Safety of Acamprosate for Alcohol Dependence in the Elderly: An Open-Label Study (SAFADIE)
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 60 - Any |
| Updated: | 4/2/2016 |
| Start Date: | December 2006 |
| End Date: | December 2008 |
| Contact: | Florian Birkmayer, M.D. |
| Email: | fbirkmayer@salud.unm.edu |
| Phone: | 505-272-2223 |
Safety of Acamprosate for Alcohol Dependence in the Elderly: An Open-Label Study
Alcohol abuse and dependence are very prevalent and result in significant morbidity,
mortality and cost to society (Harwood 2000). Pharmacotherapies to assist with alcohol
dependence consist of disulfiram, naltrexone and acamprosate. Of these, acamprosate is
unique in that it is not metabolized by the liver, but rather completely excreted renally.
In contrast, naltrexone is metabolized by the CYP450 system of the liver and less than 2% is
excreted unchanged and can cause liver damage (PDR 2005). Multiple cases of hepatitis,
including both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in
transplantation or death, have been reported with administration of disulfiram (PDR 2005).
The incidence of liver disease among alcoholics is high and increases with age and years of
drinking and this may preclude the use of antabuse or naltrexone to help alcohol dependent
patients with liver disease or that are elderly . Thus acamprosate has a unique safety
profile that would make it ideally suited for treating alcohol dependence in the elderly,
even in the presence of hepatic impairment. The current study is to evaluate the safety
profile of acamprosate in elderly patients with alcohol dependence.
Acamprosate, calcium acetyl homotaurinate, has been approved in most European countries and
the U.S. for the maintenance of abstinence in recently detoxified alcoholics. The mechanism
of action involves primarily the restoration of a normal N-methyl- D -aspartate (NMDA)
receptor tone in glutamatergic systems (Rammes et al 2001). Several trials of acamprosate
confirm its efficacy in the maintenance of abstinence in alcohol dependence (Lesch et al.
2001; Slattery et al. 2003; Mann et al. 2004; Verheul et al. 2004). It also reduces the
severity of relapse in alcoholics in abstinence based treatment programs (Chick et al.
2003). There is limited data on the safety of acamprosate in the elderly (PDR 2005).
For the purposes of this study, elderly will be defined as 60 years or older.
STUDY OBJECTIVE: To determine the short-term safety of Acamprosate in the treatment of
alcohol dependence in the elderly.
mortality and cost to society (Harwood 2000). Pharmacotherapies to assist with alcohol
dependence consist of disulfiram, naltrexone and acamprosate. Of these, acamprosate is
unique in that it is not metabolized by the liver, but rather completely excreted renally.
In contrast, naltrexone is metabolized by the CYP450 system of the liver and less than 2% is
excreted unchanged and can cause liver damage (PDR 2005). Multiple cases of hepatitis,
including both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in
transplantation or death, have been reported with administration of disulfiram (PDR 2005).
The incidence of liver disease among alcoholics is high and increases with age and years of
drinking and this may preclude the use of antabuse or naltrexone to help alcohol dependent
patients with liver disease or that are elderly . Thus acamprosate has a unique safety
profile that would make it ideally suited for treating alcohol dependence in the elderly,
even in the presence of hepatic impairment. The current study is to evaluate the safety
profile of acamprosate in elderly patients with alcohol dependence.
Acamprosate, calcium acetyl homotaurinate, has been approved in most European countries and
the U.S. for the maintenance of abstinence in recently detoxified alcoholics. The mechanism
of action involves primarily the restoration of a normal N-methyl- D -aspartate (NMDA)
receptor tone in glutamatergic systems (Rammes et al 2001). Several trials of acamprosate
confirm its efficacy in the maintenance of abstinence in alcohol dependence (Lesch et al.
2001; Slattery et al. 2003; Mann et al. 2004; Verheul et al. 2004). It also reduces the
severity of relapse in alcoholics in abstinence based treatment programs (Chick et al.
2003). There is limited data on the safety of acamprosate in the elderly (PDR 2005).
For the purposes of this study, elderly will be defined as 60 years or older.
STUDY OBJECTIVE: To determine the short-term safety of Acamprosate in the treatment of
alcohol dependence in the elderly.
STUDY DESIGN: This trial will be conducted as an open-label, fixed dose design for safety of
Acamprosate in the elderly. Subjects will receive Acamprosate for 12 weeks. The schedule of
visits will include screening, baseline and three monthly follow-up visits at days 30, 60
and 90. We will recruit 25 subjects in the total study period of 15 month.
