<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03825536</url>
  </required_header>
  <id_info>
    <org_study_id>18-26765</org_study_id>
    <secondary_id>1R61DA047024-01</secondary_id>
    <nct_id>NCT03825536</nct_id>
  </id_info>
  <brief_title>Effect of Methamphetamine on Residual Latent HIV Disease Study</brief_title>
  <acronym>EMRLHD</acronym>
  <official_title>Short-term Effects of Methamphetamine Exposure on Residual Viral Transcription During Treated HIV Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA).&#xD;
      Prior studies demonstrate strong evidence that MA promotes increased HIV transcription as&#xD;
      well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting&#xD;
      specific marginalized populations who are most likely to benefit from an HIV cure but possess&#xD;
      poorer immune responses. For this study, HIV+ infected ART-suppressed individuals with no&#xD;
      prior history of MA use disorder will be administered oral methamphetamine (the maximum FDA&#xD;
      approved daily dose for the treatment of childhood obesity) to determine the effects of&#xD;
      short-term MA exposure on residual virus production, gene expression, and inflammation.&#xD;
      Measures of MA exposure in urine and serum will then be associated with residual virus&#xD;
      production, gene expression, cell surface immune marker protein expression, and systemic&#xD;
      markers of inflammation. The clinical trial data will generate advanced gene expression and&#xD;
      immunologic data to identify potential novel targets for reversing HIV latency, reducing&#xD;
      inflammation, and personalizing future therapies in HIV+ individuals who use MA.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA),&#xD;
      and prior studies demonstrate strong evidence that MA promotes increased HIV transcription as&#xD;
      well as immune dysregulation. HIV cure has emerged as an important clinical and research&#xD;
      priority given evidence of ongoing immune dysfunction in HIV-infected individuals despite&#xD;
      effective antiretroviral therapy (ART). A challenge in achieving worldwide HIV eradication is&#xD;
      targeting specific vulnerable populations who are most likely to benefit from an HIV cure but&#xD;
      possess poorer immune responses as a result of residual viral replication due to suboptimal&#xD;
      ART adherence and/or direct immune dysfunction from illicit substance use. Prior non-human&#xD;
      studies demonstrate that MA directly induces HIV production and promotes immune activation&#xD;
      and inflammation. These preclinical findings suggest that HIV+ individuals who use MA may&#xD;
      experience greater immune dysfunction and face additional challenges for future HIV&#xD;
      eradication. This study will investigate the effects of short-term MA exposure in HIV+&#xD;
      ART-suppressed individuals without a prior history of MA use. Participants will be enrolled&#xD;
      in an interventional study where they will be administered oral methamphetamine (the maximum&#xD;
      FDA approved daily dose for the treatment of childhood obesity) to determine the effects of&#xD;
      short-term MA exposure on residual virus production, gene expression, inflammation, and trace&#xD;
      amine-associated 1 (TAAR1, a promising drug target for psychostimulant addiction) signaling.&#xD;
      MA exposure will be quantified with multiple serum samples collected over a 24-hour&#xD;
      monitoring period and associated with residual viral transcription, host gene and cell&#xD;
      surface protein expression, and inflammation (plasma inflammatory cytokine levels)&#xD;
      quantification. The proposed study will be the first human genetic study to directly evaluate&#xD;
      the effect of MA exposure on residual viral transcription during effective ART. The overall&#xD;
      goals of the study are to integrate a rigorous clinical study designs with high throughput&#xD;
      'omics data to identify novel targets for reversing HIV latency, reducing inflammation, and&#xD;
      personalizing future therapeutic strategies specific to HIV+ ART-suppressed individuals who&#xD;
      use MA.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2021</start_date>
  <completion_date type="Actual">January 11, 2023</completion_date>
