, +8, +16, +24
6. Hypothalamic-Pituitary-Adrenal (HPA) axis function assessed by salivary cortisol awakening response (CAR) and sample at 11 pm at weeks 0, +3 and +5
7. Safety assessments including blood pressure, urea and electrolytes and plasma cortisol levels at weeks -2, +1 and +5

Previous secondary outcome measures until 28/06/2013:
1. Secondary outcomes related to mood will be the MADRS measured at time 0, +3, +5, +8, +16, +24 weeks relative to baseline (protocol amendement approved 15/08/2011)
2. Quality of lfe, assessed using the EQ-5D at weeks 0, +3, +5, +8, +16, +24
3. Cortisol awakening response (CAR) from salivary samples at weeks 0, +3 and +5

Previous secondary outcome measures until 05/02/2013:
1. Secondary outcomes related to mood will be the MADRS measured at time +3, +8, +16 and + 24 weeks relative to baseline

Previous secondary outcome measures until 16/06/2011:
2. Quality of life, assessed using the EQ-5D at weeks 0, +3 and +5

Overall trial start date

01/02/2011

Overall trial end date

30/06/2013

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 05/02/2013:
1. Males and females aged 18-65 years
2. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) confirmed diagnosis of major depression
3. Severity - Patients must have a Hamilton Depression Rating Scale (HDRS17) score of 18 or greater, consistent with a moderate to severe episode. The stability of the patients' clinical state will also be confirmed with a 2 week baseline lead in period (week -2 to 0). A repeat HDRS17 score at time 0 is required to be 18 or greater.
4. Treatment refractoriness - assessed using the Massachusetts General Hospital (MGH) staging method. This defines minimum effective doses of all currently available antidepressants and an "adequate trial" as being for at least 6 weeks. For the trial to be considered as a "failure" it must have been considered by the clinical team to have been ineffective rather than the drug not taken or not tolerated. For inclusion, patients will have failed to have responded to at least their second trial of an antidepressant. This equates to a minimum score of 2 on MGH staging. The maximum MGH score for inclusion in the study will be 10.
5. At trial entry, patients must be taking monotherapy or combination antidepressant therapy that includes a serotonergic drug (a selective serotonin reuptake inhibitor [SSRI], a tertiary amine tricyclic, venlafaxine, duloxetine or mirtazepine). They must not be on noradrenergic antidepressant monotherapy eg. lofepramine, imipramine or reboxitene. At the point of randomisation, patients must have been on their current antidepressant medication, at the current dose, for a minimum of four weeks (protocol amendment approved 05/03/2012).

Previous inclusion criteria until 05/02/2013:
5. At trial entry, patients must be taking monotherapy or combination antidepressant therapy that includes a serotonergic drug (a selective serotonin reuptake inhibitor [SSRI], a tertiary amine tricyclic, venlafaxine, duloxetine or mirtazepine). (Added 16/06/2011: They must not be on noradrenergic antidepressant monotherapy eg. lofepramine, imipramine or reboxitene).

Previous inclusion criteria until 16/06/2011:
1. Males and females aged 18 - 70 years
3. Severity - Patients must have a Hamilton Depression Rating Scale (HDRS17) score of 18 or greater, consistent with a moderate to severe episode. The stability of the patients' clinical state will also be confirmed with a 2 week baseline lead in period (week 2 to 0). A repeat HDRS17 score at time 0 is required to be 18 or greater.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

190 patients will be randomised into two groups of 95

Participant exclusion criteria

Current exclusion criteria as of 05/02/2013:
1. Any other DSM IV Axis I disorder other than an anxiety disorder unless the depressive episode is considered to be secondary to the anxiety disorder, confirmed using the Structured Clinical interview for DSM (SCID) (protocol amendment approved 15/08/20111)
2. Physical co-morbidity which would render the use of metyrapone inappropriate, including untreated hypothyroidism, disorders of steroid production, cardiac failure, angina, myocardial infarction within the last 3 years, renal failure
3. Pregnancy - determined by history and if indicated, urine pregnancy test
4. Mothers who are breastfeeding
5. Use of concomitant medication that would interfere in a pharmacodynamic or pharmacokinetic manner with metyrapone
6. Dependence on alcohol or other drug in the past 12 months and/or current harmful use of alcohol or other drug
7. Recently having taken part in another research study that could interfere with the results of this one

Previous exclusion criteria until 05/02/2013:
1. Any other DSM IV Axis I disorder
2. Physical co-morbidity which would render the use of metyrapone inappropriate, including untreated hypothyroidism, disorders of steroid production, cardiac failure, angina, myocardial infarction within the last 3 years, renal failure
3. Pregnancy - determined by history and if indicated, urine pregnancy test
4. Mothers who are breastfeeding (Added 21/06/2011)
5. Use of concomitant medication that would interfere in a pharmacodynamic or pharmacokinetic manner with metyrapone
6. Dependence on alcohol or other drug in the past 12 months and/or current harmful use of alcohol or other drug
7. Recently having taken part in another research study that could interfere with the results of this one (Added 21/06/2011)

Recruitment start date

01/02/2011

Recruitment end date

30/11/2012

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Academic Psychiatry
Newcastle Upon Tyne
NE4 6BE
United Kingdom

Sponsor information

Organisation

Northumberland, Tyne and Wear NHS Foundation Trust (UK)

Sponsor details

c/o Simon Douglas
St Nicholas Hospital
Jubilee Road
Gosforth
Newcastle Upon Tyne
NE3 3XT
United Kingdom
+44 (0)191 2232336
simon.douglas@ntw.nhs.uk

Sponsor type

Government

Website

http://www.ntw.nhs.uk

Funders

Funder type

Government

Funder name

Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/43/39)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26086063
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26727041

Publication citations

Additional files

Editorial Notes