<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/NCT03752112</url>
  </required_header>
  <id_info>
    <org_study_id>ERC0003096</org_study_id>
    <nct_id>NCT03752112</nct_id>
  </id_info>
  <brief_title>Trial Evaluating the Clinical Efficacy of Cefixime for Treatment of Early Syphilis in Non-pregnant Women</brief_title>
  <official_title>Trial Evaluating the Clinical Efficacy of Cefixime for Treatment of Early Syphilis in Non-pregnant Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>World Health Organization</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>World Health Organization</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</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>
      Hypotheses The antibiotic, Cefixime, for use in non-pregnant women with early syphilis will&#xD;
      be efficacious and safe.&#xD;
&#xD;
      Primary Objective The primary objective of the study is to demonstrate the efficacy, as&#xD;
      measured by a 4 fold decrease in Rapid Plasma Reagin (RPR) titer from baseline to 6 months&#xD;
      after treatment, with Cefixime 400mg taken orally two times a day for 10 consecutive days.&#xD;
&#xD;
      Secondary Objective The secondary objective of the study is to determine the safety, as&#xD;
      measured by the number of grade 3 or greater toxicities experienced, using the NIH/NCI&#xD;
      toxicity score, during or after treatment with Cefixime 400mg taken orally two times a day&#xD;
      for 10 consecutive days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypotheses The antibiotic, Cefixime, for use in non-pregnant women with early syphilis will&#xD;
      be efficacious and safe.&#xD;
&#xD;
      Primary Objective The primary objective of the study is to demonstrate the efficacy, as&#xD;
      measured by a 4 fold decrease in Rapid Plasma Reagin (RPR) titer from baseline to 6 months&#xD;
      after treatment, with Cefixime 400mg taken orally two times a day for 10 consecutive days.&#xD;
&#xD;
      Secondary Objective The secondary objective of the study is to determine the safety, as&#xD;
      measured by the number of grade 3 or greater toxicities experienced, using the NIH/NCI&#xD;
      toxicity score (10), during or after treatment with Cefixime 400mg taken orally two times a&#xD;
      day for 10 consecutive days.&#xD;
&#xD;
      Methods Study design This is a randomized, non-comparative, open-label study assessing the&#xD;
      efficacy and safety of cefixime 400mg taken orally two times a day for 10 consecutive days in&#xD;
      non-pregnant women with early syphilis infection.&#xD;
&#xD;
      Study population and enrolment sites Numerous regions of Brazil have experienced increases in&#xD;
      syphilis diagnoses during the previous 5 years The study sites were chosen from three cities&#xD;
      in three separate regions (states) of Brazil based on: (1) increases in syphilis case&#xD;
      reports, (2) access to clinics where patients are screened and treated for syphilis; (3)&#xD;
      willingness of clinic sites and staff to participate in this research, and (4) the&#xD;
      availability of experienced researchers with experience in studying syphilis to serve as&#xD;
      co-investigators.&#xD;
&#xD;
      The study population will include non-pregnant women (ages 18 and over) diagnosed with early&#xD;
      syphilis (RPR titers &gt;1:8) recruited from 7 clinics in three cities from three states in&#xD;
      Brazil. These include: (1) Three clinics in the city of Fortaleza (Ceara State), coordinated&#xD;
      by the University of Fortaleza (UNIFOR): (a) Carlos Ribeiro, (a) Meireles, and (c) Federal&#xD;
      University. Syphilis epidemiology for each site in Annex 1. (2) Two University ObGyn Clinics&#xD;
      in the city of Pelotas (state of Rio Grande do Sul) (5-6 cases of syphilis/week) a)&#xD;
      Ambulatorio de Ginecologia e Obstetrícia - Faculdade de Medicina - Universidade Federal de&#xD;
      Pelotas and b) Ambulatorio de Ginecologia e Obstetrícia - Campus da Saúde - Universidade&#xD;
      Católica de Pelotas; and (3) Two clinics in Vitoria (State of Espirito Santo): (1) Reference&#xD;
      Center for Sexually Transmitted Diseases&#xD;
      (http://www.vitoria.es.gov.br/cidadao/centro-de-referencia-em-infeccoes-sexualmente-transmiss&#xD;
      iveis). (2) Hospital Universitário Cassiano Antonio Moraes - UFES.&#xD;
&#xD;
      Patients identified during standard of care testing with a positive rapid syphilis test and&#xD;
      an RPR titer of greater than or equal to 1:8 will be referred to the study and offered&#xD;
      enrollment according to the following description.&#xD;
&#xD;
      Non-study clinic-site staff will perform the first screening rapid finger-stick test for&#xD;
      syphilis. The rapid syphilis test currently used in these clinics detects both new (acute)&#xD;
      infection and old treated infection but does not distinguish between the two. Patients that&#xD;
      are positive for the syphilis rapid finger-stick test will be notified by non-study staff of&#xD;
