<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/NCT03761979</url>
  </required_header>
  <id_info>
    <org_study_id>BIO-1703</org_study_id>
    <nct_id>NCT03761979</nct_id>
  </id_info>
  <brief_title>Safety and Pharmacokinetics of Orally Administered Strontium L-Lactate in Healthy Adults</brief_title>
  <official_title>Safety and Pharmacokinetics of Orally Administered Strontium L-Lactate in Healthy Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>BioLink Life Sciences, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Biofortis Innovation Services, a division of Merieux Nutrisciences, Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>NMS Laboratories</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>BioLink Life Sciences, Inc.</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>
      No clinical trials have evaluated strontium L-lactate (SrLac), the strontium salt of the&#xD;
      L-enantiomer of lactic acid. Therefore, this clinical study was conducted to obtain general&#xD;
      safety and pharmacokinetic (PK) information following acute oral intakes of three doses of&#xD;
      SrLac by healthy adults. The data provided valuable comparisons with the pharmacokinetics of&#xD;
      other strontium salts that are in clinical use and allowed determination of the dose of SrLac&#xD;
      that will be useful for the management of bone health.neficial for the treatment of low bone&#xD;
      density of osteoporosis and osteopenia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose: The aim of this clinical study was to obtain safety and pharmacokinetic information&#xD;
      following acute oral intakes of three ascending doses of strontium L-lactate by healthy&#xD;
      adults.&#xD;
&#xD;
      Subjects and methods: Ten healthy men and women, mean age 43 ± 2 years, ingested one of three&#xD;
      ascending doses of strontium L-lactate (SrLac) once per week for three weeks in succession.&#xD;
      Fasting blood collections were performed pre-dose and 1, 2, 3, 4, 5, 6, 8 and 12 hours&#xD;
      post-dose for determination of serum strontium at each interval.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 9, 2017</start_date>
  <completion_date type="Actual">July 17, 2017</completion_date>
  <primary_completion_date type="Actual">June 1, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This was an unblinded, sequential, three dose study. The study consisted of one screening visit (Visit 1; day -7) and three test visits (Visits 2, 3, and 4; days 0, 7, and 14) with at least a 6-d washout between test visits.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
    <masking_description>Subjects' anonymity was maintained on electronic case report forms (eCRFs) and other documents by utilization of initials, number, or code, and not by using a subject's name. The Investigator kept a separate log showing codes, names, and addresses. All documents showing the subjects' identity were kept in strict confidence by the Investigator.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>iAUC-0.25-12h</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>The primary outcome variable was the incremental area under the curve (iAUC) for serum strontium from pre-product consumption (t = -0.25 h) to 12 h (iAUC-0.25-12h).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>(iAUC-0.25-∞)</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>iAUC for serum strontium from pre-product consumption (t = -0.25 h) to infinity (iAUC-0.25-∞)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>Maximum serum concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>Time to Cmax (Tmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>K</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>Rate of elimination (K)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>t1/2</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>Half life (t1/2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oral bioavailability (F)</measure>
    <time_frame>0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing</time_frame>
    <description>The fraction of the amount of strontium given orally that reaches the systemic circulation</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Low Bone Density</condition>
  <condition>Osteopenia</condition>
  <condition>Osteoporosis, Postmenopausal</condition>
  <arm_group>
    <arm_group_label>Strontium dose of 170 mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The Sponsor provided each 170 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>strontium dose of 340 mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The Sponsor provided each 340 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Strontium dose of 680 mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The Sponsor provided each 680 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Strontium L-lactate</intervention_name>
