Testing Doxazosin to Treat Stress Mechanisms in Alcoholism
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 2

Summary: 
      Double-blind, placebo controlled, randomized controlled trial (RCT) for Alcohol Use Disorder
      examining the effects of doxazosin, a norepinephrine alpha1 receptor antagonist, on stress
      reactivity and clinical outcomes.
    

Detailed description: 
      OBJECTIVES:

        1. To translate the preclinical evidence from animal models to stress-induced relapse in
           humans via direct pharmacological antagonism of the noradrenergic system in abstinent
           alcoholics with doxazosin, an alpha1 noradrenergic receptor blocker.

        2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in
           abstinent alcoholics as a cost-effective first step to repurpose this alpha1
           noradrenergic antagonist for relapse prevention in addiction.

      PARTICIPANTS:

      136 participants with an Alcohol Use Disorder in early abstinence.

      STUDY OVERVIEW:

      136 adults with an Alcohol Use Disorder in early abstinence (1-8 weeks abstinent) will
      participate in a randomized controlled trial (RCT) to examine the efficacy of 8 mg doxazosin
      (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g.,
      drinks/week, alcohol craving) during a 8 week treatment period. Doxazosin's impact on
      stress-related relapse mechanisms will be assessed using a well-validated human model of
      stressor reactivity (No Shock, Predictable Shock, Unpredictable Shock [NPU] task) at baseline
      (pre-treatment) and after 4 weeks of treatment. The NPU task has strong translational ties to
      both methods (e.g., unpredictable vs. predictable electric shock) and measures (e.g., startle
      potentiation) from the preclinical literature in animals. This laboratory stress task serves
      as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and
      examine stress mechanisms.

      AIMS and HYPOTHESIS:

      AIM 1: Examine effects of a therapeutic dose of doxazosin on responses to unpredictable
      stressors in NPU task. The aim is to obtain preliminary evidence via a laboratory surrogate
      endpoint to repurpose doxazosin for the treatment of stress-induced relapse mechanisms in
      alcoholism.

      PREDICTIONS: Following four weeks of therapeutic dosing, doxazosin (8 mg vs. placebo,
      between-subjects) will selectively reduce response to unpredictable (vs. predictable)
      stressors indexed by physiological defensive reactivity (startle potentiation) and
      self-reported negative affect and craving in abstinent alcoholics.

      AIM 2: Examine effects of a therapeutic dose of doxazosin on early clinical outcome measures.
      The aim is to obtain additional evidence via clinical outcome measures to repurpose doxazosin
      for the treatment of stress-induced relapse mechanisms in alcoholism.

      PREDICTIONS: Following eight weeks of therapeutic dosing, doxazosin (8 mg vs. placebo,
      between-subjects) will increase continuous abstinence and decrease drinking days per week and
      drinks per week during the medication treatment period. Doxazosin will also decrease craving
      measured during the 8th week of medication use when participants have achieved the maximum
      dose for 4.5 weeks.

      AIM 3: Examine predictive validity of pre-treatment laboratory tests of noradrenergic
      relevant stress-reactivity on surrogate endpoint and clinical outcome measures. The aim is to
      link individual differences in stress reactivity at baseline (i.e. pre-treatment) to
      laboratory surrogate endpoints and early clinical outcome measures following therapeutic
      dosing.

      PREDICTIONS: Higher pre-treatment reactivity during unpredictable stressors will predict
      poorer surrogate endpoint and clinical outcomes overall. Therapeutic 8 mg dose effects of
      doxazosin will be greater among alcoholics who display higher pre-treatment reactivity to
      unpredictable stressors.

      AIM 4: Examine if the effects of doxazosin on clinical outcome measures are mediated by a
      reduction of stress-reactivity as measured by the NPU task. The aim is to identify whether
      reductions in stress-reactivity (NPU task) is the mechanism through which doxazosin has its
      effect on drinking behavior (clinical outcome).

      PREDICTIONS: The direct effect of doxazosin (vs. placebo) following 8 weeks of therapeutic 8
      mg dosing on clinical outcomes (e.g., continuous abstinence, drinking days/week, drinks/week)
      will be partially mediated by the indirect effect of doxazosin on surrogate endpoint of NPU
      stress reactivity at 4 weeks.
    

Intervention name(s): Doxazosin; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Doxazosin; Placebo
Intervention MeSH terms: Doxazosin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alcoholism; Stress; Norepinephrine; Doxazosin; Anxiety; Startle Potentiation; Relapse; Adrenergic Antagonists; Surrogate Endpoint