Ignite Creation Date:
2024-05-05 @ 11:43 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00114595
Status:
COMPLETED
Last Update Posted:
2005-06-24
First Post:
2005-06-15
Brief Title:
Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
Sponsor:
University of Stellenbosch
Organization:
University of Stellenbosch
Study Overview
Official Title:
A Double-Blind Randomised Parallel-Group Comparison of Ethyl-Eicosapentaenoic Acid Ethyl-EPA Versus Placebo as Add-on Medication in Patients With Established Tardive Dyskinesia
Status:
COMPLETED
Status Verified Date:
2005-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Tardive dyskinesia is a common complication of conventional antipsychotic treatment in subjects with schizophrenia This study investigates whether the addition of the omega-3 fatty acid ethyl-eicosapentaenoic acid EPA to usual treatment improves movement disorder in 84 schizophrenia subjects with established tardive dyskinesia The initial double-blinded randomised trial duration is 12 weeks followed by further 46 weeks of open-label treatment
Detailed Description:
Background
One of the major limitations of conventional antipsychotics is their high propensity to cause extrapyramidal symptoms EPS Tardive dyskinesia TD in particular causes problems insofar as it is common and resistant to treatment TD is under-recognised in clinical settings However prevalence studies indicate that 5 of patients treated with conventional antipsychotics develop TD each year for the first eight years with an average reported prevalence rate in the region between 17 and 23 Although in the majority of cases the disorder is mild and not distressing TD contributes to social and vocational impairment as well as to the further stigmatization of the illness A minority develop severe symptoms which are extremely distressing and disabling and may even be life-threatening Treatment of TD is difficult Dose-reduction or discontinuation of antipsychotic medication may paradoxically result in exacerbation of the TD symptoms and also run the risk of precipitating a psychotic relapse With the exception of clozapine and possibly botulinum toxin for tardive dystonia vitamin E7 and vitamin B6 little evidence exists to indicate efficacy for any treatment modality for TD
The novel antipsychotics have had a huge impact upon the treatment of schizophrenia The major advantage of these agents over their predecessors is their reduced risk of inducing EPS and probably TD However high acquisition costs have limited their availability worldwide and many patients will continue to be exposed to conventional antipsychotics for the foreseeable future Development of an effective and affordable treatment for TD would therefore be of great benefit
Rationale for this trial
One possible candidate for an effective and affordable treatment for TD is eicosapentaenoic acid EPA an omega-3 polyunsaturated fatty acid obtained from marine and plant sources In addition to the evidence suggesting that EPA may improve the symptoms of schizophrenia when combined with standard antipsychotic treatment there is also reason to believe that EPA may have a role in the treatment of TD An open study in 20 hospitalised subjects with chronic schizophrenia reported a significant inverse correlation between dietary EPA and severity of TD Treatment of these subjects with a standard EPA-rich marine oil for 6 weeks resulted in significant improvement in TD We recently completed a 12-week randomised double-blind study with ethyl-EPA 3gday versus placebo as add-on to standard antipsychotic treatment in forty subjects with chronic refractory schizophrenia submitted for publication While there were no differences between the groups for the changes in the Extrapyramidal Symptom Rating Scale ESRS for parkinsonism dystonia or akathisia scores the ethyl-EPA group showed a significantly greater reduction in ESRS dyskinesia scores at 12 weeks p0008 This result is potentially of great importance Given the chronic nature of illness in our sample most of these dyskinetic symptoms are likely to have been due to TD This same study also reported a significant advantage for the ethyl-EPA group in terms of overall symptom reduction PANSS total p003 and analysis of co-variance indicated an association between PANSS total score reduction and ESRS dyskinesia score reduction
This study will also investigate whether EPA may have an antipsychotic effect that is associated with an anti-dyskinetic effect It has been suggested that an intrinsic aspect of the disease process of schizophrenia predisposes individuals with severe forms of the illness to antipsychotic-induced TD These authors hypothesise that pathologic over-activity of mesolimbic and mesocortical dopamine neural systems may mediate persistence of psychotic symptoms despite adequate treatment while increased TD vulnerability may be caused by overactive nigrostriatal dopamine activity from this process that is enhanced by antipsychotic drug exposure If this is so then it is possible that EPA could by a common mechanism have both an anti-dyskinetic and antipsychotic effect This would explain the significant association that we found between reduction in dyskinesia scores and reduction in overall symptoms in our preliminary study unpublished
