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| [ Print-friendly version ] |
| Bipolar Affective disorder: Lithium/ANti-Convulsant Evaluation |
| ISRCTN | ISRCTN55261332 |
| ClinicalTrials.gov identifier | |
| Public title | Bipolar Affective disorder: Lithium/ANti-Convulsant Evaluation |
| Scientific title | |
| Acronym | BALANCE |
| Serial number at source | BALANCE 1 |
| Study hypothesis |
Combination therapy with lithium plus valproate semisodium is superior to either lithium or valproate monotherapy in the long term treatment of bipolar disorder.
For information: 1. Goodwin, G: Better data for bipolar disorder will help improve management. Keynote lecture. Progress In Neurology and Psychiatry -Guildford. 2004; 8(2): 26-30. 2. Rendell JM, Juszczak E, Hainsworth J, Van der Gucht E, Healey C, Morriss R, Ferrier N, Young AH, Young H, Goodwin GM, Geddes JR: Developing the BALANCE trial - the role of the pilot study and start-up phase. Bipolar Disorders 2004; 6(1): 26-31. 3. Rendell JM, Geddes JR, Ostacher MJ: Older patients are eligible for trial of lithium and valproate. BMJ 2003; 327: 395-96. 4. Geddes JR, Rendell JM, Goodwin GM: BALANCE: a large simple trial of maintenance treatment for bipolar disorder: World Psychiatry 2002; 1: 48-51. 5. Geddes JR: Can we conduct some large simple trials in bipolar disorder? Bipolar Disorders 2002; 4 (Suppl. 1): 62-63. 6. Geddes J, Goodwin G, Rendell J, Hainsworth J, Van Der Gucht E, Young H: New trial should clarify lithium use in bipolar disorder. BMJ 2002; 325:441. 7. Geddes J, Goodwin G: Bipolar disorder: clinical uncertainty, evidence-based medicine and large-scale randomised trials. Br.J Psychiatry 2001; 178:S191-S194. |
| Lay summary | |
| Ethics approval | Not provided at time of registration |
| Study design | Randomised controlled trial |
| Countries of recruitment | France, Germany, Ireland, Italy, United Kingdom, United States of America |
| Disease/condition/study domain | Bipolar disorder |
| Participants - inclusion criteria |
For entry to the run-in phase:
1. Previous episode of mania (clinical diagnosis, guided by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) that merited treatment (whether or not treatment was provided) 2. Agreement between investigator and patient to commence/continue treatment to prevent relapse 3. It is considered clinically reasonable to try combination treatment with lithium and valproate semisodium For randomisation: 1. Uncertainty about which trial treatment would be best for the participant 2. Lithium plasma level 0.4 to 1.0 mmol/litre on stable dose of lithium 3. If valproate semisodium dose is less than 750 mg a day, the participant must have a valproic acid serum level of at least 50 µg/ml 4. The participant can tolerate the combination of lithium and valproate semisodium 5. Adherence during the run-in phase is judged satisfactory by the investigator |
| Participants - exclusion criteria |
1. Maintenance treatment is considered unnecessary
2. A particular maintenance treatment is definitely indicated or contraindicated, or the patient is unwilling to take one or other of the study treatments 3. A medical disorder or condition coexists which contraindicates either of the investigational drugs, e.g., pregnancy 4. The patient is not normally resident in the UK or is of no fixed abode |
| Anticipated start date | 01/07/2002 |
| Anticipated end date | 31/12/2005 |
| Status of trial | Completed |
| Patient information material | |
| Target number of participants | 231 |
| Interventions |
1. Lithium monotherapy
2. Valproate semisodium monotherapy 3. Lithium plus valproate semisodium combination therapy |
| Primary outcome measure(s) |
1. Hospital admission: the primary outcome will be the time to hospital admission during the scheduled randomised treatment period. Admission is a useful indicator of a severe relapse of illness because, since bed provision is now minimal, the clinical threshold for admission is high. Admission to hospital is a useful pragmatic outcome: the majority of patients and clinicians view admission as a negative event that an effective maintenance treatment would be expected to prevent. In certain sites, because some mental health services use intensive alternatives to hospital treatment, the primary outcome will need to be a comparable administrative event such as new attendance at a day patient facility or active home treatment. The appropriate primary outcome will be established with each site before the trial starts and, for the purposes of the trial, a proxy must be 7 days per week treatment at day hospital or 7 days per week home treatment or 24 hour admission to flats and hostel accommodation under regular staff supervision.
2. Concurrent use of adjunctive medication: although there is general agreement that admission to hospital is a clinically meaningful and measurable outcome, it is a somewhat insensitive measure of the less severe mood fluctuations that cause considerable disability in bipolar disorder. Furthermore, manic episodes are more likely than depressive episodes to result in hospital admission. The use of adjunctive antidepressant and antipsychotic medication and of mood stabilizers other than lithium and valproate semisodium will provide a measure of the occurrence of mood episodes that are not severe enough to lead to admission. |
| Secondary outcome measure(s) |
1. Global Assessment of Functioning Scale (GAF): the GAF is a brief scale of overall functioning of demonstrated reliability and validity that is used in routine clinical practice and in recent trials in bipolar disorder. The GAF will be used to provide an overall estimate of functioning during the previous year.
2. Deliberate self-harm: deliberate self-harm of suicidal intent (including suicide) is a common outcome in bipolar disorder and of obvious clinical importance. There is observational evidence that lithium therapy reduces the incidence of suicide and it is important to measure this outcome, although it is unlikely that BALANCE will have sufficient power to detect a treatment effect reliably. 3. Quality of life: the EuroQol (EQ-5D) will be used to assess quality of life. This questionnaire has been used successfully in two contemporary trials in psychiatry - the ongoing NHS R&D CUtLASS trial of atypical antipsychotics and the recent MRC-funded trial of cognitive behaviour therapy in bipolar disorder. 4. Adverse events: patients have identified adverse events and side-effects as being one of the main negative aspects of long term medication. Valproate semisodium is a newly licensed drug in the UK and it is essential to record the occurrence of all adverse events. 5. Withdrawal from study treatment: withdrawal from allocated treatment is a useful and pragmatic, although non-specific, measure of the overall acceptability and efficacy of a drug 6. Adherence to study medication: adherence to maintenance treatment is frequently overlooked in maintenance trials in bipolar disorder but is essential for interpreting the trial results |
| Sources of funding |
1. The Stanley Medical Research Institute (SMRI) (USA)
2. Sanofi-Aventis (UK) |
| Trial website | |
| Publications |
1. 2002 protocol in http://www.ncbi.nlm.nih.gov/pubmed/16946823
2. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20092882 |
| Contact name | Prof John Geddes |
| Address |
Department of Psychiatry
University of Oxford Warneford Hospital |
| City/town | Oxford |
| Zip/Postcode | OX3 7JX |
| Country | United Kingdom |
| Tel | +44 (0)1865 226480 |
| Fax | +44 (0)1865 793101 |
| john.geddes@psych.ox.ac.uk | |
| Sponsor | University of Oxford (UK) |
| Address |
University Offices
Wellington Place |
| City/town | Oxford |
| Zip/Postcode | OX1 2JD |
| Country | United Kingdom |
| Sponsor website: | http://www.ox.ac.uk/ |
| Date applied | 22/08/2005 |
| Last edited | 29/10/2010 |
| Date ISRCTN assigned | 10/10/2005 |
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| © 2012 ISRCTN unless otherwise stated. | |
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