  <primary_completion_date type="Actual">January 11, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>This is a phase IV open label randomized, double-blinded, placebo-controlled crossover study. A placebo treatment arm will be assigned to participants in a randomized crossover design. HIV+ ART-suppressed individuals with no prior history of MA use disorder will be administered 10mg oral methamphetamine hydrochloride, followed by 15 mg methamphetamine hydrochloride two hours later, for a total of 25mg in one 24-hour period (the maximum FDA approved daily dose for the treatment of childhood obesity). Participants will complete the study twice (once on a placebo treatment arm and once with the oral methamphetamine treatment arm). Which treatment arm occurs first will be randomly assigned and will include a 31-day washout period between the two phases.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The order in which participants complete the two treatment phases (i.e., oral methamphetamine and placebo) will be unknown to both the participants and the PI/study team. Both the oral methamphetamine and placebo will be prepared in identical capsules by the UCSF investigational pharmacist, out of sight of the study participant, study coordinator, and study site PI and administered to the participant to maintain double blinding. The investigational pharmacist will randomize each participant according to the methods described above. In the event that participant experiences an adverse event that requires the identity of the study drug be revealed, the PI will be able to contact the investigational pharmacist to break the blind. In the event that a participant blind is broken, the study PIs will determine the impact upon the un-blinded participant's continued participation in the study and if a replacement participant is needed on a case-by-case basis.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>HIV transcription (cell-associated HIV RNA) in peripheral blood</measure>
    <time_frame>4 hours</time_frame>
    <description>The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 4 hour study period.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Systemic inflammation (plasma pro-inflammatory cytokine levels)</measure>
    <time_frame>4 hours</time_frame>
    <description>The change in systemic inflammation (plasma pro-inflammatory cytokine levels) over a 4 hour study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Host gene expression (RNA sequencing) in peripheral blood</measure>
    <time_frame>4 hours</time_frame>
    <description>The change in host gene expression (RNA sequencing) over a 4 hour study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trace amine receptor 1 (TAAR1) signaling metabolite levels in in peripheral blood</measure>
    <time_frame>4 hours</time_frame>
    <description>The change in TAAR1 signaling metabolite levels over a 4 hour study period.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>HIV-1-infection</condition>
  <condition>Methamphetamine-dependence</condition>
  <arm_group>
    <arm_group_label>Oral methamphetamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be randomized to either oral methamphetamine versus placebo treatment first using a random number generator. Whichever treatment the participant receives first, they will receive the other treatment (placebo or oral methamphetamine) for their second treatment phase starting at approximately Day 77. For the experimental treatment arm, an initial 10 mg of oral methamphetamine study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose two hours later.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo oral capsule</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be randomized to either oral methamphetamine versus placebo treatment first using a random number generator. Whichever treatment the participant receives first, they will receive the other treatment (placebo or oral methamphetamine) for their second treatment phase starting at approximately Day 77. For the placebo treatment arm, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oral Methamphetamine</intervention_name>
    <description>In this phase IV open label double-blind randomized crossover study, participants will be randomized to either of two treatment arms, oral methamphetamine or placebo, using a crossover design with a 31-day washout period in between treatment arms. For the oral methamphetamine treatment arm, an initial 10 mg of oral methamphetamine (over-encapsulated to look similar to placebo capsule) study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose (over-encapsulated to look similar to placebo capsule) two hours later.</description>
    <arm_group_label>Oral methamphetamine</arm_group_label>
    <other_name>Desoxyn</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo oral capsule</intervention_name>