Objectives
Primary objective
To compare the efficacy of ethyl-eicosapentaenoic acid ethyl-EPA versus placebo as supplementary medication in reducing symptoms of tardive dyskinesia TD
Secondary objectives
To compare the efficacy of ethyl-EPA versus placebo as supplementary medication in reducing symptoms of psychosis in these subjects
To assess whether there is an association between the antidyskinetic and antipsychotic actions of ethyl-EPA
To investigate the safety and tolerability of ethyl-EPA
Trial design
This is a double-blind randomised parallel-group comparison of ethyl-EPA and placebo in the treatment of established TD in patients with schizophrenia or schizo-affective disorder There will be a pre-trial screen following which subjects will enter the randomised treatment phase for 12 weeks Responders will then be offered the option of open add-on treatment with ethyl-EPA for a further 40 weeks
Patient selection
Source of patients In- and out-patients from state hospital and community psychiatric services in the greater Cape Town area
Number of patients Recruitment will stop when 84 eligible patients have been randomised to trial treatment A recruitment period of 12 to 18 months is anticipated
Pre-trial screenings
Written informed consent will be obtained prior to screening procedures All patients will be screened to assess their eligibility for the trial The screening visit will include the following
Informed consent
Psychiatric history
Medical history
Physical examination
Diagnosis
Demography
Vital signs
Laboratory tests
Trial treatment
Subjects will be randomly assigned to receive either an encapsulated ethyl-EPA supplement 2 gday 2X500 mg capsules twice daily Laxdale Ltd or placebo medicinal liquid paraffin BP 2 gday in addition to the medication that they had been receiving for the duration of the study Ethyl EPA is a highly purified derivative of fish-oil The Food and Drug Administration has affirmed the status of fish-oil as generally recognised as safe with EPA doses up to 3 gday Trial supplies will be packed by an independent contract clinical trials supplies company DHP who will prepare the placebo and active packs for the entire trial and assign the randomisation numbers to the packs The randomisation code will be broken after completion of the trial
Concomitant treatment
Only subjects who have been on stable medication for the preceding 6 weeks will be considered Psychotropic medication will be fixed for the duration of the trial
Anticholinergic medication
Anticholinergic medication may be prescribed following randomisation for treatment-emergent extrapyramidal symptoms EPS
Other psychotropic medication
Patients who were stabilised on other psychotropic medications anxiolytic hypnotic antidepressant mood stabilising before entry to the trial may continue on these medications Anxiolytic or hypnotic medication may be prescribed for treatment-emergent conditions eg insomnia or acute anxiety
Other concomitant medication
Any medication for physical conditions that was taken prior to the commencement of the trial may be continued
Medication for other conditions that arise during the course of the trial will be permitted at the investigators discretion
Other omega-3 fatty acid preparations are not permitted
Trial methods
Assessments
Primary outcome measure
Change in Extrapyramidal Symptom Rating Scale ESRS dyskinesia score from baseline to week 12
Secondary outcome measures for effect on TD
Change in ESRS for parkinsonism dystonia akathisia and total scores from baseline to week 12
The proportion of subjects in each group who achieve a 30 reduction in ESRS total scores at week 12
Time to remission defined as a 30 reduction in ESRS total scores
The proportion of patients achieving a CGI Severity of TD score of 3 at 12 weeks
Secondary outcome measures for effect on psychosis
Change in Positive and Negative Syndrome Scale PANSS total positive negative and general psychopathology scores from baseline to week 12
Assessment of relationship between change in TD scores and change in symptoms of psychosis
Correlations between the above measures of TD and psychosis symptoms will be sought
Secondary outcome measures for safety and tolerability
1 The incidence of treatment-emergent EPS will be assessed at each visit by the proportion of subjects requiring anticholinergic medication
2 Other tolerability and safety measures will include the reporting of adverse events vital signs and weight
3 All concurrent medication will be recorded
4 A physical examination will be carried out at visit 1
5 Laboratory tests
