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Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia (SMART)

Primary Purpose

Schizophrenia, Schizoaffective Disorder, Bipolar Affective Disorder

Status
Completed
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Placebo
Melatonin
Sponsored by
Lone Baandrup
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Schizophrenia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Sites / Locations

  • 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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Melatonin

Placebo

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
August 31, 2011
Last Updated
June 5, 2014
Sponsor
Lone Baandrup
Collaborators
Glostrup University Hospital, Copenhagen, Copenhagen Trial Unit, Center for Clinical Intervention Research
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1. Study Identification

Unique Protocol Identification Number
NCT01431092
Brief Title
Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia
Acronym
SMART
Official Title
Prolonged-release Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia: a Randomized Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
June 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lone Baandrup
Collaborators
Glostrup University Hospital, Copenhagen, Copenhagen Trial Unit, Center for Clinical Intervention Research

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia, Schizoaffective Disorder, Bipolar Affective Disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
86 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Melatonin
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Both Circadin and placebo are encapsulated in lactose containing gelatin capsules to optimize the blinding.
Intervention Type
Drug
Intervention Name(s)
Melatonin
Other Intervention Name(s)
Prolonged-release melatonin, Circadin®
Intervention Description
Prolonged-release melatonin (Circadin®) 2 mg, once daily, 1-2 hours before bedtime.
Primary Outcome Measure Information:
Title
Benzodiazepine (including benzodiazepine related drugs) dose at 6 months follow-up.
Description
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.
Time Frame
6 months follow-up.
Secondary Outcome Measure Information:
Title
Pattern of benzodiazepine dose over time.
Description
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.
Time Frame
2, 4, and 6 months.
Title
The fraction of participants who has completely discontinued benzodiazepines 6 months after initiating trial medication.
Description
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.
Time Frame
6 months follow-up.
Title
Pattern of P300 amplitude (psychophysiology) over time.
Description
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.
Time Frame
2, 4, and 6 months.
Title
Pattern of Brief Assessment of Cognition in Schizophrenia (BACS) composite score over time.
Description
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.
Time Frame
2, 4, and 6 months.
Title
Sleep efficiency (polysomnography) at 6 months follow-up.
Description
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.
Time Frame
6 months.
Title
Pittsburgh Sleep Quality Index (PSQI) global score at 6 months follow-up.
Description
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.
Time Frame
6 months.
Title
Pattern of Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ-2) score over time.
Description
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.
Time Frame
2, 4, and 6 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lone Baandrup, MD, PhD
Organizational Affiliation
CNSR/CINS
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Birte Glenthøj, MD, MSc
Organizational Affiliation
CNSR/CINS
Official's Role
Study Chair
Facility Information:
Facility Name
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
City
Glostrup
ZIP/Postal Code
2600
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
17253592
Citation
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.
Results Reference
background
PubMed Identifier
16194796
Citation
Monti JM, Monti D. Sleep disturbance in schizophrenia. Int Rev Psychiatry. 2005 Aug;17(4):247-53. doi: 10.1080/09540260500104516.
Results Reference
background
PubMed Identifier
16473858
Citation
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.
Results Reference
background
PubMed Identifier
10847313
Citation
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.
Results Reference
background
PubMed Identifier
17335321
Citation
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.
Results Reference
background
PubMed Identifier
10665894
Citation
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.
Results Reference
background
PubMed Identifier
27737649
Citation
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.
Results Reference
derived
PubMed Identifier
21975110
Citation
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.
Results Reference
derived

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Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia

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