Resources: Research Paper

Full study results presented June 21, 2006 at the College on Problems of Drug Dependence’s (CPDD) annual meeting in Scottsdale, Ariz.Full study by Harold Urschel, MD at the College on Problems of Drug Dependence’s (CPDD) annual meeting in Scottsdale,

Study of PROMETA Protocol Shows Clinical Effectiveness

Wednesday June 21, 7:00 am ET

Statistically Significant Reduction in Methamphetamine Cravings and Methamphetamine Use
DALLAS–(BUSINESS WIRE)–June 21, 2006–Research Across America:

* Immediate and Persistent Positive Effect More Than Two Months Following Treatment Completion — Even without Benefit of Psychosocial Treatment
* 85% Retention to Treatment; 97% of Patients Experienced Reduction in Cravings; 80% of Participants Reported Reduction in Methamphetamine Use

Research Across America, a nationally-recognized clinical research center, today announced results of its study of the PROMETA(TM) treatment protocol for methamphetamine dependence. Board Certified psychiatrist and addiction expert Harold C. Urschel, III, M.D., M.M.A. and lead investigator on the first clinical study of the PROMETA treatment protocol for stimulant dependence, presented the full study results today at the College on Problems of Drug Dependence’s (CPDD) annual meeting in Scottsdale, Ariz.

According to Dr. Urschel’s presentation, after treatment more than 80% of study participants experienced a significant clinical benefit with no adverse events. Clinical benefit was measured through decrease in cravings, reduction of methamphetamine use, and treatment retention.

The study, which contained no psychosocial counseling support, concluded that PROMETA has demonstrated clinical utility with chronic, relapsing methamphetamine-dependent patients to help them attain and maintain abstinence, is effective in decreasing cravings and can be safely administered in an outpatient setting. Males and females appear to benefit equally from the treatment protocol.

“As investigators looking at potential treatments for stimulant dependence, we traditionally seek some signal of effect in at least one of the primary endpoints of a study. What we have discovered in this study is positive trending in all of the primary endpoints. The PROMETA treated patients improved almost immediately with many positive benefits from the treatment, including abstinence, reduced cravings and significant improvement in their memory and concentration sustaining beyond the treatment period,” said Dr. Urschel. “We observed these improvements early in the treatment period, in most cases within the first three days of starting the treatment. These results are in sharp contrast to most studies on substance dependence therapies, as other pharmacologic agents tested to date usually only show a gradual improvement over time, even when they are combined with behavioral support and environmental modifications.”
Urschel continued, “Because we were testing the PROMETA Treatment Protocols in an outpatient setting, I was very worried that due to the lack of psychosocial support, the subjects would drop out early in the study.

However with the PROMETA treatment protocols, we had a high percentage of subjects complete both the treatment phase and the follow-up phase of this study, even though the subjects received no psychosocial treatment or additional treatment incentive to return weekly for two months post treatment completion. Especially noteworthy is the high rate of patient adherence to completing treatment in a patient population that is known by addiction treatment providers to inconsistently comply with medication regimens — most stimulant addicts drop out of treatment and stop their medications after only 1-2 days. For all of these reasons, I feel confident that we have found the first clinically effective treatment for methamphetamine dependence.

“Clinical observations during our study also suggested that the PROMETA treatment resulted in immediate improvement in our subject’s cognitive functioning, including memory, alertness and concentration. Additionally we saw improved sleep patterns and a decrease in anxiety,” continued Dr. Urschel. “This observed effect of PROMETA in restoring subjects’ cognitive functioning suggests its potential benefit to assist patients in their intensive outpatient treatment programs in learning the new coping skills they will need to maintain long-term abstinence from psychostimulants. Methamphetamine-dependent patients often do not benefit from psychosocial and educational treatment programs during early abstinence because they have difficulty with memory and concentration and are preoccupied with methamphetamine cravings. What is also remarkable in this case is that cravings for methamphetamine were significantly decreased, methamphetamine usage dropped dramatically, and adherence to the treatment was much higher than expected for this patient population.”

Study Design

Subject screening consisted of informed consent; psychiatric evaluation; medical history and evaluation; laboratory screening; methamphetamine and other drug use history; administration of the Stimulant Craving Scale (SCS), a 10-item questionnaire that measures the subjective perception of frequency and intensity of cravings for methamphetamine; and recording of methamphetamine use during the previous 90 days using timeline follow back. Changes in self-reported cravings for methamphetamine were assessed from the screening visit to the end of the 12-week study. Medication treatment lasted 4 weeks followed by 8 weeks of follow-up in which subjects returned for weekly office visits to provide self-report of drug use and to provide a urine specimen collected under observation.
Endpoints and Results

Patient improvement was measured by adherence to the treatment protocol, changes in self-reported cravings for methamphetamine and reduction of methamphetamine use as measured by self-report and correlated with urine testing.

1. Retention (Adherence) to treatment: 45 of 50 subjects, or 90%
completed both treatment cycles, returning for 5 infusions
over 23 days. There was an overall compliance rate of 85% with
the treatment regimen. Thirty-six subjects (72%) attended the
final follow-up visit at week 12.