      this result and the need for additional testing using the RPR test according to standard of&#xD;
      care. Blood will be collected for the confirmatory RPR test by non-study staff. These&#xD;
      patients will be notified of RPR results in approximately 3 days to 1 week. The results a&#xD;
      confirmed syphilis diagnosis and of the RPR test results for those patients that are eligible&#xD;
      for enrolment in the study (RPR &gt;1:8) will be provided by a study nurse. The study will be&#xD;
      explained to eligible participants (RPR titer of &gt;1:8) by this study nurse, and if women&#xD;
      express interest in participating, informed consent will be obtained. It is expected that an&#xD;
      enrolment visit could last approximately 1.5 hours.&#xD;
&#xD;
      Patients that are not eligible for the study (negative RPR or RPR with titer &lt;1:8) will&#xD;
      receive syphilis RPR results from non-study staff.&#xD;
&#xD;
      Pregnancy tests will be completed on all potential participants and those that test positive&#xD;
      will not be enrolled in the study.&#xD;
&#xD;
      The timing of the recruitment process will depend on the number of women diagnosed with&#xD;
      syphilis and who have an RPR titer &gt;1:8 and who consent to participate in the study. It is&#xD;
      anticipated that enrollment will take approximately 1 year to complete.&#xD;
&#xD;
      To benchmark the performance of benzathine penicillin in the study population being used for&#xD;
      cefixime, The investigators will include a contemporary arm of participants that will receive&#xD;
      standard of care treatment with benzathine penicillin according to the Brazil national&#xD;
      sexually transmitted infection (STI) treatment guidelines. The investigators will use a ratio&#xD;
      of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.&#xD;
&#xD;
      This non-comparator arm of benzathine penicillin will be included to account for study&#xD;
      population differences in terms of stage of disease, history of prior infection, experience&#xD;
      of re-infection, experience of serofast state, or other co-factors that could impact&#xD;
      serological response. An estimate of performance of this standard of care will be calculated,&#xD;
      but this will not be compared directly to the study intervention.&#xD;
&#xD;
      The investigators will enrol 180 eligible women into the study: 120 for the cefixime arm and&#xD;
      60 for the benzathine penicillin arm. It is anticipated that enrollment will take&#xD;
      approximately 1 year to complete. Patients will be participating in the study for&#xD;
      approximately 9 months. The study is expected to last for approximately two years. Women that&#xD;
      are referred to the study but decline enrolment will be treated at the clinic following&#xD;
      national STI treatment guidelines for syphilis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 22, 2019</start_date>
  <completion_date type="Anticipated">September 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">March 30, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a Phase 1/2 trial to evaluate the efficacy and safety of cefixime for use in treating women with acute syphilis.&#xD;
This is a randomized, non-comparative, open label study assessing the efficacy and safety of cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection.To benchmark the performance of benzathine penicillin in the study population being used for cefixime, The investigators will include a contemporary arm of participants that will receive standard of care treatment with benzathine penicillin according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Quantitative RPR titer change</measure>
    <time_frame>6 months following last dose of Cefixime 400 mg</time_frame>
    <description>RPR titer response at 6 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE with cefixime</measure>
    <time_frame>Daily after the first dose of cefixime 400mg orally through 10 days after the first dose</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE. Information on side effects will be collected daily for 10 days of administration of cefixime using a pre-established list of most commonly reported side effects and a grade scale will be applied using the Common Terminology Criteria for Adverse Events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of participants reporting tolerability of cefixime</measure>
    <time_frame>Daily after the first dose of cefixime 400mg orally through 10 days after the first dose and qualitative overall assessment of tolerability measured via questionnaire 14 days after the first dose of cefixime</time_frame>
    <description>Tolerability: The number of participants reporting tolerability of cefixime as measured by quantitative reported experience of common side effects and qualitative experience of tolerance of the regimen as collected through daily questionnaires and an end treatment questionnaire at 14 days after the first dose of cefixime.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">180</enrollment>