    <description>In this phase IV open label double-blind randomized crossover study, participants will be randomized to either of two treatment arms, oral methamphetamine or placebo, using a crossover design with a 31-day washout period in between treatment arms. For placebo treatment phase, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.</description>
    <arm_group_label>Placebo oral capsule</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able to provide written informed consent&#xD;
&#xD;
          2. Male or female, age ≥ 18 and ≤ 65 years&#xD;
&#xD;
          3. HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or&#xD;
             chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and&#xD;
             confirmed by a licensed Western blot or a second antibody test by a method other than&#xD;
             the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral&#xD;
             load.&#xD;
&#xD;
          4. Continuous therapy with a Department of Health and Human Services (DHHS)&#xD;
             recommended/alternative combination ART for least 24 months (at least 3 agents) at&#xD;
             study entry with no regimen changes in the preceding 12 weeks&#xD;
&#xD;
          5. Maintenance of undetectable plasma HIV-1 RNA (&lt;40 copies/ml) for at least 12 months.&#xD;
             Episodes of single HIV plasma RNA 50-500 copies/ml will not exclude participation if&#xD;
             subsequent HIV plasma RNA is &lt;40 copies/ml.&#xD;
&#xD;
          6. No plans to modify ART during the study period (146 days, or approximately 5 months)&#xD;
&#xD;
          7. Screening CD4+ (cluster of differentiation 4) T-cell count ≥ 350 cells/mm3&#xD;
&#xD;
          8. Screening hemoglobin ≥ 12.5 g/dL&#xD;
&#xD;
          9. No current or prior history of methamphetamine (MA) use disorder by DSM-5 diagnostic&#xD;
             criteria. Participants may have a prior history of taking prescription medications&#xD;
             containing amphetamines-type stimulants such as Adderall® or Dexedrine® or Ritalin for&#xD;
             the treatment of conditions such as attention deficit hyperactivity disorder as long&#xD;
             as the participant has not taken these medications in the last 12 months or plans to&#xD;
             take these medications during the entire study period.&#xD;
&#xD;
         10. Willingness to use two forms of contraception throughout the study period as well as&#xD;
             up to 30 days after the last day of study completion.&#xD;
&#xD;
         11. Ability and availability to participate in the full 146 days of the study&#xD;
             (approximately 5 month) and maintain the inclusion/exclusion criteria.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of methamphetamine (&quot;meth&quot;) use disorder by DSM-5 diagnostic criteria.&#xD;
&#xD;
          2. Evidence of MA use other than due to the administered oral methamphetamine study drug,&#xD;
             based on urine, hair, or serum MA measurements collected at baseline and follow-up&#xD;
             study visits.&#xD;
&#xD;
          3. Current use of prescription medications containing amphetamine-type stimulants (e.g.,&#xD;
             Adderall®, Dexedrine®, Ritalin, etc.) within the last 1 year.&#xD;
&#xD;
          4. Sensitivity or allergy to amphetamine-type stimulants&#xD;
&#xD;
          5. Current use of any other &quot;psychoactive&quot; drug within the last 1 year. These include&#xD;
             cocaine, ecstasy, lysergic acid diethylamide (LSD), mushrooms, or other recreational&#xD;
             drugs - but nicotine or caffeine use is ok.&#xD;
&#xD;
          6. Marijuana use in the last 30 days; marijuana may influence the interpretation of the&#xD;
             study drug's effect on viral transcription, inflammation, and/or gene expression.&#xD;
&#xD;
          7. Current use of opioids (heroin, methadone) or prescription opioid agonists such as&#xD;
             hydrocodone (Norco®), buprenorphine/naloxone (Suboxone®), oxycodone (Oxycontin®),&#xD;
             hydromorphone (Dilaudid®) within the last 1 year by self-report and/or urine&#xD;
             qualitative screening.&#xD;
&#xD;
          8. Current use of alcohol use disorder (DSM-5 criteria) within the last 1 year as this&#xD;
             might put patient at risk of withdrawal during the study.&#xD;
&#xD;
          9. Significant physical or psychiatric illness that might impair the ability to safely&#xD;
             complete the study or that might be complicated by the study drugs, including prior&#xD;