2. Changes in cravings: Complete craving data were available on 31
subjects at visit 17 (day 84). Of these, 30 subjects, 97%
reported a decrease in cravings (frequency of urge to use
methamphetamine during the past week). Only one subject
reported no change and no subject reported an increase in
cravings. Among the 30 subjects whose frequency of
methamphetamine cravings decreased, the mean reduction in
cravings from the screening visit to study completion was 66%.
This reduction is significant at p lower than .0001. There was
no evidence of a gender effect on craving reduction.

3. Reduction of methamphetamine use: 40 of the 50 (80%)
participants reported reduction in methamphetamine use during
the course of the study. Of the completers (n=36), an average
reduction in methamphetamine use of 65% was found with 72% of
days abstinent. Among those participants who completed the
study, the average frequency of methamphetamine abstinent days
increased from 20% of days (during the 90 days prior to
treatment) to 72% of the 84 days following the first infusion.
Among study completers, the average frequency of days used
dropped from 80% of days (during the 90 days prior to
treatment), to 28% of the 84 days following the first
treatment. This reduction in self-reported use days is 65% (p
lower than .0001). Negative urine drug screen results matched
self-reported denials of methamphetamine use in 84.7% of
samples. There was no evidence of a gender effect.

4. No serious adverse events occurred during any portion of the
PROMETA treatment. Mild and transient side effects of the
treatment protocol included fatigue, dizziness, dry mouth,
unusual taste and discomfort at the IV infusion site. No
subject discontinued the protocol because of side effects.

Excerpted from Poster

Discussion

In summary, investigators observed a highly significant reduction in methamphetamine use which persisted over the 2-month, non-medication follow-up period. There was an immediate and persisting positive treatment effect for PROMETA for more than 2 months following treatment completion in the intent-to-treat samples. Taking into account decreased cravings, reduction in methamphetamine use, and treatment retention, 80% of subjects experienced a significant clinical benefit as the result of the PROMETA treatment.
The limitations of an open-label study notwithstanding, the magnitude and persistence of this effect are remarkable in several respects, as clinical benefit was seen in daily using, chronically relapsing methamphetamine addicts. The results are all the more remarkable when one takes into account the fact that most psychostimulant addicts drop out of outpatient treatment after only a few days. Seventy-two percent (72%) of the subjects returned for the final follow-up visit, 8 weeks after completing medication treatment.
Second, the findings were observed in the context of what was essentially a pharmacologic intervention only. Since the study did not include psychotherapy or a specific substance abuse counseling component (e.g., cognitive behavioral therapy), the investigators contend that the data reflect a primary pharmacologic effect. If the psychosocial component of the PROMETA treatment protocol had been implemented in this study the results in all likelihood would be even more robust.

Third, PROMETA was clinically effective in reducing the severity of methamphetamine cravings and frequency of methamphetamine use during the medication treatment phase and during the 2 months following treatment. In view of the lasting positive impact of the PROMETA treatment over this time span, it is not likely that this benefit can be attributed to a placebo effect.
The PROMETA treatment protocols, provided to RAA by Hythiam, Inc. (Nasdaq:HYTM – News), are designed for use by healthcare providers seeking to treat individuals diagnosed with dependencies to alcohol, cocaine or methamphetamine, as well as combinations of these drugs. The medical component of the PROMETA treatment protocol for methamphetamine dependence evaluated in this study is designed to address neurological changes caused or worsened by addiction. It comprises nutritional supplementation, as well as FDA-approved oral and IV medications used off-label and separately administered in a unique dosing algorithm. Information about Hythiam is available www.hythiam.com.

Dr. Harold C. Urschel III is an accomplished researcher, clinician and a recognized leader in addiction medicine. He is a Clinical Instructor of Psychiatry at The University of Texas Southwestern Medical Center at Dallas’ Department of Psychiatry and has published numerous articles on addiction treatment in journals and textbooks including Psychopharmacology Bulletin, Archives of General Psychiatry and the DSM-IV Sourcebook. He is also a national lecturer on current pharmacological agents to enhance addiction treatment for all major classes of alcohol and drug dependence, Chief of Medical Strategy for EnterHealth LLC, an internet site delivering addiction and mental health treatment online www.enterhealth.com and an advisory Board Member for the Betty Ford Center Children’s Program. Dr. Urschel has a Masters in Management (Sloan Fellow) from Stanford University Graduate School of Business.

About Research Across America

Research Across America is an Investigator Site Network (Non-SMO) with multi-specialty sites located in Dallas, TX, El Paso, TX, New York, NY, Reading, PA, and their surrounding areas. The physicians affiliated with Research Across America have conducted over 1,000 clinical trials since 1989. Since that time, Research Across America has worked with most major pharmaceutical companies and contract research organizations (CROs) in a wide variety of therapeutics including cardiology, endocrinology, gastroenterology, neurology, and urology. Dr Urschel is a founding partner of the CNS Research division within RAA, which investigates new treatments in the Addiction and General Psychiatric areas. For further information, please visit www.ResearchAcrossAmerica.com.

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