    <description>The Study Product was a highly pure form of SrLac, the strontium salt of L-lactic acid. SrLac was manufactured in compliance with current Good Manufacturing Practices. SrLac was thoroughly tested and met rigorous purity specifications. It was free from contamination by D-lactic acid and trace metals known to harm human health.</description>
    <arm_group_label>Strontium dose of 170 mg</arm_group_label>
    <arm_group_label>Strontium dose of 680 mg</arm_group_label>
    <arm_group_label>strontium dose of 340 mg</arm_group_label>
    <other_name>SrLac</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Subject is a generally healthy male or female, 18-65 years of age, inclusive.&#xD;
&#xD;
          2. Subject has a score of 7 to l O on the Vein Access Scale at Visit l (day -7).&#xD;
&#xD;
          3. Subjects exhibits a body weight &gt;60 kg and has a BMI of2:l 8.0 and &lt;32.0 kg/m2 at&#xD;
             Visit 1 (day -7).&#xD;
&#xD;
          4. Subject is willing to avoid use of any over-the-counter medications and/or dietary&#xD;
             supplements (vitamins, minerals and/or other supplements) within 3 d prior to visit 1&#xD;
             (day-7) and/or prescription medications (except for stable-dose oral contraceptives)&#xD;
             within 14 d prior to visit l (day -7) and throughout the study period.&#xD;
&#xD;
          5. Subject is willing to avoid alcohol 3 d prior to each test visit (Visits 2, 3, and 4;&#xD;
             days 0, 7, and 14).&#xD;
&#xD;
          6. Subject is willing to avoid grapefruit and/or grapefruit juice 3 d prior to each test&#xD;
             visit (Visits 2, 3, and 4; days 0, 7, and 14).&#xD;
&#xD;
          7. Subject is willing to maintain habitual diet, physical activity patterns, and body&#xD;
             weight throughout the trial.&#xD;
&#xD;
          8. Subject is a non-user of all tobacco, smoking products (including, but not limited to&#xD;
             cigarettes, cigars, chewing tobacco, e-cigarettes), and nicotine products (e.g.,&#xD;
             nicotine gum and/or nicotine patches) within 6 months of Visit 1 (day -7) and has no&#xD;
             plans to change status during the study period.&#xD;
&#xD;
          9. Subject has no health conditions that would prevent him/her from fulfilling the study&#xD;
             requirements as judged by the Clinical Investigator on the basis of medical history&#xD;
             and routine laboratory test results.&#xD;
&#xD;
        l 0. Subject understands the study procedures and signs forms providing informed consent to&#xD;
        participate in the study and authorizes the release of relevant protected health&#xD;
        information to the Clinical Investigator.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subject has abnormal laboratory test results of clinical significance at Visit 1 (day&#xD;
             -7) at the discretion of the Investigator. One re-test will be allowed on a separate&#xD;
             day prior to Visit 2 (day 0), for subjects with abnormal laboratory test results.&#xD;
&#xD;
          2. Subject has a known allergy or sensitivity to any of the ingredients in the study&#xD;
             products and/or any ingredients of the meals provided.&#xD;
&#xD;
          3. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, and/or a&#xD;
             clinically important reaction to any drug.&#xD;
&#xD;
          4. Subject has a history or presence of clinically important endocrine (including&#xD;
             hyperparathyroidism, type l or 2 diabetes mellitus and/or hypoglycemia),&#xD;
             cardiovascular (including, but not limited to history of myocardial infarction,&#xD;
             peripheral arterial disease, stroke), pulmonary (including uncontrolled asthma),&#xD;
             hepatic, renal, hematologic, immunologic, dermatologic, neurologic (such as&#xD;
             Alzheimer's or Parkinson's patients), rheumatic (including gout), biliary, and/or&#xD;
             psychiatric disorders (including depression and/or anxiety disorders), that, in the&#xD;
             opinion of the Investigator, could interfere with the interpretation of the study&#xD;
             results.&#xD;
&#xD;
          5. Subject has had a loss of 400 mL of blood (e.g., blood/plasma donation) during the&#xD;
             prior 30 d of visit 2 (day 0).&#xD;
&#xD;