  <condition>Syphilis Female</condition>
  <arm_group>
    <arm_group_label>Cefixime</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Benzathine penicillin</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>To benchmark the performance of benzathine penicillin in the study population being used for cefixime, the investigators will include a contemporary arm of participants that will receive standard of care treatment with benzathine penicillin according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cefixime</intervention_name>
    <description>Cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection</description>
    <arm_group_label>Cefixime</arm_group_label>
    <other_name>Intervention</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Benzathine penicillin 2.4 million units</intervention_name>
    <description>Benzathine penicillin 2.4 million units: The investigators will include a contemporary arm of participants that will receive standard of care treatment with Benzathine penicillin 2.4 million units according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.This non-comparator arm of benzathine penicillin will be included to account for study population differences in terms of stage of disease, history of prior infection, experience of re-infection, experience of serofast state, or other co-factors that could impact serological response</description>
    <arm_group_label>Benzathine penicillin</arm_group_label>
    <other_name>Standard treatment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Female, 18 years of age or older&#xD;
&#xD;
          2. Non-pregnant&#xD;
&#xD;
          3. Able to provide informed consent&#xD;
&#xD;
          4. Test positive for syphilis with a positive TPPA AND an RPR titer equal to or greater&#xD;
             than 1:8&#xD;
&#xD;
          5. Non-cephalosporin allergic&#xD;
&#xD;
          6. Non-penicillin allergic&#xD;
&#xD;
          7. Agree to be called once a day by study staff to be reminded to take study drug&#xD;
&#xD;
          8. Able to swallow pills&#xD;
&#xD;
          9. Willing to attend follow-up visits at 3, 6, and 9 months after completion of the study&#xD;
             treatment&#xD;
&#xD;
         10. Willing to take oral contraceptive or use condom to prevent pregnancy during the study&#xD;
             period&#xD;
&#xD;
         11. HIV negative&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        1) Female under 18 years of age 2) HIV positive 3) Pregnancy test positive or clinical&#xD;
        pregnancy 4) Prior history of syphilis or syphilis treatment within 6 months of study&#xD;
        screening 5) Allergy to penicillin or cephalosporins (including allergy to cefixime) 6) In&#xD;
        the judgment of the interviewer, has a medical condition or other factor that might affect&#xD;
        their ability to follow the protocol 7) Previous enrollment in the study 8) Presenting a&#xD;
        condition that would not allow reliable informed consent (alcohol abuse or substance&#xD;
        misuse) 9) Lacking mental capacity to give informed consent to participation&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Participant eligibility is based on biologic gender</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Melanie M Taylor, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>World Health Organization</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nathalie JN Broutet, MD</last_name>
    <role>Study Director</role>
    <affiliation>World Health Organization</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Edna O Kara, MD</last_name>
    <role>Study Chair</role>
    <affiliation>World Health Organization</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Melanie M Taylor, MD</last_name>
    <phone>+41 22 791 2172</phone>
    <email>mtaylor@who.int</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Edna O Kara, MD</last_name>
    <phone>+41 22 791 2649</phone>
    <email>karae@who.int</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fortaleza University</name>
      <address>
        <city>Fortaleza</city>
        <state>Ceara</state>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alix Araujo, PhD</last_name>
      <email>alix.araujo@hotmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Ivo Castell Branco Coelho, MD</last_name>
      <email>ivo@ufc.br</email>
    </contact_backup>
    <investigator>
      <last_name>Alix Araujo, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mariangela Silveira, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Angelica Miranda, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <reference>
    <citation>Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1-137. Erratum In: MMWR Recomm Rep. 2015 Aug 28;64(33):924.</citation>
    <PMID>26042815</PMID>
  </reference>
  <reference>
    <citation>WHO. WHO guidelines for the treatment of Treponema pallidum (syphilis). http://wwwwhoint/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/. 2016.</citation>
  </reference>
  <reference>
