Complementary Combination Therapy for Cocaine Dependence
Condition: Cocaine Dependence
MeSH terms: Cocaine-Related Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators will assess the impact of treatment with doxazosin and modafinil, alone and
      in combination, on the subjective and reinforcing effects of cocaine in
      non-treatment-seeking, cocaine-dependent volunteers. The investigators will use a hybrid
      design in which participants will be randomized into two groups: placebo and doxazosin 8
      mg/d. They will remain in their assigned group for the duration of the study. After titrating
      doxazosin to the target dose, study procedures will be completed three times, once during
      treatment with each dose of modafinil (0, 200, and 300 mg/d), in pseudo-random order such
      that 200 mg precedes 300 mg).
    

Detailed description: 
      During a screening session participants will provide buccal swab for genetics testing, as
      preliminary data shows that effects of cocaine and of doxazosin are impacted significantly by
      the genotype at ADRA1A, in that those with the CC genotype respond robustly to both cocaine
      and doxazosin whereas those with the CT genotype do not. Participants will be enrolled
      regardless of genotype, though the investigators plan to retrospectively exclude those with
      the rare TT genotype.

      During screening, the investigators will collect participants' demographic and medical
      histories, conduct a physical exam, and record an ECG. A trained assistant will administer
      the MINI to collect diagnostic data. The investigators will draw blood and for CBC and a
      comprehensive metabolic panel including electrolytes, liver function tests (total bilirubin,
      ALT, AST, and alkaline phosphatase) and renal function tests (creatinine and BUN).

      All applicants for study participation will receive counseling as part of their
      participation, and will be advised that treatment for drug abuse is indicated and available.
      Applicants not participating in the study will receive treatment referral information as
      appropriate. At completion of their participation, study subjects will again be advised that
      treatment is indicated and available, and will be given treatment referral information and
      assistance.

      General Procedures Participants will report to the research commons three-times-weekly during
      the 11 day doxazosin titration period. They will be allowed to miss up to 3 visits but will
      be discontinued if they miss more that 3 visits. At the initial screening visit, restrictions
      on use of alcohol, drugs of abuse, and medications will be reviewed. All subjects will be
      required to sign a written statement that they will abstain from all psychostimulants
      throughout the duration of their participation in the trial.

      After determining that volunteers meet inclusion and exclusion criteria, participants will
      receive screening doses of cocaine (0, 20, 40 mg, IV, constrained such that 20 mg precedes 40
      mg). To be retained in the study participants must report a change in ratings of "high" of at
      least 20 points from before to following the 40 mg dose.

      Remaining participants will be randomized into the two treatment groups (placebo and
      doxazosin 8 mg/d). Doxazosin will be titrated to the target dose over 11 days to minimize
      side-effects. Participants will complete the doxazosin titration phase of the study as
      outpatients because doxazosin alone is known to be safe when combined with cocaine.
      Participants will report to research commons every 4 days. The titration schedule is attached
      in Table 2.

      The investigators will use standard riboflavin labeling to monitor treatment adherence
      throughout the study. Riboflavin (25mg) will be encapsulated with the study medication and
      adherence will be monitored by measuring riboflavin in urine using quantitative fluorescence
      39,40. Because riboflavin is contained in many vitamin preparations, positive riboflavin
      tests may not truly reflect adherence to study medication treatment. To confirm adherence,
      the investigators will add 15 mg acetazolamide (ACZ) to the doxazosin capsules. ACZ will be
      included in doxazosin study medication from the beginning of the study until day 6 when
      capsules not containing ACZ will be substituted. The team will continue monitoring urine for
      several days after day 6 to characterize how long it takes for ACZ to become undetectable.

      Participants must test cocaine negative on day 1 or they will be discontinued from the study,
      though they may reenter later if the investigators agree. After dose titration investigators
      will initiate treatment with the target doses of study medications. As shown below in Table 3
      (attached), participants remain in their original doxazosin treatment group for the duration
      of the study (the two groups are listed to emphasize this point). Participants will complete
      non-contingent cocaine dosing and cocaine self-administration procedures three times, once
      during treatment with each dose of modafinil. Non-contingent dosing and self-administration
      will be done on the same day, with non-contingent dosing occuring in the am and
      self-administration in the pm. One treatment order is illustrated (0, 200, 300 mg/d), but in
      practice the order in which participants receive the three modafinil doses (placebo, 200
      mg/d, and 300 mg/d) will be randomized.

      Participants will be followed as outpatients for most of the study. They report to the clinic
      about every 4 days as shown in Table 3 for observed dosing and urine testing for adherence
      monitoring. Participants must test cocaine-negative on days 1, 4, 9, and 14 to remain in the
      study. This is so that participants are not enrolled in the study or admitted to research
      commons with unknown amounts of cocaine in their bodies.

      Participants will take three capsules daily at 7:00 am. The capsules will contain placebo,
      doxazosin 8 mg, or modafinil 200 or 300 mg, depending on their randomization group and
      modafinil dose. On the 4th day of study medication treatment they will be admitted to
      research commons to ensure that procedures the following day occur under fairly standard
      conditions. On the 5th day of study medication treatment they will receive non-contingent
      doses of cocaine and participate in cocaine self-administration sessions. After completing
      these study activities, modafinil will be discontinued and there will be a modafinil wash-out
      period of 4 days during which time they will continue to take their assigned dose of
      doxazosin. They will then complete the study procedures during treatment with their next
      assigned modafinil dose. This will be repeated until participants have completed the study
      three times, once at each modafinil dose. As noted above, participants remain in their
      original doxazosin treatment group and participants continue to receive their assigned
      doxazosin dose throughout the study.