          6. Subject has a history or current GI disorder that, in the judgment of the&#xD;
             Investigator, may have the potential to disrupt normal digestion and absorption.&#xD;
&#xD;
          7. Subject has a history or presence of cancer in the prior two years, except for non-&#xD;
             melanoma skin cancer.&#xD;
&#xD;
          8. Subject has a history of bariatric surgery for weight reducing purposes.&#xD;
&#xD;
          9. Subject has recently (within 6 months prior to Visit 1; day -7) had a weight loss or&#xD;
             gain &gt;4.5 kg.&#xD;
&#xD;
        I 0. Subject has uncontrolled hypertension (systolic blood pressure 2:160 mm Hg or&#xD;
        diastolic blood pressure 2:100 mm Hg) as defined by the blood pressure measured at Visit 1&#xD;
        (day -7). One re-test will be allowed on a separate day prior to Visit 2 (day 0), for&#xD;
        subjects with abnormal blood pressure.&#xD;
&#xD;
        11. Subject has extreme dietary habits (e.g., Atkins diet, very high protein, vegetarian,&#xD;
        intentional consumption of a high fiber diet), in the opinion of the Clinical Investigator.&#xD;
&#xD;
        12. Subject is a female, who is pregnant, planning to be pregnant during the study period,&#xD;
        lactating, or is of childbearing potential and is unwilling to commit to the use of a&#xD;
        medically approved form of contraception throughout the study period. The method of&#xD;
        contraception must be recorded in the source documentation.&#xD;
&#xD;
        13. Subject has been exposed to any non-registered drug product within 30 d prior to visit&#xD;
        I (day-7).&#xD;
&#xD;
        14. Subject has a recent history of (within 12 months of screening; Visit I; day -7) or&#xD;
        strong potential for alcohol or substance abuse. Alcohol abuse is defined as &gt;14 drinks per&#xD;
        week (1 drink= 12 oz beer, 5 oz wine, or I Yi oz distilled spirits).&#xD;
&#xD;
        15. Individual has a condition the Clinical Investigator believes would interfere with his&#xD;
        or her ability to provide informed consent, comply with the study protocol, which might&#xD;
        confound the interpretation of the study results, or put the subject at undue risk.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristin Sanoshy</last_name>
    <role>Study Director</role>
    <affiliation>Biofortis Innovation Services</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Biofortis Innovation Services</name>
      <address>
        <city>Addison</city>
        <state>Illinois</state>
        <zip>60101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>November 30, 2018</last_update_submitted>
  <last_update_submitted_qc>November 30, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Bone density</keyword>
  <keyword>Osteopenia</keyword>
  <keyword>Osteoporosis</keyword>
  <keyword>Bone health</keyword>
  <keyword>Pharmacokinetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoporosis</mesh_term>
    <mesh_term>Bone Diseases, Metabolic</mesh_term>
    <mesh_term>Osteoporosis, Postmenopausal</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Study data will be shared as needed to complete Institutional Review Board (IRB) reviews, enable statistical analyses, and prepare study reports.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>3/1/2017 - 7/17/2017</ipd_time_frame>
    <ipd_access_criteria>Access must be authorized by Study Director at Biofortis Innovation Services</ipd_access_criteria>
  </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>March 9, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03761979/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>December 5, 2018</submitted>
    <returned>March 22, 2019</returned>
    <submitted>July 8, 2019</submitted>
    <returned>August 16, 2019</returned>
  </pending_results>
  <!-- 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/NCT03761979
org study id: BIO-1703
nct id: NCT03761979
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
No clinical trials have evaluated strontium L-lactate (SrLac), the strontium salt of the
      L-enantiomer of lactic acid. Therefore, this clinical study was conducted to obtain general
      safety and pharmacokinetic (PK) information following acute oral intakes of three doses of
      SrLac by healthy adults. The data provided valuable comparisons with the pharmacokinetics of
      other strontium salts that are in clinical use and allowed determination of the dose of SrLac
      that will be useful for the management of bone health.neficial for the treatment of low bone
      density of osteoporosis and osteopenia.