    <citation>Liang Z, Chen YP, Yang CS, Guo W, Jiang XX, Xu XF, Feng SX, Liu YQ, Jiang G. Meta-analysis of ceftriaxone compared with penicillin for the treatment of syphilis. Int J Antimicrob Agents. 2016 Jan;47(1):6-11. doi: 10.1016/j.ijantimicag.2015.10.020. Epub 2015 Nov 23.</citation>
    <PMID>26724187</PMID>
  </reference>
  <reference>
    <citation>Norris SJ, Cox DL, Weinstock GM. Biology of Treponema pallidum: correlation of functional activities with genome sequence data. J Mol Microbiol Biotechnol. 2001 Jan;3(1):37-62.</citation>
    <PMID>11200228</PMID>
  </reference>
  <reference>
    <citation>Faulkner RD, Fernandez P, Lawrence G, Sia LL, Falkowski AJ, Weiss AI, Yacobi A, Silber BM. Absolute bioavailability of cefixime in man. J Clin Pharmacol. 1988 Aug;28(8):700-6. doi: 10.1002/j.1552-4604.1988.tb03203.x.</citation>
    <PMID>3216036</PMID>
  </reference>
  <reference>
    <citation>Faulkner RD, Bohaychuk W, Haynes JD, Desjardins RE, Yacobi A, Silber BM. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol. 1988;34(5):525-8. doi: 10.1007/BF01046715.</citation>
    <PMID>3203716</PMID>
  </reference>
  <reference>
    <citation>Barbee LA, Nayak SU, Blumer JL, O'Riordan MA, Gray W, Zenilman JM, Golden MR, Griffiss JM. A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx. Sex Transm Dis. 2018 Oct;45(10):677-683. doi: 10.1097/OLQ.0000000000000844.</citation>
    <PMID>29624558</PMID>
  </reference>
  <reference>
    <citation>Rafal'skii VV, Dovgan' EV, Kozyrev IuV, Gustovarova TA, Khlybova SV, Novoselova AV, Filippenko NG, Likhikh DG. [The efficacy and safety of cefixime and amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women: a randomized, prospective, multicenter study]. Urologiia. 2013 Sep-Oct;(5):24, 26-8. Russian.</citation>
    <PMID>24437236</PMID>
  </reference>
  <reference>
    <citation>Nurse-Findlay S, Taylor MM, Savage M, Mello MB, Saliyou S, Lavayen M, Seghers F, Campbell ML, Birgirimana F, Ouedraogo L, Newman Owiredu M, Kidula N, Pyne-Mercier L. Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews. PLoS Med. 2017 Dec 27;14(12):e1002473. doi: 10.1371/journal.pmed.1002473. eCollection 2017 Dec.</citation>
    <PMID>29281619</PMID>
  </reference>
  <reference>
    <citation>U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 . https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf</citation>
  </reference>
  <reference>
    <citation>Hook EW 3rd, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC, Martin D, Langley C, McNeil L, Wolff M. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010 Jun 1;201(11):1729-35. doi: 10.1086/652239.</citation>
    <PMID>20402591</PMID>
  </reference>
  <reference>
    <citation>Cao Y, Su X, Wang Q, Xue H, Zhu X, Zhang C, Jiang J, Qi S, Gong X, Zhu X, Pan M, Ren H, Hu W, Wei Z, Tian M, Liu W. A Multicenter Study Evaluating Ceftriaxone and Benzathine Penicillin G as Treatment Agents for Early Syphilis in Jiangsu, China. Clin Infect Dis. 2017 Oct 30;65(10):1683-1688. doi: 10.1093/cid/cix611.</citation>
    <PMID>29020150</PMID>
  </reference>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 23, 2018</study_first_posted>
  <last_update_submitted>January 29, 2020</last_update_submitted>
  <last_update_submitted_qc>January 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>World Health Organization</investigator_affiliation>
    <investigator_full_name>Melanie Taylor</investigator_full_name>
    <investigator_title>Medical Offier</investigator_title>
  </responsible_party>
  <keyword>Syphilis</keyword>
  <keyword>Women</keyword>
  <keyword>Cefixime</keyword>
  <keyword>Brazil</keyword>
  <keyword>Sexually Transmitted Infection</keyword>
  <keyword>STI</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Syphilis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Penicillins</mesh_term>
    <mesh_term>Cefixime</mesh_term>
    <mesh_term>Penicillin G Benzathine</mesh_term>
    <mesh_term>Penicillin G</mesh_term>
    <mesh_term>Penicillin G Procaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Beginning 9 months and ending 24 months following article publication, the supporting information that will be shared for IPD are all data that underlie the results in the publication.</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>Beginning 9 months and ending 24 months following article publication,</ipd_time_frame>
    <ipd_access_criteria>Access will be provided to investigators whose proposed use of data has been approved by an independent review committee identified for this purpose&#xD;
Data whose goal is to achieve aims in the approved proposal&#xD;
The way proposals should be submitted will be decided and informed after WHO standard operating procedure (in development) for this purpose is complete.</ipd_access_criteria>
  </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/NCT03752112
org study id: ERC0003096
nct id: NCT03752112
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Hypotheses The antibiotic, Cefixime, for use in non-pregnant women with early syphilis will
      be efficacious and safe.

