Modafinil for Methamphetamine Dependence

Condition(s) targeted: Methamphetamine Dependence

Intervention: modafinil (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: National Institute on Drug Abuse (NIDA)

STUDY OBJECTIVES: To evaluate the efficacy and safety of modafinil in reducing methamphetamine use in subjects with methamphetamine dependence. It is hypothesized that modafinil, compared to placebo, will be associated with an increase in the number of methamphetamine non-use weeks over time as measured by quantitative urine analysis for methamphetamine.

STUDY DESIGN: This is a double-blind, placebo-controlled, parallel-group study in which, after a 14-day screening/baseline period, subjects will be randomly assigned to one of three treatment arms. Subjects will receive 200 mg modafinil, 400 mg modafinil or matched placebo daily for 12 weeks, with a follow-up assessment 4 weeks after treatment completion/termination. Adaptive randomization will be used to balance treatment groups based on site, gender, ADHD, and frequency of historical self report of methamphetamine use in the 30 days prior to informed consent (18 versus >18).

STUDY POPULATION: Two hundred and ten subjects with Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for methamphetamine dependence, determined by structured clinical interview (SCID), will be randomized into one of three treatment arms (70 subjects per arm). The subject population will include those who provide at least one methamphetamine-positive urine during the 2-week screening/baseline period prior to randomization, and who verbalize the ability to understand and provide written informed consent.

TREATMENTS: During the 12 weeks of treatment, subjects will receive 200 mg or 400 mg of modafinil daily, or matched placebo. Modafinil/placebo is administered orally once a day. All subjects will receive standardized psychosocial therapy, which will consist of manual-guided cognitive behavioral therapy (CBT) three times a week during the 12-week study drug administration period. Human immunodeficiency virus (HIV) counseling will be provided at baseline, at the end of study participation, and at follow-up.

SAFETY ASSESSMENTS: All potential subjects for study enrollment will have a physical examination, a 12-lead electrocardiogram (ECG), clinical laboratory studies (blood chemistry, hematology, infectious diseases, urinalysis, and pregnancy test, if female), and the Hamilton Depression Rating Scale (HAM-D) completed during screening/baseline. Vital signs, concomitant medication use, and a urine screen for other substances of abuse will be assessed three times per week during screening/baseline and weekly during the study drug administration period. A HAM-D and clinical laboratory studies (including a pregnancy test, if female) will be performed at weeks 4, 8, and 12. Adverse Events (AEs) will be assessed three times per week during the screening/baseline period and at each study visit, and reviewed by a study physician once a week. At week 12 or at the time of study discontinuation, all subjects will have an ECG, vital signs, physical examination, HAM-D, clinical laboratory studies (including pregnancy test, if female) and an AE assessment. A final AE assessment will be performed at the follow-up 4 weeks after study completion/termination.

EFFICACY ASSESSMENTS: The primary efficacy outcome measure is methamphetamine use or non-use weeks during the study medication administration period. Secondary assessments include analyses of other measures of success in the reduction of methamphetamine use including the proportion of successful subjects with 21 consecutive days of abstinence in which all urine samples are negative for methamphetamine, the maximum number of consecutive methamphetamine non-use days, reductions in methamphetamine use as compared to baseline, treatment effects on other substances of abuse and reduction in scores of HIV risk-taking behavior assessed by the HIV Risk-Taking Behavior Scale (HRBS). Severity of methamphetamine dependence will be assessed by comparing the change in scores of the Addiction Severity Index (ASI-Lite and ASI-Lite Follow-up), Brief Substance Craving Scale (BSCS), and Clinical Global Impression as assessed by the subject (CGI-S) and an observer (CGI-O). The ASI-Lite will be performed at screening/baseline and the ASI-Lite Follow-up at the first visit of weeks 4 and 8, and at week 12 or early termination. The BSCS, CGI-S, and CGI-O will be performed at each week during screening/baseline and at the first visit of each study week during the study medication administration period. The HRBS will be used to characterize the population. s HIV risk-taking behavior at baseline, at the end of the study, and at follow-up. End-of-study assessments to be performed if a subject completes the protocol or is terminated early for any reason are listed in Section 13.

Official title: CSP #1026 - Phase 2, Double-Blind, Placebo-Controlled Trial of Modafinil for Methamphetamine Dependence

Study design: Interventional, Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Detailed description: STUDY OBJECTIVES: To evaluate the efficacy and safety of modafinil in reducing methamphetamine use in subjects with methamphetamine dependence. It is hypothesized that modafinil, compared to placebo, will be associated with an increase in the number of methamphetamine non-use weeks over time as measured by quantitative urine analysis for methamphetamine.

STUDY DESIGN: This is a double-blind, placebo-controlled, parallel-group study in which, after a 14 to 21-day screening/baseline period, subjects will be randomly assigned to one of three treatment arms. Subjects will receive 200 mg modafinil, 400 mg modafinil or matched placebo daily for 12 weeks, with a follow-up assessment 4 weeks after treatment completion/termination. Randomization to treatment groups will be done by stratifying by clinical site then using an adaptive randomization procedure based on ADHD, gender, and frequency of historical self report of methamphetamine use in the 30 days prior to informed consent (18 versus >18).

STUDY POPULATION: Two hundred and ten subjects with Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for methamphetamine dependence, determined by structured clinical interview (SCID), will be randomized into one of three treatment arms (70 subjects per arm). The subject population will include those who provide at least one methamphetamine-positive urine during the 14-day baseline period prior to randomization, and who verbalize the ability to understand and provide written informed consent.

TREATMENTS: During the 12 weeks of treatment, subjects will receive 200 mg or 400 mg of modafinil daily, or matched placebo. Modafinil/placebo is administered orally once a day. All subjects will receive standardized psychosocial therapy, which will consist of manual-guided cognitive behavioral therapy (CBT) three times a week during the 12-week study drug administration period.

SAFETY ASSESSMENTS: All potential subjects for study enrollment will have a physical examination, a 12-lead electrocardiogram (ECG), clinical laboratory studies (blood chemistry, hematology, infectious diseases, urinalysis, and pregnancy test, if female), and the Hamilton Depression Rating Scale (HAM-D) completed during screening/baseline. Vital signs are done three times a week during baseline and for the first three weeks and then weekly thereafter. Adverse events and concomitant medication use will be assessed three times per week during baseline and during the study drug administration period. Adverse events (AEs) will be assessed at each study visit and reviewed by a study physician once a week. A HAM-D will be performed at screening or baseline and at weeks 4, 8, and 12. A pregnancy test, if female, will be performed at screening, prior to randomization and at weeks 4, 8, 12 and 16. At week 12 or at the time of study discontinuation, all subjects will have an ECG, vital signs, physical examination, HAM-D, clinical laboratory studies (including pregnancy test, if female) and an AE assessment. A final AE assessment will be performed at the follow-up 4 weeks after study completion/termination.

EFFICACY ASSESSMENTS: The primary efficacy outcome measure is methamphetamine use or non-use weeks during the study medication administration period. Secondary assessments include analyses of other measures of success in the reduction of methamphetamine use including the proportion of successful subjects with 21 consecutive days of abstinence in which all urine samples are negative for methamphetamine, overall proportion of negative methamphetamine use days by self report, the maximum number of consecutive methamphetamine non-use days, reductions in methamphetamine use as compared to baseline, and reduction in scores of HIV risk-taking behavior assessed by the HIV Risk-Taking Behavior Scale (HRBS). Severity of methamphetamine dependence will be assessed by comparing the change in scores of the Addiction Severity Index (ASI and ASI-Lite Follow-up), Brief Substance Craving Scale (BSCS), Clinical Global Impression as assessed by the subject (CGI-S) and an observer (CGI-O) ), Barratt Impulsiveness Scale (BIS), and the Adult ADHD Investigator Symptom Rating Scale (AISRS). The ASI will be performed at baseline and the ASI-Lite will be performed at the first visit of week 6 and at week 12 or early termination. The BIS will be assessed at baseline and at weeks 6 and 12 or early termination. The ASIRS will be gathered at baseline and at weeks 4, 8 and 12 or early termination. The BSCS, CGI-S, and CGI-O will be performed at each week during baseline and at the first visit of each study week during the study medication administration period. The HRBS will be used to characterize the population. s HIV risk-taking behavior at baseline and at the end of the study. End-of-study assessments to be performed if a subject completes the protocol or is terminated early for any reason are listed in Section 12.

ANALYSIS: Each primary and secondary outcome variable will be analyzed using appropriate statistical methods for the intent-to-treat (ITT), evaluable and treatment completer populations. The ITT population is defined as the subjects who are randomized to treatment and who receive the first dose of study agent. The evaluable population is defined as the ITT subjects who contribute at least six (6) usable on-treatment urine samples and 21 days of self-report. Treatment completers are the ITT population who take at least one dose of study medication in week 12, provide at least one urine sample in week 12, and provide self reports of substance use through the last day of week 11. The individual effects, if any, of gender, age, race, prior methamphetamine use, usual route of methamphetamine use (oral/nasal inhalation versus intravenous/smoked), depression, and clinical site on the primary outcome will be determined. Statistical tests will be two-sided at a 5% Type I error rate.