             seizures (after age 8) or other active neurological disease.&#xD;
&#xD;
         10. Clinically significant abnormalities on physical examination or screening laboratory&#xD;
             values&#xD;
&#xD;
         11. History of serious adverse event or hypersensitivity to MA or corn starch (the latter&#xD;
             is used in the placebo).&#xD;
&#xD;
         12. Recent use within the last month of the following medications given potential&#xD;
             interactions with oral methamphetamine: acebrophylline, iobenguane, isocarboxazid,&#xD;
             methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide,&#xD;
             selegiline, tranylcypromine, asunaprevir, buproprion, topical cocaine, fluoxetine,&#xD;
             iohexol, linezolid, paroxetine, potassium citrate, quinidine, sodium bicarbonate,&#xD;
             sodium citrate, sodium lactate, tipranavir, and tromethamine.&#xD;
&#xD;
         13. Recent hospitalization in the last 90 days.&#xD;
&#xD;
         14. Recent infection in the last 90 days requiring systemic antibiotics.&#xD;
&#xD;
         15. Screening hemoglobin below 12.5 g/dL.&#xD;
&#xD;
         16. Prior diagnosis or abnormal screening labs consistent with a diagnosis of&#xD;
             hyperthyroidism or hypothyroidism.&#xD;
&#xD;
         17. Poorly controlled hypertension with systolic blood pressure &gt; 160 on more than one&#xD;
             occasion.&#xD;
&#xD;
         18. History of glaucoma.&#xD;
&#xD;
         19. Significant myocardial disease (current myocarditis or reduced left ventricular&#xD;
             ejection fraction below the lower limit of normal) or diagnosed coronary artery&#xD;
             disease.&#xD;
&#xD;
         20. History of psychotic symptoms (e.g., hallucinations, delusional thinking).&#xD;
&#xD;
         21. History of bipolar disorder.&#xD;
&#xD;
         22. Significant respiratory disease requiring oxygen.&#xD;
&#xD;
         23. A history of hypersensitivity to sympathomimetic amines (e.g., epinephrine,&#xD;
             norepinephrine, or dopamine).&#xD;
&#xD;
         24. Diabetes or current hypothyroidism.&#xD;
&#xD;
         25. Participants of reproductive potential or breastfeeding. Women of childbearing&#xD;
             potential must have a negative serum pregnancy test at screening. All participants of&#xD;
             childbearing potential must agree to use a double-barrier method of contraception&#xD;
             throughout the study period and up to 90 days after the last dose of MA.&#xD;
&#xD;
         26. Exposure to any immunomodulatory drug (including maraviroc) in the 16 weeks prior to&#xD;
             study.&#xD;
&#xD;
         27. Prior or current use of experimental agents used with the intent to perturb the HIV-1&#xD;
             viral reservoir.&#xD;
&#xD;
         28. History of seizures, psychosis, abnormal electroencephalogram or brain damage with&#xD;
             significant persisting neurological deficit&#xD;
&#xD;
         29. Recent vaccination within the last 2 weeks prior to study baseline visit. Routine or&#xD;
             standard of care vaccinations (such as influenza, pneumococcal, and meningococcal&#xD;
             vaccinations) are allowed but must be administered greater than 14 days prior to&#xD;
             baseline study visit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sulggi A Lee, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>San Francisco General Hospital</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Castillo-Mancilla JR, Brown TT, Erlandson KM, Palella FJ Jr, Gardner EM, Macatangay BJ, Breen EC, Jacobson LP, Anderson PL, Wada NI. Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression. Clin Infect Dis. 2016 Dec 15;63(12):1661-1667. doi: 10.1093/cid/ciw650. Epub 2016 Sep 22.</citation>
    <PMID>27660234</PMID>
  </reference>
  <reference>
    <citation>Passaro RC, Pandhare J, Qian HZ, Dash C. The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis. J Neuroimmune Pharmacol. 2015 Sep;10(3):477-86. doi: 10.1007/s11481-015-9604-2. Epub 2015 Apr 8.</citation>
    <PMID>25850893</PMID>
  </reference>
  <reference>
    <citation>Centers for Disease Control and Prevention (CDC). Increasing morbidity and mortality associated with abuse of methamphetamine--United States, 1991-1994. MMWR Morb Mortal Wkly Rep. 1995 Dec 1;44(47):882-6.</citation>
    <PMID>7476843</PMID>
  </reference>
  <reference>
    <citation>Marquez C, Mitchell SJ, Hare CB, John M, Klausner JD. Methamphetamine use, sexual activity, patient-provider communication, and medication adherence among HIV-infected patients in care, San Francisco 2004-2006. AIDS Care. 2009 May;21(5):575-82. doi: 10.1080/09540120802385579.</citation>