In addition to liver functions haematology and prolactin the following tests will be done bleeding time fasting blood sugar and fasting lipogram Although EPA is classified by the FDA as Generally Recognised as Safe in doses up to 3gday there have been reports of adverse effects on bleeding time glycaemic control and low-density lipoprotein cholesterol
Venepuncture will be performed at the pre-trial screen visit 1 visit 4 week 4 and at endpoint visit 6
The following tests will be performed
alkaline phosphatase alanine aminotransferase aspartate aminotransferase
haemoglobin platelet count total white cell count differential white cell count
prolactin
bleeding time
lipogram fasting
blood-sugar fasting
Adverse events and patient withdrawals
Any new medical condition or the deterioration of a pre-existing medical condition occurring during the wash-out and randomised phase will be recorded on the case record forms CRFs
Withdrawal from trial
This may occur for any of the following reasons
Protocol violation
Withdrawal of consent
Deterioration in the patients condition or lack of efficacy
The occurrence of an adverse event
Patient lost to follow-up
Data management
All the data will be recorded in the case record forms Two trained persons will independently perform a double data entry in a database Verifications will be conducted during each of the two data entry processes and after comparison of the double data entry
Statistical plan
Statistical analyses will be performed by a biostatistician The primary intent of this study is to evaluate the ability of ethyl-EPA versus placebo to reduce TD symptoms in 12 weeks of treatment The principal null hypothesis is therefore that ethyl-EPA will not differ from placebo on the primary efficacy measure
Sample size estimation
We obtained an estimate of the variability of the change in ESRS dyskinesia scores after 12 weeks of treatment with ethyl-EPA and placebo as add-on to their previous antipsychotic medication from a previous trial conducted at our centre which gave 213 as the standard deviation unpublished Using this estimate and with a significance level of 5 and 90 power 32 patients per randomised group would be sufficient to detect a 175 point difference in change in ESRS dyskinesia scores the difference obtained in our preliminary study from baseline to endpoint Allowing for an estimated withdrawal rate of 30 we will need to recruit 42 patients per treatment group into this study
Statistical Analysis
A single statistical analysis will be performed at the end of the study All of the tests will be interpreted at 5 significance level 2-tailed Data analyses will be performed with Statistica software StatSoft Inc
Analysis of efficacy
Primary efficacy endpoint
The primary efficacy measure will be the change in the ESRS dyskinesia score from baseline to endpoint This will be analysed using analysis of covariance including baseline score treatment received the centre and the centre-by-treatment interaction as factors Comparisons will be performed by intention-to-treat with last observation carried forward LOCF An additional analysis will be performed on the per-protocol population and an analysis will be performed on the per-protocol population without the LOCF to assess the effects of any withdrawals from this trial
Secondary efficacy endpoints
The ESRS scores for parkinsonism akathisia and dystonia as well as the PANSS total and subscale scores will be analysed in the same way as the ESRS dyskinesia score
Both p-values and 95 confidence intervals will be presented to evaluate the main comparison of interest
Students t test and Pearsons Product Moment Correlation Coefficient will be used for univariate differences and correlations respectively between numeric variables To determine the contributions of individual variables toward TD scores significant univariate results will be followed with regression analysis with simultaneous entry using the method of least squares
The significance of the contributions of the predictor variables to the proportion of patients classed as responders will be analysed using logistic regression
Time to remission will be calculated Comparison of the time to remission for the two groups will be in terms of Kaplan-Meier estimates for their survival curves Controlling for covariates will be done by Cox proportional hazard regression
All patients receiving at least one dose of trial medication will be included in the assessments of safetytolerability
Adverse events
Adverse event frequencies will be summarised by body system All adverse events will be presented in a table sorted by body system classification along with degree of severity and relationship to treatment Adverse events will be listed in full in an Appendix
Laboratory tests
Laboratory findings haematology and biochemistry will be summarized and evaluated using the laboratorys normal ranges The data will be tabulated in normalabnormal categories Shift tables will be constructed where appropriate to summarize changes in the data over the course of testing
Vital signs and physical examination
Systolic blood pressure diastolic blood pressure double pressure product and heart rate will be summarized descriptively by treatment group Frequency tables will be calculated for the respective physical examination variables
Ethical considerations
The study will comply with The Declaration of Helsinki Republic of South Africa Revision 1996 and ICH Guidelines for Good Clinical Practice 1997
The trial will be submitted for approval to the Institutional Review Board of the University of Stellenbosch and the Medicines Control Council of South Africa regulatory authority
One of the major limitations of conventional antipsychotics is their high propensity to cause extrapyramidal symptoms EPS Tardive dyskinesia TD in particular causes problems insofar as it is common and resistant to treatment TD is under-recognised in clinical settings However prevalence studies indicate that 5 of patients treated with conventional antipsychotics develop TD each year for the first eight years with an average reported prevalence rate in the region between 17 and 23 Although in the majority of cases the disorder is mild and not distressing TD contributes to social and vocational impairment as well as to the further stigmatization of the illness A minority develop severe symptoms which are extremely distressing and disabling and may even be life-threatening Treatment of TD is difficult Dose-reduction or discontinuation of antipsychotic medication may paradoxically result in exacerbation of the TD symptoms and also run the risk of precipitating a psychotic relapse With the exception of clozapine and possibly botulinum toxin for tardive dystonia vitamin E7 and vitamin B6 little evidence exists to indicate efficacy for any treatment modality for TD
The novel antipsychotics have had a huge impact upon the treatment of schizophrenia The major advantage of these agents over their predecessors is their reduced risk of inducing EPS and probably TD However high acquisition costs have limited their availability worldwide and many patients will continue to be exposed to conventional antipsychotics for the foreseeable future Development of an effective and affordable treatment for TD would therefore be of great benefit
Rationale for this trial
One possible candidate for an effective and affordable treatment for TD is eicosapentaenoic acid EPA an omega-3 polyunsaturated fatty acid obtained from marine and plant sources In addition to the evidence suggesting that EPA may improve the symptoms of schizophrenia when combined with standard antipsychotic treatment there is also reason to believe that EPA may have a role in the treatment of TD An open study in 20 hospitalised subjects with chronic schizophrenia reported a significant inverse correlation between dietary EPA and severity of TD Treatment of these subjects with a standard EPA-rich marine oil for 6 weeks resulted in significant improvement in TD We recently completed a 12-week randomised double-blind study with ethyl-EPA 3gday versus placebo as add-on to standard antipsychotic treatment in forty subjects with chronic refractory schizophrenia submitted for publication While there were no differences between the groups for the changes in the Extrapyramidal Symptom Rating Scale ESRS for parkinsonism dystonia or akathisia scores the ethyl-EPA group showed a significantly greater reduction in ESRS dyskinesia scores at 12 weeks p0008 This result is potentially of great importance Given the chronic nature of illness in our sample most of these dyskinetic symptoms are likely to have been due to TD This same study also reported a significant advantage for the ethyl-EPA group in terms of overall symptom reduction PANSS total p003 and analysis of co-variance indicated an association between PANSS total score reduction and ESRS dyskinesia score reduction
This study will also investigate whether EPA may have an antipsychotic effect that is associated with an anti-dyskinetic effect It has been suggested that an intrinsic aspect of the disease process of schizophrenia predisposes individuals with severe forms of the illness to antipsychotic-induced TD These authors hypothesise that pathologic over-activity of mesolimbic and mesocortical dopamine neural systems may mediate persistence of psychotic symptoms despite adequate treatment while increased TD vulnerability may be caused by overactive nigrostriatal dopamine activity from this process that is enhanced by antipsychotic drug exposure If this is so then it is possible that EPA could by a common mechanism have both an anti-dyskinetic and antipsychotic effect This would explain the significant association that we found between reduction in dyskinesia scores and reduction in overall symptoms in our preliminary study unpublished
Objectives
Primary objective
To compare the efficacy of ethyl-eicosapentaenoic acid ethyl-EPA versus placebo as supplementary medication in reducing symptoms of tardive dyskinesia TD
Secondary objectives
To compare the efficacy of ethyl-EPA versus placebo as supplementary medication in reducing symptoms of psychosis in these subjects