Summaries of the characteristics of the subject population in all three treatment arms at baseline will be prepared for the ITT, evaluable and treatment completer subjects. A summary will be prepared to show dropouts/retention over time in each treatment arm, along with the reason for early termination. The number of missing observations will be compared between treatment arms. Weekly study medication compliance and behavioral therapy compliance in each treatment arm will be summarized. The types and frequency of other drugs used by self-report of use and by positive urine drug screen will also be reported for each treatment arm. The proportion of subjects in each treatment arm that are abstinent at Week 16 will be summarized (abstinent is defined as no self-reported use since Week 12 and the Week 16 methamphetamine urine drug screen is negative). All AEs will be reported in tabular form indicating the frequency of each type of event.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria

Potential subjects must:

1. Be male or female between 18 and 65 years-of-age.

2. Have a DSM-IV diagnosis of methamphetamine dependence as determined by SCID.

3. Be seeking treatment for methamphetamine dependence.

4. Have at least 1 amphetamine or methamphetamine positive urine specimen (> 500 ng/mL) within 14-day baseline period prior to the date the subject is eligible to be randomized with a minimum of 4 samples tested (urines should be collected 3 times a week, generally on Monday, Wednesday and Friday).

5. Be able to verbalize understanding of consent form, provide written informed consent, verbalize willingness to complete study procedures, and pass the study consent quiz with 100% accuracy (if necessary quiz may be administered more than one time).

6. If female, should be surgically sterile or 2 years post-menopausal. If of child bearing potential, agree to use one of the following methods of birth control, and to continue to use this method for at least 30 days after the last dose of study drug:

a. barrier (diaphragm, sponge or condom with spermicide)

b. intrauterine progesterone or non-hormonal contraceptive system/device (IUD)

c. complete abstinence from sexual intercourse

d. oral contraceptives

e. patch

f. implant

g. medroxyprogesterone acetate contraceptive injection

h. hormonal vaginal contraceptive ring

Note: Steroidal contraceptives (methods d through h above) must be used in conjunction with a barrier method or IUD. Heterosexual female participants who do not engage in sex must agree to use one of these methods if they decide to have sex during the study and for 30 days after the last dose of study drug.

7. Be willing and able to comply with study procedures.

9. 2 Exclusion Criteria

Potential subjects must not:

1. Have current dependence, defined by DSM-IV criteria, on any psychoactive substance (e. g., opioids) other than methamphetamine, nicotine, or marijuana or have physiological dependence on alcohol or a sedative-hypnotic (e. g., a benzodiazepine) requiring medical detoxification.

2. Be mandated by the court to obtain treatment for methamphetamine dependence where such mandate required the results of urine toxicology tests to be reported to the court.

3. Be anyone who in the opinion of the investigator would not be expected to complete the study protocol due to probable incarceration or relocation from the clinic area.

4. Have a psychiatric disorder, such as current major depression, psychosis, bipolar illness, organic brain disorder, or dementia as assessed by SCID interview or ADHD by ACDS assessment, which require ongoing medication treatment or which would make medication compliance difficult. Have had electroconvulsive therapy within the past 90 days before screening, or have a history of Bipolar I Disorder (see Notes).

5. Have current suicidal ideation or plan as assessed by the SCID interview or HAM-D question #3. (Current is identified as within the past 30 days.)

6. Be pregnant or lactating.

7. Have serious medical illnesses including, but not limited to:

" uncontrolled hypertension or uncontrolled diabetes " significant heart disease (including myocardial infarction within one year of enrollment), or any clinically significant cardiovascular abnormality (ECG), " hepatic, renal or gastrointestinal disorders that could result in a clinically significant alteration of metabolism or excretion of the study agent, " potentially life-threatening or progressive medical illness other than addiction that may compromise subject safety or study conduct.

8. Have clinically significant abnormal laboratory values, in the judgment of the investigator.

" have liver function tests (LFTs) > 3 times normal.

9. Have AIDS according to the current CDC criteria for AIDS . MMWR 1999; 48 (No. RR-13: 29-31). http://www. cdc. gov/MMWR/preview/MMWRhtml/00018871. htm

10. Have active syphilis that has not been treated or refuse treatment for syphilis (see Notes).

11. Have active tuberculosis (positive tuberculin test and confirmatory diagnostic chest x-ray).

12. Be undergoing HIV treatment with antiviral and/or non-antiviral therapy.

13. Have a current or past history of anorexia nervosa or bulimia disorder.

14. Have a diagnosis of adult (i. e., 21 years or older) asthma, or chronic obstructive pulmonary disease (COPD), including those with a history of acute asthma within the past two years, and those with current or recent (past 3 months) treatment with inhaled or oral beta-agonist or steroid therapy (because of potential serious adverse interactions with methamphetamine), or have an FEV1 <70 %.