      Primary Objective The primary objective of the study is to demonstrate the efficacy, as
      measured by a 4 fold decrease in Rapid Plasma Reagin (RPR) titer from baseline to 6 months
      after treatment, with Cefixime 400mg taken orally two times a day for 10 consecutive days.

      Secondary Objective The secondary objective of the study is to determine the safety, as
      measured by the number of grade 3 or greater toxicities experienced, using the NIH/NCI
      toxicity score, during or after treatment with Cefixime 400mg taken orally two times a day
      for 10 consecutive days.
Hypotheses The antibiotic, Cefixime, for use in non-pregnant women with early syphilis will
      be efficacious and safe.

      Primary Objective The primary objective of the study is to demonstrate the efficacy, as
      measured by a 4 fold decrease in Rapid Plasma Reagin (RPR) titer from baseline to 6 months
      after treatment, with Cefixime 400mg taken orally two times a day for 10 consecutive days.

      Secondary Objective The secondary objective of the study is to determine the safety, as
      measured by the number of grade 3 or greater toxicities experienced, using the NIH/NCI
      toxicity score (10), during or after treatment with Cefixime 400mg taken orally two times a
      day for 10 consecutive days.

      Methods Study design This is a randomized, non-comparative, open-label study assessing the
      efficacy and safety of cefixime 400mg taken orally two times a day for 10 consecutive days in
      non-pregnant women with early syphilis infection.

      Study population and enrolment sites Numerous regions of Brazil have experienced increases in
      syphilis diagnoses during the previous 5 years The study sites were chosen from three cities
      in three separate regions (states) of Brazil based on: (1) increases in syphilis case
      reports, (2) access to clinics where patients are screened and treated for syphilis; (3)
      willingness of clinic sites and staff to participate in this research, and (4) the
      availability of experienced researchers with experience in studying syphilis to serve as
      co-investigators.

      The study population will include non-pregnant women (ages 18 and over) diagnosed with early
      syphilis (RPR titers >1:8) recruited from 7 clinics in three cities from three states in
      Brazil. These include: (1) Three clinics in the city of Fortaleza (Ceara State), coordinated
      by the University of Fortaleza (UNIFOR): (a) Carlos Ribeiro, (a) Meireles, and (c) Federal
      University. Syphilis epidemiology for each site in Annex 1. (2) Two University ObGyn Clinics
      in the city of Pelotas (state of Rio Grande do Sul) (5-6 cases of syphilis/week) a)
      Ambulatorio de Ginecologia e Obstetrícia - Faculdade de Medicina - Universidade Federal de
      Pelotas and b) Ambulatorio de Ginecologia e Obstetrícia - Campus da Saúde - Universidade
      Católica de Pelotas; and (3) Two clinics in Vitoria (State of Espirito Santo): (1) Reference
      Center for Sexually Transmitted Diseases
      (http://www.vitoria.es.gov.br/cidadao/centro-de-referencia-em-infeccoes-sexualmente-transmiss
      iveis). (2) Hospital Universitário Cassiano Antonio Moraes - UFES.

      Patients identified during standard of care testing with a positive rapid syphilis test and
      an RPR titer of greater than or equal to 1:8 will be referred to the study and offered
      enrollment according to the following description.

      Non-study clinic-site staff will perform the first screening rapid finger-stick test for
      syphilis. The rapid syphilis test currently used in these clinics detects both new (acute)
      infection and old treated infection but does not distinguish between the two. Patients that
      are positive for the syphilis rapid finger-stick test will be notified by non-study staff of
      this result and the need for additional testing using the RPR test according to standard of
      care. Blood will be collected for the confirmatory RPR test by non-study staff. These
      patients will be notified of RPR results in approximately 3 days to 1 week. The results a
      confirmed syphilis diagnosis and of the RPR test results for those patients that are eligible
      for enrolment in the study (RPR >1:8) will be provided by a study nurse. The study will be
      explained to eligible participants (RPR titer of >1:8) by this study nurse, and if women
      express interest in participating, informed consent will be obtained. It is expected that an
      enrolment visit could last approximately 1.5 hours.