To assess whether there is an association between the antidyskinetic and antipsychotic actions of ethyl-EPA
To investigate the safety and tolerability of ethyl-EPA
Trial design
This is a double-blind randomised parallel-group comparison of ethyl-EPA and placebo in the treatment of established TD in patients with schizophrenia or schizo-affective disorder There will be a pre-trial screen following which subjects will enter the randomised treatment phase for 12 weeks Responders will then be offered the option of open add-on treatment with ethyl-EPA for a further 40 weeks
Patient selection
Source of patients In- and out-patients from state hospital and community psychiatric services in the greater Cape Town area
Number of patients Recruitment will stop when 84 eligible patients have been randomised to trial treatment A recruitment period of 12 to 18 months is anticipated
Pre-trial screenings
Written informed consent will be obtained prior to screening procedures All patients will be screened to assess their eligibility for the trial The screening visit will include the following
Informed consent
Psychiatric history
Medical history
Physical examination
Diagnosis
Demography
Vital signs
Laboratory tests
Trial treatment
Subjects will be randomly assigned to receive either an encapsulated ethyl-EPA supplement 2 gday 2X500 mg capsules twice daily Laxdale Ltd or placebo medicinal liquid paraffin BP 2 gday in addition to the medication that they had been receiving for the duration of the study Ethyl EPA is a highly purified derivative of fish-oil The Food and Drug Administration has affirmed the status of fish-oil as generally recognised as safe with EPA doses up to 3 gday Trial supplies will be packed by an independent contract clinical trials supplies company DHP who will prepare the placebo and active packs for the entire trial and assign the randomisation numbers to the packs The randomisation code will be broken after completion of the trial
Concomitant treatment
Only subjects who have been on stable medication for the preceding 6 weeks will be considered Psychotropic medication will be fixed for the duration of the trial
Anticholinergic medication
Anticholinergic medication may be prescribed following randomisation for treatment-emergent extrapyramidal symptoms EPS
Other psychotropic medication
Patients who were stabilised on other psychotropic medications anxiolytic hypnotic antidepressant mood stabilising before entry to the trial may continue on these medications Anxiolytic or hypnotic medication may be prescribed for treatment-emergent conditions eg insomnia or acute anxiety
Other concomitant medication
Any medication for physical conditions that was taken prior to the commencement of the trial may be continued
Medication for other conditions that arise during the course of the trial will be permitted at the investigators discretion
Other omega-3 fatty acid preparations are not permitted
Trial methods
Assessments
Primary outcome measure
Change in Extrapyramidal Symptom Rating Scale ESRS dyskinesia score from baseline to week 12
Secondary outcome measures for effect on TD
Change in ESRS for parkinsonism dystonia akathisia and total scores from baseline to week 12
The proportion of subjects in each group who achieve a 30 reduction in ESRS total scores at week 12
Time to remission defined as a 30 reduction in ESRS total scores
The proportion of patients achieving a CGI Severity of TD score of 3 at 12 weeks
Secondary outcome measures for effect on psychosis
Change in Positive and Negative Syndrome Scale PANSS total positive negative and general psychopathology scores from baseline to week 12
Assessment of relationship between change in TD scores and change in symptoms of psychosis
Correlations between the above measures of TD and psychosis symptoms will be sought
Secondary outcome measures for safety and tolerability
1 The incidence of treatment-emergent EPS will be assessed at each visit by the proportion of subjects requiring anticholinergic medication
2 Other tolerability and safety measures will include the reporting of adverse events vital signs and weight
3 All concurrent medication will be recorded
4 A physical examination will be carried out at visit 1
5 Laboratory tests
In addition to liver functions haematology and prolactin the following tests will be done bleeding time fasting blood sugar and fasting lipogram Although EPA is classified by the FDA as Generally Recognised as Safe in doses up to 3gday there have been reports of adverse effects on bleeding time glycaemic control and low-density lipoprotein cholesterol
Venepuncture will be performed at the pre-trial screen visit 1 visit 4 week 4 and at endpoint visit 6
The following tests will be performed
alkaline phosphatase alanine aminotransferase aspartate aminotransferase
haemoglobin platelet count total white cell count differential white cell count
prolactin
bleeding time
lipogram fasting
blood-sugar fasting
Adverse events and patient withdrawals