Purpose: The aim of this clinical study was to obtain safety and pharmacokinetic information
      following acute oral intakes of three ascending doses of strontium L-lactate by healthy
      adults.

      Subjects and methods: Ten healthy men and women, mean age 43 ± 2 years, ingested one of three
      ascending doses of strontium L-lactate (SrLac) once per week for three weeks in succession.
      Fasting blood collections were performed pre-dose and 1, 2, 3, 4, 5, 6, 8 and 12 hours
      post-dose for determination of serum strontium at each interval.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This was an unblinded, sequential, three dose study. The study consisted of one screening visit (Visit 1; day -7) and three test visits (Visits 2, 3, and 4; days 0, 7, and 14) with at least a 6-d washout between test visits.
primary purpose: Other
masking: Double (Participant, Outcomes Assessor)
masking description: Subjects' anonymity was maintained on electronic case report forms (eCRFs) and other documents by utilization of initials, number, or code, and not by using a subject's name. The Investigator kept a separate log showing codes, names, and addresses. All documents showing the subjects' identity were kept in strict confidence by the Investigator.
measure: iAUC-0.25-12h
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: The primary outcome variable was the incremental area under the curve (iAUC) for serum strontium from pre-product consumption (t = -0.25 h) to 12 h (iAUC-0.25-12h).
measure: (iAUC-0.25-∞)
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: iAUC for serum strontium from pre-product consumption (t = -0.25 h) to infinity (iAUC-0.25-∞)
measure: Cmax
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: Maximum serum concentration (Cmax)
measure: Tmax
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: Time to Cmax (Tmax)
measure: K
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: Rate of elimination (K)
measure: t1/2
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: Half life (t1/2)
measure: Oral bioavailability (F)
time frame: 0.25 hour pre-dosing to 12 hours post-dosing on each day of dosing
description: The fraction of the amount of strontium given orally that reaches the systemic circulation
arm group label: Strontium dose of 170 mg
arm group type: Active Comparator
description: The Sponsor provided each 170 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.
arm group label: strontium dose of 340 mg
arm group type: Active Comparator
description: The Sponsor provided each 340 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.
arm group label: Strontium dose of 680 mg
arm group type: Active Comparator
description: The Sponsor provided each 680 mg dose of strontium as strontium L-lactate dry powder packaged in individual vials. The powder was prepared for consumption by adding 10 mL of distilled water to the vial and stirring until dissolution was complete. This liquid was then poured into an administration cup. An additional 10 mL of distilled water was used to rinse the remaining SrLac into the administration cup. Then 80 mL of distilled water was added directly into the administration cup. Following consumption of the 100 mL solution of SrLac, another 100 mL of distilled water was added into the administration cup, swirled, and consumed by the subject.
intervention type: Dietary Supplement
intervention name: Strontium L-lactate
description: The Study Product was a highly pure form of SrLac, the strontium salt of L-lactic acid. SrLac was manufactured in compliance with current Good Manufacturing Practices. SrLac was thoroughly tested and met rigorous purity specifications. It was free from contamination by D-lactic acid and trace metals known to harm human health.
arm group label: Strontium dose of 170 mg
arm group label: Strontium dose of 680 mg
arm group label: strontium dose of 340 mg
other name: SrLac
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kristin Sanoshy
role: Study Director
affiliation: Biofortis Innovation Services
facility: 
country: United States
responsible party type: Sponsor
mesh term: Osteoporosis
mesh term: Bone Diseases, Metabolic
mesh term: Osteoporosis, Postmenopausal
sharing ipd: Yes
ipd description: Study data will be shared as needed to complete Institutional Review Board (IRB) reviews, enable statistical analyses, and prepare study reports.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: 3/1/2017 - 7/17/2017
ipd access criteria: Access must be authorized by Study Director at Biofortis Innovation Services
provided document: 
submitted: December 5, 2018
returned: March 22, 2019
submitted: July 8, 2019
returned: August 16, 2019