Clinical trial NCT03013400: Ebselen as an add-on Treatment in Hypo/Mania
Official title: A Randomised, Parallel Group, Double Blind, Placebo Controlled, Add on Clinical Trial to Investigate Whether the Lithium Mimetic, Ebselen, Can Reduce Symptoms of Hypomania and Mania in Bipolar Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bipolar Disorder
Bipolar Disorder, Manic
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
name: Sound Pharmaceuticals, Incorporated
First posted: 2017-01-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the effect of a 'lithium like' drug called ebselen (SP-1005) versus placebo as an 'add on' treatment to help stabilise hypo/manic symptoms in bipolar disorder. Half of the participants will receive ebselen and the other half placebo. The trial, will last a total of four weeks.

Detailed description: Ebselen, a new drug for mania

Bipolar disorder, formerly known as manic depression, is a condition that affects mood, which can swing from one extreme to another.

Typically, there will be periods of:

* Depression - very low mood and energy levels
* Mania or hypomania (less severe) - very high mood and overactive energy levels

A drug called lithium, used to stabilise mood, is an important treatment for bipolar disorder but has a number of problematic side effects, is not well tolerated by patients and requires careful monitoring. To replace lithium with other, safer medicines would have clear advantages. The investigators are interested in an antioxidant medicine(substance that may prevent or delay cell damage) called ebselen which has been shown to work in a similar way as lithium and the investigators are investigating whether it might help improve recovery from manic episodes.

The present study aims to see whether ebselen, used as an 'add-on' treatment can help stabilise mood in patients experiencing high mood (hypo/mania). Sixty patients experiencing hypo/mania will be given in a randomised order (similar to tossing a coin) either ebselen or placebo (dummy) in addition to their usual medication for three weeks after which the add-on treatment will be stopped. A final follow up visit will take place one week after the study medication has been stopped. Participants can be in or outpatients and mood will be monitored with questionnaires and interviews. Activity will also be monitored with the use of an actiwatch (similar to a wrist watch) which will be worn continuously throughout the study. A single blood sample will be optional and occur after the first week of treatment to check plasma levels of ebselen and inflammatory markers. A positive outcome in this trial will be followed by longer term studies of ebselen in bipolar disorder.

Eligibility criteria: Inclusion Criteria:

* Participant is willing and able to give informed consent for participation in the trial.
* Male or Female, aged 18-70 years
* Diagnosed with bipolar disorder, screened using the Structured Clinical Interview for DSM-5 (SCID) to meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Manic or Hypomanic Episode.
* Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial
* In the Investigator's opinion, is able and willing to comply with all trial requirements.
* Willing to allow clinical care team (including General Practitioner (GP)) to be made aware of trial participation.
* The Clinical team treating the patient are in agreement.

Exclusion Criteria:

* Female participant who is pregnant, lactating or planning pregnancy during the course of the trial.
* Known significant renal or hepatic impairment.
* Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
* Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.
* Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
* Clinically significant illicit substance or alcohol misuse where dependence criteria are satisfied.
* Taking lithium.
* Previous randomisation to this trial.

Primary outcomes:
measure: Change in Young Mania Rating Scale (YMRS)
timeFrame: Change between groups, every week, up to 4 weeks
Secondary outcomes:
measure: Change in Clinical Global Impressions Bipolar (CGI-BP) mania scale
timeFrame: Change between groups, every week, up to 4 weeks
measure: Change in Altman Self Rating Mania Scale (ASRM)
timeFrame: Change between groups, 3 x weekly, up to 4 weeks
measure: Change in Hamilton Rating Scale for Depression (HAM-D)
timeFrame: Change between groups, every week, up to 4 weeks
measure: Change in Quick Inventory of Depressive Symptomology-Self Rating 16 (QIDS-SR-16)
timeFrame: Change between groups, 3 x weekly, up to 4 weeks
measure: Change in Actigraphy
timeFrame: Change in activity between groups, each 24 hours, up to 4 weeks
measure: Change in Leeds Sleep Evaluation Questionnaire (LSEQ)
timeFrame: Change between groups, every week, up to 4 weeks
measure: Levels of markers of inflammation in Plasma sample
timeFrame: Once at week 1 visit
measure: Ebselen levels in Plasma sample
timeFrame: Once at week 1 visit
measure: Adverse Events reported
timeFrame: Every week, up to 4 weeks
measure: Change in Concomitant medication recorded
timeFrame: Change between groups, every week, up to 4 weeks
measure: Compliance assessment
timeFrame: Change between groups, every week, up to 3 weeks
Other outcomes:
measure: Researcher and participant blinding questionnaire to determine treatment concealment
timeFrame: Once, at week 4
measure: Participant and Researcher Randomisation Guess Visual Analogue Scale (VAS)
timeFrame: Once, at week 4
measure: Public Participant Involvement (PPI) feedback questionnaire
timeFrame: Once, at week 4
Locations:
city: Oxford
country: United Kingdom
facility: Neurosciences Building, Dept. Psychiatry, Warneford Hospital
state: Oxfordshire
Study officials:
affiliation: University of Oxford
name: Philip J Cowen, MBBS, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Masaki C, Sharpley AL, Cooper CM, Godlewska BR, Singh N, Vasudevan SR, Harmer CJ, Churchill GC, Sharp T, Rogers RD, Cowen PJ. Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing. Psychopharmacology (Berl). 2016 Jul;233(14):2655-61. doi: 10.1007/s00213-016-4319-5. Epub 2016 Jun 2.
citation: Masaki C, Sharpley AL, Godlewska BR, Berrington A, Hashimoto T, Singh N, Vasudevan SR, Emir UE, Churchill GC, Cowen PJ. Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla. Psychopharmacology (Berl). 2016 Mar;233(6):1097-104. doi: 10.1007/s00213-015-4189-2. Epub 2016 Jan 12.
citation: Singh N, Sharpley AL, Emir UE, Masaki C, Herzallah MM, Gluck MA, Sharp T, Harmer CJ, Vasudevan SR, Cowen PJ, Churchill GC. Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans. Neuropsychopharmacology. 2016 Jun;41(7):1768-78. doi: 10.1038/npp.2015.343. Epub 2015 Nov 23.
citation: Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC. A safe lithium mimetic for bipolar disorder. Nat Commun. 2013;4:1332. doi: 10.1038/ncomms2320.
citation: Sharpley AL, Williams C, Holder AA, Godlewska BR, Singh N, Shanyinde M, MacDonald O, Cowen PJ. A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania. Psychopharmacology (Berl). 2020 Dec;237(12):3773-3782. doi: 10.1007/s00213-020-05654-1. Epub 2020 Sep 9.
citation: Garland M, Hryckowian AJ, Tholen M, Bender KO, Van Treuren WW, Loscher S, Sonnenburg JL, Bogyo M. The Clinical Drug Ebselen Attenuates Inflammation and Promotes Microbiome Recovery in Mice after Antibiotic Treatment for CDI. Cell Rep Med. 2020 Apr 21;1(1):100005. doi: 10.1016/j.xcrm.2020.100005.