    <PMID>19444665</PMID>
  </reference>
  <reference>
    <citation>Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK. Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. J Neurovirol. 2012 Oct;18(5):400-10. doi: 10.1007/s13365-012-0103-4. Epub 2012 May 22.</citation>
    <PMID>22618514</PMID>
  </reference>
  <reference>
    <citation>Liang H, Wang X, Chen H, Song L, Ye L, Wang SH, Wang YJ, Zhou L, Ho WZ. Methamphetamine enhances HIV infection of macrophages. Am J Pathol. 2008 Jun;172(6):1617-24. doi: 10.2353/ajpath.2008.070971. Epub 2008 May 5.</citation>
    <PMID>18458095</PMID>
  </reference>
  <reference>
    <citation>Toussi SS, Joseph A, Zheng JH, Dutta M, Santambrogio L, Goldstein H. Short communication: Methamphetamine treatment increases in vitro and in vivo HIV replication. AIDS Res Hum Retroviruses. 2009 Nov;25(11):1117-21. doi: 10.1089/aid.2008.0282.</citation>
    <PMID>19895343</PMID>
  </reference>
  <reference>
    <citation>Jiang J, Wang M, Liang B, Shi Y, Su Q, Chen H, Huang J, Su J, Pan P, Li Y, Wang H, Chen R, Liu J, Zhao F, Ye L, Liang H. In vivo effects of methamphetamine on HIV-1 replication: A population-based study. Drug Alcohol Depend. 2016 Feb 1;159:246-54. doi: 10.1016/j.drugalcdep.2015.12.027. Epub 2016 Jan 4.</citation>
    <PMID>26790825</PMID>
  </reference>
  <reference>
    <citation>Saito M, Yamaguchi T, Kawata T, Ito H, Kanai T, Terada M, Yokosuka M, Saito TR. Effects of methamphetamine on cortisone concentration, NK cell activity and mitogen response of T-lymphocytes in female cynomolgus monkeys. Exp Anim. 2006 Oct;55(5):477-81. doi: 10.1538/expanim.55.477.</citation>
    <PMID>17090965</PMID>
  </reference>
  <reference>
    <citation>Harms R, Morsey B, Boyer CW, Fox HS, Sarvetnick N. Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression. PLoS One. 2012;7(12):e49897. doi: 10.1371/journal.pone.0049897. Epub 2012 Dec 5.</citation>
    <PMID>23227154</PMID>
  </reference>
  <reference>
    <citation>Carrico AW, Flentje A, Kober K, Lee S, Hunt P, Riley ED, Shoptaw S, Flowers E, Dilworth SE, Pahwa S, Aouizerat BE. Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection. Brain Behav Immun. 2018 Jul;71:108-115. doi: 10.1016/j.bbi.2018.04.004. Epub 2018 Apr 18.</citation>
    <PMID>29679637</PMID>
  </reference>
  <reference>
    <citation>Jing L, Li JX. Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol. 2015 Aug 15;761:345-52. doi: 10.1016/j.ejphar.2015.06.019. Epub 2015 Jun 16.</citation>
    <PMID>26092759</PMID>
  </reference>
  <reference>
    <citation>Pei Y, Asif-Malik A, Hoener M, Canales JJ. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Addict Biol. 2017 Sep;22(5):1246-1256. doi: 10.1111/adb.12410. Epub 2016 May 19.</citation>
    <PMID>27193165</PMID>
  </reference>
  <reference>
    <citation>Panas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM. Trace amine associated receptor 1 signaling in activated lymphocytes. J Neuroimmune Pharmacol. 2012 Dec;7(4):866-76. doi: 10.1007/s11481-011-9321-4. Epub 2011 Oct 29.</citation>
    <PMID>22038157</PMID>
  </reference>
  <reference>
    <citation>Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK. Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.</citation>
    <PMID>18316681</PMID>
  </reference>
  <reference>
    <citation>Breen MS, Uhlmann A, Nday CM, Glatt SJ, Mitt M, Metsalpu A, Stein DJ, Illing N. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report. Transl Psychiatry. 2016 May 10;6(5):e802. doi: 10.1038/tp.2016.67.</citation>
    <PMID>27163203</PMID>
  </reference>
  <reference>
    <citation>Li MD, Wang J, Niu T, Ma JZ, Seneviratne C, Ait-Daoud N, Saadvandi J, Morris R, Weiss D, Campbell J, Haning W, Mawhinney DJ, Weis D, McCann M, Stock C, Kahn R, Iturriaga E, Yu E, Elkashef A, Johnson BA. Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction. BMC Med Genomics. 2014 Dec 12;7:65. doi: 10.1186/s12920-014-0065-x.</citation>
    <PMID>25495887</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>May 8, 2023</last_update_submitted>
  <last_update_submitted_qc>May 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>methamphetamine</keyword>
  <keyword>viral transcription</keyword>
  <keyword>inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methamphetamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03825536
org study id: 18-26765
secondary id: 1R61DA047024-01
nct id: NCT03825536
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA).