15. Be suspect for adult obstructive airways disease, but without formal diagnosis, for example: 1) have a history of wheezing and/or chronic coughing, 2) have a history of adult obstructive airways and/or treatment for this condition more than two years before the current application for the study, 3) have a history of other respiratory illness, e. g., complications of pulmonary disease (exclude if on beta-agonists), 4) use over-the-counter agonist or allergy medication for respiratory problems (e. g., Primatene Mist). If suspect, a detailed history and physical exam should be performed, and possibly pulmonary consult and/or pulmonary function tests, prior to including or excluding from the study.

16. Have received a drug with known potential for toxicity to a major organ system within 30 days prior to screening including, but not limited to, chemotherapeutic agents for neoplastic disease (i. e., methotrexate, vincristine, vinblastine, fluorouracil), agents used for parasitic infections (i. e., isoniazid, chlorambucil, dactinomycin, chloramphenicol), or immunosuppressive and cytotoxic agents (i. e., cyclosporine, tacrolimis, indomethacin, protease inhibitors, amphotericin B, cephalosporins, aminoglycosides, interferon, and sulfonamides).

17. Have received medication that could interact adversely with modafinil, with the time of administration of study agent and other medications based on the longest time interval of A, B, or C, below:

A) Five half lives of other medication or active metabolite(s), whichever is longer B) Two weeks C) Interval recommended by other medication. s product labeling

Medications that fall into this category include:

" Bupropion " Antipsychotics " Neuroleptics " Psychostimulants " Tricyclic antidepressants and anxiolytics " CNS depressants (tranquilizers, sleeping pills), e. g., secobarbital (Seconal), zolpidem (Ambien), temazepam (Restoril) " MAO inhibitors, e. g., phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl) " Inducers of CYP3A4 (e. g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e. g., ketoconazole, itraconazole) " Substrates of CYP3A4, e. g., cyclosporin A, triazolam and ethinyl estradiol- containing products " Substrates of CYP2A9, such as warfarin " Substrates of CYP2C19, e. g., S-mephenytoin, omeprazole, lansoprazole, proguanil, diazepam or propranolol

" Selective serotonin reuptake inhibitors (SSRIs), e. g., citalopram (Celexa, Cipramil, Emocal, Sepram), escitalopram oxalate (Lexapro, Cipralex, Esertia), fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR)), fluvoxamine maleate (Luvox, Faverin), paroxetine (Paxil, Seroxat, Aropax, Deroxat), sertraline (Zoloft, Lustral, Serlain)

18. Have participated in any experimental study within 2 months preceding screening.

19. Have known or suspected hypersensitivity to modafinil.

20. Be taking modafinil for any reason currently or during the past year.

UCLE Integrated Substance Abuse Program-Torrance, Torrance, California 90502, United States
Richard Rawson, Ph.D., Phone: 301-267-5311, Email: rrawson@mednet.ucla.edu

Matrix Institute on Addictions, West Los Angeles, California 90025, United States
Michael ` McCann, M.A., Phone: 310-207-4322, Email: mickex@aol.com

South Bay Tratment Center, San Diego, California 92115, United States
Joseph Mawhinney, M.D., Phone: 858-581-5776, Email: jmawhin1@san.rr.com

VA Medical Center (116-A1), Denver, Colorado 80220, United States
Thomas P. Beresford, M.D., Phone: 303-399-8020, Ext: 3732, Email: thomas.beresford@uchsc.edu

University of Hawaii, Honolulu, Hawaii 96813, United States
William Haning, M.D., Phone: 808-692-0877, Email: haning@hawaii.edu

Lutheran Hospital, Des Moines, Iowa 50316, United States
Dennis Weis, M.D., Phone: 515-263-2401, Email: weisda@ihs.org

University of Kansas Medical Center, Kansas City, Kansas 66160, United States
Jan Campbell, M.D., Phone: 913-588-6493, Email: jcampbell@kc.rr.com

VA Medical Center, Salt Lake City, Utah 84148, United States
Christopher J. Stock, Pharm.D., Phone: 801-582-1565, Ext: 1172, Email: christopher.stock@va.gov

Ending date: March 2009
Last updated: April 25, 2007