Regarding the number of subjects, chi-squared analysis of the total number of side effects
(61%, i.e. 1230 out of 2018 subjects in prior studies) and the possible number of subjects
in the study with side effects (from 0 to 25), indicates that a significant (alpha=0.05)
difference from the previously observed rate would occur if less than 11 (p<=0.05) or more
than 20 (p<=0.025) subjects report side effects. Side effects in 11 to 20 subjects would be
nonsignificantly different from the previously published rates. Thus 25 subjects are
sufficient to detect significant deviation in frequency of overall side effects in this
sample compared to the subjects in prior studies. Total number of side effects was used for
this calculation because there is no single common or significant side effect that would
lend itself as an appropriate surrogate for the side effects overall.
During the course of the study subjects will be supplied with 333mg tablets of Acamprosate
provided by the Sponsor. The study medication will be administered at a dose of 666mg (=two
tablets) three times a day for subjects with a creatinine clearance >50. The dose will be
333mg three times a day for subjects with a creatinine clearance in the range of 30-50.
Safety will be monitored by subject's report of adverse events at all treatment visits
throughout both, open label and double blind phases of the Trial. The report of adverse
events or new symptoms by the subject will be reviewed and summarized. This may also include
any clinically significant changes in the vital signs (blood pressure and pulse readings,
weight, temperature), physical examinations, laboratory evaluations (blood chemistry,
hematology, urinalysis, EKG) and recording of concomitant treatment. A DSMB plan has been
set up.
Treatment compliance will be monitored by counts of returned medication, and subjects are to
be counseled if they do not adhere, or if they are thought to be at risk for not adhering to
the medication regimen.
Acamprosate in the elderly. Subjects will receive Acamprosate for 12 weeks. The schedule of
visits will include screening, baseline and three monthly follow-up visits at days 30, 60
and 90. We will recruit 25 subjects in the total study period of 15 month.
Regarding the number of subjects, chi-squared analysis of the total number of side effects
(61%, i.e. 1230 out of 2018 subjects in prior studies) and the possible number of subjects
in the study with side effects (from 0 to 25), indicates that a significant (alpha=0.05)
difference from the previously observed rate would occur if less than 11 (p<=0.05) or more
than 20 (p<=0.025) subjects report side effects. Side effects in 11 to 20 subjects would be
nonsignificantly different from the previously published rates. Thus 25 subjects are
sufficient to detect significant deviation in frequency of overall side effects in this
sample compared to the subjects in prior studies. Total number of side effects was used for
this calculation because there is no single common or significant side effect that would
lend itself as an appropriate surrogate for the side effects overall.
During the course of the study subjects will be supplied with 333mg tablets of Acamprosate
provided by the Sponsor. The study medication will be administered at a dose of 666mg (=two
tablets) three times a day for subjects with a creatinine clearance >50. The dose will be
333mg three times a day for subjects with a creatinine clearance in the range of 30-50.
Safety will be monitored by subject's report of adverse events at all treatment visits
throughout both, open label and double blind phases of the Trial. The report of adverse
events or new symptoms by the subject will be reviewed and summarized. This may also include
any clinically significant changes in the vital signs (blood pressure and pulse readings,
weight, temperature), physical examinations, laboratory evaluations (blood chemistry,
hematology, urinalysis, EKG) and recording of concomitant treatment. A DSMB plan has been
set up.
Treatment compliance will be monitored by counts of returned medication, and subjects are to
be counseled if they do not adhere, or if they are thought to be at risk for not adhering to
the medication regimen.
Inclusion Criteria:
1. Patients, men and women, age 60 and older.
2. Patients with Alcohol Dependence as determined by SCID I section for substance use
disorders who are not in full sustained remission.
3. Patients who have consumed significant amounts of alcohol in the past 30 days, as
determined by Time Line Follow Back report by patient and patient's spouse, partner
or friend. Significant amounts is defined for these purposes as at least one episode
of 5 or more drinks, with a drink defined as one bottle of beer, one glass of wine or
one shot of liquor.
4. Patients, who are able to comprehend and satisfactorily comply with protocol
requirements.
5. Patients, who signed the written informed consent given prior to entering any study
procedure and completed the informed consent quiz.
Exclusion Criteria:
1. Patients with the following concurrent DSM-IV Axis I diagnoses as determined by the
relevant sections of SCID I:
- Current, acute psychosis regardless of etiology
- Moderate to severe dementia regardless of etiology, defined as a MMSE score of
18 or less out of 30.
- Current opioid, cocaine or amphetamine dependence, defined as not meeting
criteria for sustained full remission.
2. Patients with significant or unstable medical conditions as determined by
investigator. This is defined as a medical condition that, in the Investigator's
opinion, would expose them to an increased risk of a significant adverse event or
interfere with assessments of safety during the course of the trial.
3. Patients with significantly abnormal lab values, as determined by the investigator,
including creatinine clearance less than 30 as determined by Cockcroft-Gault
estimate.
4. Patients with a history of intolerance or hypersensitivity to acamprosate.
5. Patients who are actively suicidal.
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