      Prior studies demonstrate strong evidence that MA promotes increased HIV transcription as
      well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting
      specific marginalized populations who are most likely to benefit from an HIV cure but possess
      poorer immune responses. For this study, HIV+ infected ART-suppressed individuals with no
      prior history of MA use disorder will be administered oral methamphetamine (the maximum FDA
      approved daily dose for the treatment of childhood obesity) to determine the effects of
      short-term MA exposure on residual virus production, gene expression, and inflammation.
      Measures of MA exposure in urine and serum will then be associated with residual virus
      production, gene expression, cell surface immune marker protein expression, and systemic
      markers of inflammation. The clinical trial data will generate advanced gene expression and
      immunologic data to identify potential novel targets for reversing HIV latency, reducing
      inflammation, and personalizing future therapies in HIV+ individuals who use MA.
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA),
      and prior studies demonstrate strong evidence that MA promotes increased HIV transcription as
      well as immune dysregulation. HIV cure has emerged as an important clinical and research
      priority given evidence of ongoing immune dysfunction in HIV-infected individuals despite
      effective antiretroviral therapy (ART). A challenge in achieving worldwide HIV eradication is
      targeting specific vulnerable populations who are most likely to benefit from an HIV cure but
      possess poorer immune responses as a result of residual viral replication due to suboptimal
      ART adherence and/or direct immune dysfunction from illicit substance use. Prior non-human
      studies demonstrate that MA directly induces HIV production and promotes immune activation
      and inflammation. These preclinical findings suggest that HIV+ individuals who use MA may
      experience greater immune dysfunction and face additional challenges for future HIV
      eradication. This study will investigate the effects of short-term MA exposure in HIV+
      ART-suppressed individuals without a prior history of MA use. Participants will be enrolled
      in an interventional study where they will be administered oral methamphetamine (the maximum
      FDA approved daily dose for the treatment of childhood obesity) to determine the effects of
      short-term MA exposure on residual virus production, gene expression, inflammation, and trace
      amine-associated 1 (TAAR1, a promising drug target for psychostimulant addiction) signaling.
      MA exposure will be quantified with multiple serum samples collected over a 24-hour
      monitoring period and associated with residual viral transcription, host gene and cell
      surface protein expression, and inflammation (plasma inflammatory cytokine levels)
      quantification. The proposed study will be the first human genetic study to directly evaluate
      the effect of MA exposure on residual viral transcription during effective ART. The overall
      goals of the study are to integrate a rigorous clinical study designs with high throughput
      'omics data to identify novel targets for reversing HIV latency, reducing inflammation, and
      personalizing future therapeutic strategies specific to HIV+ ART-suppressed individuals who
      use MA.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: This is a phase IV open label randomized, double-blinded, placebo-controlled crossover study. A placebo treatment arm will be assigned to participants in a randomized crossover design. HIV+ ART-suppressed individuals with no prior history of MA use disorder will be administered 10mg oral methamphetamine hydrochloride, followed by 15 mg methamphetamine hydrochloride two hours later, for a total of 25mg in one 24-hour period (the maximum FDA approved daily dose for the treatment of childhood obesity). Participants will complete the study twice (once on a placebo treatment arm and once with the oral methamphetamine treatment arm). Which treatment arm occurs first will be randomly assigned and will include a 31-day washout period between the two phases.
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The order in which participants complete the two treatment phases (i.e., oral methamphetamine and placebo) will be unknown to both the participants and the PI/study team. Both the oral methamphetamine and placebo will be prepared in identical capsules by the UCSF investigational pharmacist, out of sight of the study participant, study coordinator, and study site PI and administered to the participant to maintain double blinding. The investigational pharmacist will randomize each participant according to the methods described above. In the event that participant experiences an adverse event that requires the identity of the study drug be revealed, the PI will be able to contact the investigational pharmacist to break the blind. In the event that a participant blind is broken, the study PIs will determine the impact upon the un-blinded participant's continued participation in the study and if a replacement participant is needed on a case-by-case basis.
measure: HIV transcription (cell-associated HIV RNA) in peripheral blood
time frame: 4 hours
description: The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 4 hour study period.
measure: Systemic inflammation (plasma pro-inflammatory cytokine levels)
time frame: 4 hours
description: The change in systemic inflammation (plasma pro-inflammatory cytokine levels) over a 4 hour study period.
measure: Host gene expression (RNA sequencing) in peripheral blood
time frame: 4 hours
description: The change in host gene expression (RNA sequencing) over a 4 hour study period.
measure: Trace amine receptor 1 (TAAR1) signaling metabolite levels in in peripheral blood
time frame: 4 hours
description: The change in TAAR1 signaling metabolite levels over a 4 hour study period.
arm group label: Oral methamphetamine
arm group type: Experimental
description: Participants will be randomized to either oral methamphetamine versus placebo treatment first using a random number generator. Whichever treatment the participant receives first, they will receive the other treatment (placebo or oral methamphetamine) for their second treatment phase starting at approximately Day 77. For the experimental treatment arm, an initial 10 mg of oral methamphetamine study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose two hours later.
arm group label: Placebo oral capsule
arm group type: Placebo Comparator
description: Participants will be randomized to either oral methamphetamine versus placebo treatment first using a random number generator. Whichever treatment the participant receives first, they will receive the other treatment (placebo or oral methamphetamine) for their second treatment phase starting at approximately Day 77. For the placebo treatment arm, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.
intervention type: Drug
intervention name: Oral Methamphetamine
description: In this phase IV open label double-blind randomized crossover study, participants will be randomized to either of two treatment arms, oral methamphetamine or placebo, using a crossover design with a 31-day washout period in between treatment arms. For the oral methamphetamine treatment arm, an initial 10 mg of oral methamphetamine (over-encapsulated to look similar to placebo capsule) study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose (over-encapsulated to look similar to placebo capsule) two hours later.
arm group label: Oral methamphetamine
other name: Desoxyn
intervention type: Other
intervention name: Placebo oral capsule
description: In this phase IV open label double-blind randomized crossover study, participants will be randomized to either of two treatment arms, oral methamphetamine or placebo, using a crossover design with a 31-day washout period in between treatment arms. For placebo treatment phase, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.
arm group label: Placebo oral capsule
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Sulggi A Lee, MD PhD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
citation: Castillo-Mancilla JR, Brown TT, Erlandson KM, Palella FJ Jr, Gardner EM, Macatangay BJ, Breen EC, Jacobson LP, Anderson PL, Wada NI. Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression. Clin Infect Dis. 2016 Dec 15;63(12):1661-1667. doi: 10.1093/cid/ciw650. Epub 2016 Sep 22.
PMID: 27660234
citation: Passaro RC, Pandhare J, Qian HZ, Dash C. The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis. J Neuroimmune Pharmacol. 2015 Sep;10(3):477-86. doi: 10.1007/s11481-015-9604-2. Epub 2015 Apr 8.
PMID: 25850893
citation: Centers for Disease Control and Prevention (CDC). Increasing morbidity and mortality associated with abuse of methamphetamine--United States, 1991-1994. MMWR Morb Mortal Wkly Rep. 1995 Dec 1;44(47):882-6.
PMID: 7476843
citation: Marquez C, Mitchell SJ, Hare CB, John M, Klausner JD. Methamphetamine use, sexual activity, patient-provider communication, and medication adherence among HIV-infected patients in care, San Francisco 2004-2006. AIDS Care. 2009 May;21(5):575-82. doi: 10.1080/09540120802385579.
PMID: 19444665
citation: Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK. Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. J Neurovirol. 2012 Oct;18(5):400-10. doi: 10.1007/s13365-012-0103-4. Epub 2012 May 22.
PMID: 22618514
citation: Liang H, Wang X, Chen H, Song L, Ye L, Wang SH, Wang YJ, Zhou L, Ho WZ. Methamphetamine enhances HIV infection of macrophages. Am J Pathol. 2008 Jun;172(6):1617-24. doi: 10.2353/ajpath.2008.070971. Epub 2008 May 5.
PMID: 18458095
citation: Toussi SS, Joseph A, Zheng JH, Dutta M, Santambrogio L, Goldstein H. Short communication: Methamphetamine treatment increases in vitro and in vivo HIV replication. AIDS Res Hum Retroviruses. 2009 Nov;25(11):1117-21. doi: 10.1089/aid.2008.0282.
PMID: 19895343
citation: Jiang J, Wang M, Liang B, Shi Y, Su Q, Chen H, Huang J, Su J, Pan P, Li Y, Wang H, Chen R, Liu J, Zhao F, Ye L, Liang H. In vivo effects of methamphetamine on HIV-1 replication: A population-based study. Drug Alcohol Depend. 2016 Feb 1;159:246-54. doi: 10.1016/j.drugalcdep.2015.12.027. Epub 2016 Jan 4.
PMID: 26790825
citation: Saito M, Yamaguchi T, Kawata T, Ito H, Kanai T, Terada M, Yokosuka M, Saito TR. Effects of methamphetamine on cortisone concentration, NK cell activity and mitogen response of T-lymphocytes in female cynomolgus monkeys. Exp Anim. 2006 Oct;55(5):477-81. doi: 10.1538/expanim.55.477.
PMID: 17090965
citation: Harms R, Morsey B, Boyer CW, Fox HS, Sarvetnick N. Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression. PLoS One. 2012;7(12):e49897. doi: 10.1371/journal.pone.0049897. Epub 2012 Dec 5.
PMID: 23227154
citation: Carrico AW, Flentje A, Kober K, Lee S, Hunt P, Riley ED, Shoptaw S, Flowers E, Dilworth SE, Pahwa S, Aouizerat BE. Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection. Brain Behav Immun. 2018 Jul;71:108-115. doi: 10.1016/j.bbi.2018.04.004. Epub 2018 Apr 18.
PMID: 29679637
citation: Jing L, Li JX. Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol. 2015 Aug 15;761:345-52. doi: 10.1016/j.ejphar.2015.06.019. Epub 2015 Jun 16.
PMID: 26092759
citation: Pei Y, Asif-Malik A, Hoener M, Canales JJ. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Addict Biol. 2017 Sep;22(5):1246-1256. doi: 10.1111/adb.12410. Epub 2016 May 19.
PMID: 27193165
citation: Panas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM. Trace amine associated receptor 1 signaling in activated lymphocytes. J Neuroimmune Pharmacol. 2012 Dec;7(4):866-76. doi: 10.1007/s11481-011-9321-4. Epub 2011 Oct 29.
PMID: 22038157
citation: Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK. Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
PMID: 18316681
citation: Breen MS, Uhlmann A, Nday CM, Glatt SJ, Mitt M, Metsalpu A, Stein DJ, Illing N. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report. Transl Psychiatry. 2016 May 10;6(5):e802. doi: 10.1038/tp.2016.67.
PMID: 27163203
citation: Li MD, Wang J, Niu T, Ma JZ, Seneviratne C, Ait-Daoud N, Saadvandi J, Morris R, Weiss D, Campbell J, Haning W, Mawhinney DJ, Weis D, McCann M, Stock C, Kahn R, Iturriaga E, Yu E, Elkashef A, Johnson BA. Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction. BMC Med Genomics. 2014 Dec 12;7:65. doi: 10.1186/s12920-014-0065-x.
PMID: 25495887
responsible party type: Sponsor
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Methamphetamine
sharing ipd: No