      Daily activities for the non-contingent cocaine dosing days are shown in Table 4 and daily
      activities for the cocaine self-administration days are shown in Table 5 (see section S for
      all tables). Non-contingent doses of cocaine (placebo, 20, 40 mg, IV) will be administered at
      hourly intervals in random order. The following day there will be two self-administration
      sessions. In one session doses placebo saline will be available and in another session doses
      of 20 mg cocaine will be available with the order counterbalanced across participants. At the
      beginning of each session participants will receive a sample of the drug available in that
      session, saline or cocaine. The will then make a series of 10 choices between receiving the
      drug available in that session and monetary alternatives of increasing value. The value of
      the money choices will increase over the 10 choices: $.05, $.05, $.05, $.05, $1, $4, $7, $10,
      $13, $16. Choices will occur at 15 min intervals. The investigators have previously found
      that this arrangement produces choice behavior that reflects the magnitude of reinforcing
      effects and that is sensitive to pharmacologic manipulation.

      Criteria for Withholding Cocaine Cocaine will not be administered if there are behavioral
      manifestations of cocaine toxicity (agitation, psychosis, inability to cooperate with study
      procedures), though this has not been observed with the small doses of cocaine administered
      in human laboratory studies. To ensure that subjects will not be at risk from cocaine, the
      resting pulse must be less than 90 bpm and the blood pressure must be less than 150 mmHg
      systolic and less than 90 mmHg diastolic.

      Criteria for Participant Discontinuation:

        1. Positive urine drug screen or breath test indicating illicit use of abused drugs not
           delivered as part of this protocol

        2. Inability to comply with study procedures

        3. Have exaggerated response to cocaine (5 min or more of systolic BP greater than 180
           mmHg, diastolic BP greater than 120 mmHg, or heart rate greater than [(220 - age) ×
           0.85] bpm).

      Cocaine Administration and Medical Monitoring Participants will remain seated during
      experimental sessions except for brief visits to the lavatory. An IV will be placed for
      cocaine dosing. On days involving non-contingent cocaine dosing, after first confirming that
      vital signs are within allowed limits, the physician will administer solution by slow IV
      push. An ACLS-certified physician will be present from 15 min before drug administration
      until at least 1 hour after drug administration. The physician will be available in house and
      on pager for at least 4 hours after drug administration. Heart rate will be measured using
      continuous ECG from 15 min prior to cocaine or placebo dosing until 1 hour after dosing.
      Blood pressure will be assessed at frequent intervals from 15 min prior to cocaine or placebo
      dosing assessment for 1 hour after dosing or until baseline levels reached.

      On days involving choice sessions, an IV will be placed and patient-controlled analgesia
      (PCA) pump will be loaded with saline or 20mg cocaine doses depending on the session.
      Participants will receive one non-contingent sample dose of the drug available that session.
      Participants will then have 10 opportunities to choose between receiving repeated doses of
      the drug available that session (which will be the same as the sample dose) or receiving
      monetary alternatives of increasing value ($.05, $.05, $.05, $.05, $1, $4, $7, $10, $13,
      $16). Choices will begin 15 min after the sample dose and subsequent choices will be
      available at 15 min intervals.

      Cocaine dosing will be delayed if necessary due to elevated cardiovascular indices based on
      the stopping criteria above. Investigators selected the 15 min inter-dose interval for use in
      the self-administration sessions based on published data showing that this arrangement is
      safe and yields interpretable data 44. Heart rate will be monitored continuously and blood
      pressure will be measured prior to dosing at 15 min intervals until 45 min after the final
      cocaine dose. The physician will halt cocaine administration if stopping criteria are met.

      Assessments Substance Use Inventory (SUI). This instrument collects data on the type,
      frequency, and amounts of drugs used, as well as routes of administration. Participants will
      complete this measure during screening before each of the inpatient episodes. DSM-IV
      Diagnosis. The MINI will be administered during the initial screening and serves to determine
      whether the participant meets the DSM-IV criteria for drug dependence and to rule out any
      major psychiatric disorders (e.g., affective disorders, schizophrenia). Data from the SUI can
      be used to augment the ability of the MINI to determine if participants meet inclusion
      criteria. Beck Depression Inventory II (BDI-II). The BDI-II is the third-generation BDI,
      revised in 1996, and based on the original. The instrument retains its original 21-item
      questionnaire format that requires approximately 10 min to complete. This indicator is used
      in the trials to monitor participants' mood during the study, making it also a measure for
      participants' safety. Participants will complete this measure during screening and daily
      during inpatient episodes. Visual Analogue Scales (VAS). Subjective effects produced by
      cocaine or placebo will be measured using a VAS consisting of a continuous 10-cm line marked
      from 0 to 100. Participants will be required to rate their drug craving, dysphoria, and
      euphoria on a scale from 0 to 100. Ratings include "High," "Good Effects," "Bad Effects,"
      "Like Drug," "Dislike Drug," "Crave Cocaine," "Likely to Use Cocaine if Available", and
      "Desire Cocaine."
    

Intervention name(s): Doxazosin; Modafinil; cocaine; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Participants will be randomized into two groups: placebo and doxazosin 8 mg/d. The doxazosin dose will be increased every 4 days over 11 days, starting with 1mg on the first study day and and ending with 8mg 11 days later. Participants will receive one capsule daily that will contain either placebo or doxazosin.; After titrating doxazosin to the target dose, study procedures will be completed three times, once during treatment with each dose of modafinil (0 [placebo], 200, and 300 mg/d), in pseudo-random order such that 200 mg precedes 300 mg).; On the 5th day of study medication treatment participants will receive non-contingent doses of cocaine (placebo, 20, 40 mg, IV) and participate in cocaine self-administration sessions.
Intervention MeSH terms: Doxazosin; Cocaine; Modafinil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment