<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/NCT04405388</url>
  </required_header>
  <id_info>
    <org_study_id>30-468 ex 17/18</org_study_id>
    <nct_id>NCT04405388</nct_id>
  </id_info>
  <brief_title>Spermidine Anti-Hypertension Study</brief_title>
  <acronym>SMARTEST</acronym>
  <official_title>Spermidine Anti-Hypertension Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Graz</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Graz</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ETH Zurich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Tuebingen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical University of Graz</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The impact of daily spermidine application on arterial blood pressure and other secondary&#xD;
      parameters will be evaluated in a double-blind single center 46 patients cross-over study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Arterial hypertension is a central risk factor for cardiovascular disease, major&#xD;
      cardiovascular events and mortality. Treatment of arterial hypertension necessitates&#xD;
      lifestyle modifications, but often also requires medical intervention. In most cases, a&#xD;
      combination of two or more anti-hypertensive drugs is recommended and necessary for reaching&#xD;
      the target blood pressure levels.&#xD;
&#xD;
      Hypotheses / research questions/objectives Spermidine potentiates the blood pressure lowering&#xD;
      effect of standard anti-hypertensive medications, particularly when a combination of at least&#xD;
      two first-line drugs (as recommended by the European Society of Cardiology guidelines) has&#xD;
      not resulted in sufficient and adequate blood pressure control.&#xD;
&#xD;
      Approach/methods Spermidine Anti-Hypertension Study (SMARTEST) is a prospective, randomized&#xD;
      and double-blind placebo-controlled single-centre trial with a balanced 2x2 crossover design,&#xD;
      where 46 medically pre-treated hypertensive patients will be subsequently treated with&#xD;
      spermidine and placebo (each for eight weeks) in two arms of opposite treatment sequence. A&#xD;
      washout period of four weeks will separate the two intervention periods in both arms.&#xD;
&#xD;
      Patients will undergo physical examination, ECG (electrocardiogram), echocardiography, and&#xD;
      blood draws at four time points coinciding with the baseline and termination of each&#xD;
      treatment at: 0, 8, 12, and 20 weeks of/after recruitment at the Department of Cardiology,&#xD;
      Medical University of Graz. In addition, 24-hour ambulatory blood pressure (24-h BP)&#xD;
      monitoring (BPM; Mobil-O-Graph®) and on-site blood pressure will be obtained (the device will&#xD;
      be sent back to the hospital the following day) at these time points. A 6-minute walk test&#xD;
      (6MWT) will be performed at every visit.&#xD;
&#xD;
      Spermidine will be administered orally as an approved dietary supplement (spermidine-rich&#xD;
      wheat germ extract) at a dose of 4 mg spermidine per day for eight weeks. The primary outcome&#xD;
      will be arterial systolic blood pressure at 24h BPM. Further secondary outcomes/safety&#xD;
      outcomes will be:&#xD;
&#xD;
      24-h BP: analysis of systolic, diastolic and mean arterial blood pressures and pulse wave&#xD;
      analysis; on site ambulatory blood pressure; 6 minute walk test distance (difference in&#xD;
      meters); laboratory analysis; ECG - standard parameters; Echocardiography: standard&#xD;
      parameters as well as strain analysis&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 25, 2020</start_date>
  <completion_date type="Anticipated">November 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">November 15, 2024</primary_completion_date>
  <phase>Phase 3</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Systolic blood pressure in an ambulatory 24h blood pressure measurement</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>Patients will get RR recordings in an ambulatory setting</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pulse wave velocity</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>diastolic blood pressure</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mean blood pressure</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>central blood pressure</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 minute walk test</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>tested at every visit</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">46</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Spermidine first</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>First treatment period (8 weeks) will be 4 mg spermidine per day orally. Afterwards 4 weeks of wash-out followed by 8 weeks of placebo treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>First treatment period (8 weeks) will be placebo. Afterwards 4 weeks of wash-out followed by 8 weeks of 4 mg spermidine per day orally.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo will be given orally as capsule (same size and weight as Spermidine capula)</description>
