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SchizophreniaPhase 4SMARTNCT01431092

Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia

A Phase 4 study testing Melatonin in people with Schizophrenia and Schizoaffective Disorder, run by Lone Baandrup at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

In this trial, researchers aim to investigate if prolonged-release melatonin can facilitate the withdrawal of chronic benzodiazepine administration in patients with schizophrenia. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Melatonin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
86 participants
Where
1 siteDenmark
Study dates
Oct 2011to Jun 2014
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients diagnosed with schizophrenia, schizoaffective disorder, or bipolar affective disorder (ICD-10 criteria for schizophrenia (F20), schizoaffective disorder (F25) or bipolar affective disorder (F31) must be fulfilled at inclusion or previously as documented by chart review; fulfillment of relevant DSM-IV-TR criteria will also be registered).
  • Treated with the same antipsychotic drug for at least 3 months before inclusion (change of dose, antipsychotic polypharmacy and prescription/discontinuation of add-on drugs allowed but the basic antipsychotic treatment should be the same).
  • Continuously treated with at least one benzodiazepine (chlordiazepoxide, diazepam, clobazam, clonazepam, flunitrazepam, nitrazepam, bromazepam, alprazolam, lorazepam, lormetazepam, oxazepam, triazolam) or benzodiazepine related drug (zolpidem, zopiclone, zaleplon) for at least 3 months before inclusion.
  • Age 18+.
  • Fertile women: negative pregnancy test at baseline and use of safe contraceptives (intrauterine devices or hormonal contraception) throughout the trial period and 1 day after withdrawal of trial medication. This does not apply to sterile or infertile participants, i.e. surgically sterilized or post menopausal (missing period for at least 12 months before inclusion) women.
  • Written informed consent.

Who cannot join

  • Known aggressive or violent behavior.
  • Mental retardation, pervasive developmental disorder, or dementia.
  • Epilepsy, terminal illness, severe comorbidity or unable to understand Danish.
  • Allergic to compounds in the trial medication (melatonin, lactose, starch, gelatin, talc).
  • Hepatic impairment (known diagnosis).
  • Pregnancy and nursing.
  • Missing informed consent.

Trial locations and contacts

1 site in 1 country.

Denmark1 site
  • Center for Neuropsychiatric Schizophrenia Research (CNSR)/Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), University of Copenhagen, Mental Health Centre Glostrup, Mental Health Services - Capital Region of Denmark

    Glostrup Municipality, 2600

Other trials in Denmark

About this study

Official title: Prolonged-release Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia: a Randomized Clinical Trial

In this trial, researchers aim to investigate if prolonged-release melatonin can facilitate the withdrawal of chronic benzodiazepine administration in patients with schizophrenia. Furthermore, researchers will investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life.

Read the detailed description

Treatment of schizophrenia frequently includes prolonged administration of benzodiazepines despite lack of evidence of its use. It is often difficult to discontinue use of benzodiazepines because of development of dependence.

After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily versus matching placebo, participants are required to slowly taper off their benzodiazepine dose towards no intake. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up.

The results from this trial will assess if melatonin has a role in withdrawing long-term benzodiazepine administration in schizophrenia patients. This group of patients is difficult to treat and therefore often subject to polypharmacy which may play a role in the reduced life expectancy compared to the background population. In addition, the data of the trial are also analyzed as an observational cohort design to investigate the association of benzodiazepine dose reduction/discontinuation with psychophysiology, cognition, sleep, quality of life, and other selected variables (not further described below, see trial protocol). Knowledge of these important clinical aspects is lacking in this group of patients.

Being tested
Placebo, Melatonin
Medical subject headings
Schizophrenia, Psychotic Disorders, Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PlaceboDrug

    Both Circadin and placebo are encapsulated in lactose containing gelatin capsules to optimize the blinding.

  • MelatoninDrug

    Also called Prolonged-release melatonin, Circadin®

    Prolonged-release melatonin (Circadin®) 2 mg, once daily, 1-2 hours before bedtime.

Study groups in NCT01431092
Study groupRoleWhat they receive
MelatoninExperimentalNot described
Receives: Drug: Melatonin
PlaceboPlacebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Benzodiazepine (including benzodiazepine related drugs) dose at 6 months follow-up.

    The general linear model is used with the outcome measure (dose after 6 months) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

    Measured: 6 months follow-up.

Secondary outcomes (7)
  1. Pattern of benzodiazepine dose over time.

    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

    Measured: 2, 4, and 6 months.

  2. The fraction of participants who has completely discontinued benzodiazepines 6 months after initiating trial medication.

    The analysis will be done using a logistic regression model where logit(p) is the dependent variable, p is the probability of completing the withdrawal, and a binary intervention indicator is the independent variable.

    Measured: 6 months follow-up.

  3. Pattern of P300 amplitude (psychophysiology) over time.

    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

    Measured: 2, 4, and 6 months.

  4. Pattern of Brief Assessment of Cognition in Schizophrenia (BACS) composite score over time.

    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

    Measured: 2, 4, and 6 months.

  5. Sleep efficiency (polysomnography) at 6 months follow-up.

    The general linear model is used with the outcome measure (sleep efficiency) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

    Measured: 6 months.

  6. Pittsburgh Sleep Quality Index (PSQI) global score at 6 months follow-up.

    The general linear model is used with the outcome measure (PSQI) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

    Measured: 6 months.

  7. Pattern of Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ-2) score over time.

    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric or a first order autoregressive.

    Measured: 2, 4, and 6 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Sep 2011 (estimated)
  2. Study startOct 2011
  3. Primary completionJun 2014
  4. Study completionJun 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
86 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01431092
Sponsor's protocol ID
2010-024065-46
Other IDs
2010-024065-46
Acronym
SMART
Status last verified
Jun 2014
First submitted
31 Aug 2011
Last updated
6 Jun 2014
Results posted
No
Data monitoring committee
No

Publications

  • Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD006391. doi: 10.1002/14651858.CD006391.

    PubMed 17253592
  • Monti JM, Monti D. Sleep disturbance in schizophrenia. Int Rev Psychiatry. 2005 Aug;17(4):247-53. doi: 10.1080/09540260500104516.

    PubMed 16194796
  • Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006 Feb 18;332(7538):385-93. doi: 10.1136/bmj.38731.532766.F6. Epub 2006 Feb 10.

    PubMed 16473858
  • Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry. 2000 May;61(5):373-7. doi: 10.4088/jcp.v61n0509.

    PubMed 10847313
  • Suresh Kumar PN, Andrade C, Bhakta SG, Singh NM. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2007 Feb;68(2):237-41. doi: 10.4088/jcp.v68n0208.

    PubMed 17335321
  • Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med. 1999 Nov 8;159(20):2456-60. doi: 10.1001/archinte.159.20.2456.

    PubMed 10665894
  • Baandrup L, Fasmer OB, Glenthoj BY, Jennum PJ. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial. BMC Psychiatry. 2016 Oct 13;16(1):348. doi: 10.1186/s12888-016-1062-8.

    PubMed 27737649
  • Baandrup L, Fagerlund B, Jennum P, Lublin H, Hansen JL, Winkel P, Gluud C, Oranje B, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol. BMC Psychiatry. 2011 Oct 5;11:160. doi: 10.1186/1471-244X-11-160.

    PubMed 21975110

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Melatonin in people with Schizophrenia and Schizoaffective Disorder, run by Lone Baandrup at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Benzodiazepine (including benzodiazepine related drugs) dose at 6 months follow-up. (time frame: 6 months follow-up.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01431092, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jun 2014.

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