Any new medical condition or the deterioration of a pre-existing medical condition occurring during the wash-out and randomised phase will be recorded on the case record forms CRFs
Withdrawal from trial
This may occur for any of the following reasons
Protocol violation
Withdrawal of consent
Deterioration in the patients condition or lack of efficacy
The occurrence of an adverse event
Patient lost to follow-up
Data management
All the data will be recorded in the case record forms Two trained persons will independently perform a double data entry in a database Verifications will be conducted during each of the two data entry processes and after comparison of the double data entry
Statistical plan
Statistical analyses will be performed by a biostatistician The primary intent of this study is to evaluate the ability of ethyl-EPA versus placebo to reduce TD symptoms in 12 weeks of treatment The principal null hypothesis is therefore that ethyl-EPA will not differ from placebo on the primary efficacy measure
Sample size estimation
We obtained an estimate of the variability of the change in ESRS dyskinesia scores after 12 weeks of treatment with ethyl-EPA and placebo as add-on to their previous antipsychotic medication from a previous trial conducted at our centre which gave 213 as the standard deviation unpublished Using this estimate and with a significance level of 5 and 90 power 32 patients per randomised group would be sufficient to detect a 175 point difference in change in ESRS dyskinesia scores the difference obtained in our preliminary study from baseline to endpoint Allowing for an estimated withdrawal rate of 30 we will need to recruit 42 patients per treatment group into this study
Statistical Analysis
A single statistical analysis will be performed at the end of the study All of the tests will be interpreted at 5 significance level 2-tailed Data analyses will be performed with Statistica software StatSoft Inc
Analysis of efficacy
Primary efficacy endpoint
The primary efficacy measure will be the change in the ESRS dyskinesia score from baseline to endpoint This will be analysed using analysis of covariance including baseline score treatment received the centre and the centre-by-treatment interaction as factors Comparisons will be performed by intention-to-treat with last observation carried forward LOCF An additional analysis will be performed on the per-protocol population and an analysis will be performed on the per-protocol population without the LOCF to assess the effects of any withdrawals from this trial
Secondary efficacy endpoints
The ESRS scores for parkinsonism akathisia and dystonia as well as the PANSS total and subscale scores will be analysed in the same way as the ESRS dyskinesia score
Both p-values and 95 confidence intervals will be presented to evaluate the main comparison of interest
Students t test and Pearsons Product Moment Correlation Coefficient will be used for univariate differences and correlations respectively between numeric variables To determine the contributions of individual variables toward TD scores significant univariate results will be followed with regression analysis with simultaneous entry using the method of least squares
The significance of the contributions of the predictor variables to the proportion of patients classed as responders will be analysed using logistic regression
Time to remission will be calculated Comparison of the time to remission for the two groups will be in terms of Kaplan-Meier estimates for their survival curves Controlling for covariates will be done by Cox proportional hazard regression
All patients receiving at least one dose of trial medication will be included in the assessments of safetytolerability
Adverse events
Adverse event frequencies will be summarised by body system All adverse events will be presented in a table sorted by body system classification along with degree of severity and relationship to treatment Adverse events will be listed in full in an Appendix
Laboratory tests
Laboratory findings haematology and biochemistry will be summarized and evaluated using the laboratorys normal ranges The data will be tabulated in normalabnormal categories Shift tables will be constructed where appropriate to summarize changes in the data over the course of testing
Vital signs and physical examination
Systolic blood pressure diastolic blood pressure double pressure product and heart rate will be summarized descriptively by treatment group Frequency tables will be calculated for the respective physical examination variables
Ethical considerations
The study will comply with The Declaration of Helsinki Republic of South Africa Revision 1996 and ICH Guidelines for Good Clinical Practice 1997
The trial will be submitted for approval to the Institutional Review Board of the University of Stellenbosch and the Medicines Control Council of South Africa regulatory authority
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 02T-140 | None | None | None |
| N2190802 | None | None | None |