    <arm_group_label>Placebo first</arm_group_label>
    <arm_group_label>Spermidine first</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spermidine</intervention_name>
    <description>Spermidine will be given orally as capsule (4mg/day)</description>
    <arm_group_label>Placebo first</arm_group_label>
    <arm_group_label>Spermidine first</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Able to provide signed and dated informed consent form&#xD;
&#xD;
          -  Persistant arterial hypertension with systolic blood pressure above 150 mmHg during&#xD;
             hospitalisation and the day of randomisation&#xD;
&#xD;
          -  Stable anti-hypertensive medication with at least two guideline-recommended&#xD;
             anti-hypertensive drugs&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Systolic blood pressure ≥180mmHg on the day of randomisation&#xD;
&#xD;
          -  Spermidine intolerance&#xD;
&#xD;
          -  Significant renal impairment defined as glomerular filtration rate &lt; 45ml/min&#xD;
&#xD;
          -  Insulin-dependent diabetes mellitus (IDDM)&#xD;
&#xD;
          -  Wheat allergy or gluten intolerance&#xD;
&#xD;
          -  Life expectancy of less than 12 months&#xD;
&#xD;
          -  Participation in another clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dirk von Lewinski, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>MUG</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Simon Sedej, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Medical University of Graz</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tobias Eisenberg, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Graz</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mahmoud Abdellatif, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Medical University of Graz</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dirk von Lewinski, MD</last_name>
    <phone>+43 316 385</phone>
    <phone_ext>80684</phone_ext>
    <email>dirk.von-lewinski@medunigraz.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Markus Wallner, MD</last_name>
    <phone>+43 316 385</phone>
    <phone_ext>31262</phone_ext>
    <email>markus.wallner@medunigraz.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University of Graz</name>
      <address>
        <city>Graz</city>
        <zip>8010</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dirk von Lewinski</last_name>
      <phone>+4331638580684</phone>
      <email>dirk.von-lewinski@medunigraz.at</email>
    </contact>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <results_reference>
    <citation>Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A, Eller K, Carmona-Gutierrez D, Buttner S, Pietrocola F, Knittelfelder O, Schrepfer E, Rockenfeller P, Simonini C, Rahn A, Horsch M, Moreth K, Beckers J, Fuchs H, Gailus-Durner V, Neff F, Janik D, Rathkolb B, Rozman J, de Angelis MH, Moustafa T, Haemmerle G, Mayr M, Willeit P, von Frieling-Salewsky M, Pieske B, Scorrano L, Pieber T, Pechlaner R, Willeit J, Sigrist SJ, Linke WA, Muhlfeld C, Sadoshima J, Dengjel J, Kiechl S, Kroemer G, Sedej S, Madeo F. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222. Epub 2016 Nov 14.</citation>
    <PMID>27841876</PMID>
  </results_reference>
  <results_reference>
    <citation>Wirth M, Benson G, Schwarz C, Kobe T, Grittner U, Schmitz D, Sigrist SJ, Bohlken J, Stekovic S, Madeo F, Floel A. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex. 2018 Dec;109:181-188. doi: 10.1016/j.cortex.2018.09.014. Epub 2018 Oct 4.</citation>
    <PMID>30388439</PMID>
  </results_reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>February 25, 2020</study_first_submitted>
  <study_first_submitted_qc>May 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>January 9, 2023</last_update_submitted>
  <last_update_submitted_qc>January 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>individual data will only be shared after approval of the local EC</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 23, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/88/NCT04405388/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04405388
org study id: 30-468 ex 17/18
nct id: NCT04405388
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The impact of daily spermidine application on arterial blood pressure and other secondary
      parameters will be evaluated in a double-blind single center 46 patients cross-over study.
Arterial hypertension is a central risk factor for cardiovascular disease, major
      cardiovascular events and mortality. Treatment of arterial hypertension necessitates
      lifestyle modifications, but often also requires medical intervention. In most cases, a
      combination of two or more anti-hypertensive drugs is recommended and necessary for reaching
      the target blood pressure levels.

      Hypotheses / research questions/objectives Spermidine potentiates the blood pressure lowering
      effect of standard anti-hypertensive medications, particularly when a combination of at least
      two first-line drugs (as recommended by the European Society of Cardiology guidelines) has
      not resulted in sufficient and adequate blood pressure control.

      Approach/methods Spermidine Anti-Hypertension Study (SMARTEST) is a prospective, randomized
      and double-blind placebo-controlled single-centre trial with a balanced 2x2 crossover design,
      where 46 medically pre-treated hypertensive patients will be subsequently treated with
      spermidine and placebo (each for eight weeks) in two arms of opposite treatment sequence. A
      washout period of four weeks will separate the two intervention periods in both arms.

      Patients will undergo physical examination, ECG (electrocardiogram), echocardiography, and
      blood draws at four time points coinciding with the baseline and termination of each
      treatment at: 0, 8, 12, and 20 weeks of/after recruitment at the Department of Cardiology,
      Medical University of Graz. In addition, 24-hour ambulatory blood pressure (24-h BP)
      monitoring (BPM; Mobil-O-Graph®) and on-site blood pressure will be obtained (the device will
      be sent back to the hospital the following day) at these time points. A 6-minute walk test
      (6MWT) will be performed at every visit.

      Spermidine will be administered orally as an approved dietary supplement (spermidine-rich
      wheat germ extract) at a dose of 4 mg spermidine per day for eight weeks. The primary outcome
      will be arterial systolic blood pressure at 24h BPM. Further secondary outcomes/safety
      outcomes will be:

      24-h BP: analysis of systolic, diastolic and mean arterial blood pressures and pulse wave
      analysis; on site ambulatory blood pressure; 6 minute walk test distance (difference in
      meters); laboratory analysis; ECG - standard parameters; Echocardiography: standard
      parameters as well as strain analysis
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Systolic blood pressure in an ambulatory 24h blood pressure measurement
time frame: up to 24 weeks
description: Patients will get RR recordings in an ambulatory setting
measure: Pulse wave velocity
time frame: up to 24 weeks
description: recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany
measure: diastolic blood pressure
time frame: up to 24 weeks
description: recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany
measure: mean blood pressure
time frame: up to 24 weeks
description: recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany
measure: central blood pressure
time frame: up to 24 weeks
description: recorded with the Mobil-O-Graph® PWA, I.E.M. GmbH, Stolberg, Germany
measure: 6 minute walk test
time frame: up to 24 weeks
description: tested at every visit
arm group label: Spermidine first
arm group type: Other
description: First treatment period (8 weeks) will be 4 mg spermidine per day orally. Afterwards 4 weeks of wash-out followed by 8 weeks of placebo treatment.
arm group label: Placebo first
arm group type: Other
description: First treatment period (8 weeks) will be placebo. Afterwards 4 weeks of wash-out followed by 8 weeks of 4 mg spermidine per day orally.
intervention type: Drug
intervention name: Placebo
description: Placebo will be given orally as capsule (same size and weight as Spermidine capula)
arm group label: Placebo first
arm group label: Spermidine first
intervention type: Drug
intervention name: Spermidine
description: Spermidine will be given orally as capsule (4mg/day)
arm group label: Placebo first
arm group label: Spermidine first
criteria: 
gender: All
minimum age: 19 Years
maximum age: 99 Years
healthy volunteers: No
last name: Dirk von Lewinski, MD
role: Principal Investigator
affiliation: MUG
last name: Simon Sedej, PhD
role: Study Director
affiliation: Medical University of Graz
last name: Tobias Eisenberg, PhD
role: Study Director
affiliation: University of Graz
last name: Mahmoud Abdellatif, MD, PhD
role: Study Director
affiliation: Medical University of Graz
last name: Dirk von Lewinski, MD
phone: +43 316 385
phone ext: 80684
email: dirk.von-lewinski@medunigraz.at
last name: Markus Wallner, MD
phone: +43 316 385
phone ext: 31262
email: markus.wallner@medunigraz.at
facility: 
status: Recruiting
contact: 
country: Austria
citation: Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A, Eller K, Carmona-Gutierrez D, Buttner S, Pietrocola F, Knittelfelder O, Schrepfer E, Rockenfeller P, Simonini C, Rahn A, Horsch M, Moreth K, Beckers J, Fuchs H, Gailus-Durner V, Neff F, Janik D, Rathkolb B, Rozman J, de Angelis MH, Moustafa T, Haemmerle G, Mayr M, Willeit P, von Frieling-Salewsky M, Pieske B, Scorrano L, Pieber T, Pechlaner R, Willeit J, Sigrist SJ, Linke WA, Muhlfeld C, Sadoshima J, Dengjel J, Kiechl S, Kroemer G, Sedej S, Madeo F. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222. Epub 2016 Nov 14.
PMID: 27841876
citation: Wirth M, Benson G, Schwarz C, Kobe T, Grittner U, Schmitz D, Sigrist SJ, Bohlken J, Stekovic S, Madeo F, Floel A. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex. 2018 Dec;109:181-188. doi: 10.1016/j.cortex.2018.09.014. Epub 2018 Oct 4.
PMID: 30388439
responsible party type: Sponsor
mesh term: Hypertension
sharing ipd: No
ipd description: individual data will only be shared after approval of the local EC
provided document: 