      Patients that are not eligible for the study (negative RPR or RPR with titer <1:8) will
      receive syphilis RPR results from non-study staff.

      Pregnancy tests will be completed on all potential participants and those that test positive
      will not be enrolled in the study.

      The timing of the recruitment process will depend on the number of women diagnosed with
      syphilis and who have an RPR titer >1:8 and who consent to participate in the study. It is
      anticipated that enrollment will take approximately 1 year to complete.

      To benchmark the performance of benzathine penicillin in the study population being used for
      cefixime, The investigators will include a contemporary arm of participants that will receive
      standard of care treatment with benzathine penicillin according to the Brazil national
      sexually transmitted infection (STI) treatment guidelines. The investigators will use a ratio
      of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.

      This non-comparator arm of benzathine penicillin will be included to account for study
      population differences in terms of stage of disease, history of prior infection, experience
      of re-infection, experience of serofast state, or other co-factors that could impact
      serological response. An estimate of performance of this standard of care will be calculated,
      but this will not be compared directly to the study intervention.

      The investigators will enrol 180 eligible women into the study: 120 for the cefixime arm and
      60 for the benzathine penicillin arm. It is anticipated that enrollment will take
      approximately 1 year to complete. Patients will be participating in the study for
      approximately 9 months. The study is expected to last for approximately two years. Women that
      are referred to the study but decline enrolment will be treated at the clinic following
      national STI treatment guidelines for syphilis.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a Phase 1/2 trial to evaluate the efficacy and safety of cefixime for use in treating women with acute syphilis.
This is a randomized, non-comparative, open label study assessing the efficacy and safety of cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection.To benchmark the performance of benzathine penicillin in the study population being used for cefixime, The investigators will include a contemporary arm of participants that will receive standard of care treatment with benzathine penicillin according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.
primary purpose: Treatment
masking: None (Open Label)
measure: Quantitative RPR titer change
time frame: 6 months following last dose of Cefixime 400 mg
description: RPR titer response at 6 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE with cefixime
time frame: Daily after the first dose of cefixime 400mg orally through 10 days after the first dose
description: Number of participants with treatment-related adverse events as assessed by CTCAE. Information on side effects will be collected daily for 10 days of administration of cefixime using a pre-established list of most commonly reported side effects and a grade scale will be applied using the Common Terminology Criteria for Adverse Events.
measure: The number of participants reporting tolerability of cefixime
time frame: Daily after the first dose of cefixime 400mg orally through 10 days after the first dose and qualitative overall assessment of tolerability measured via questionnaire 14 days after the first dose of cefixime
description: Tolerability: The number of participants reporting tolerability of cefixime as measured by quantitative reported experience of common side effects and qualitative experience of tolerance of the regimen as collected through daily questionnaires and an end treatment questionnaire at 14 days after the first dose of cefixime.
arm group label: Cefixime
arm group type: Experimental
description: cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection.
arm group label: Benzathine penicillin
arm group type: Other
description: To benchmark the performance of benzathine penicillin in the study population being used for cefixime, the investigators will include a contemporary arm of participants that will receive standard of care treatment with benzathine penicillin according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.
intervention type: Drug
intervention name: Cefixime
description: Cefixime 400mg taken orally two times a day for 10 consecutive days in non-pregnant women with early syphilis infection
arm group label: Cefixime
other name: Intervention
intervention type: Drug
intervention name: Benzathine penicillin 2.4 million units
description: Benzathine penicillin 2.4 million units: The investigators will include a contemporary arm of participants that will receive standard of care treatment with Benzathine penicillin 2.4 million units according to the Brazil national STI treatment guidelines. The investigators will use a ratio of 2 patients receiving cefixime to 1 patient receiving benzathine penicillin.This non-comparator arm of benzathine penicillin will be included to account for study population differences in terms of stage of disease, history of prior infection, experience of re-infection, experience of serofast state, or other co-factors that could impact serological response
arm group label: Benzathine penicillin
other name: Standard treatment
criteria: 
gender: Female
gender based: Yes
gender description: Participant eligibility is based on biologic gender
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Melanie M Taylor, MD
role: Principal Investigator
affiliation: World Health Organization
last name: Nathalie JN Broutet, MD
role: Study Director
affiliation: World Health Organization
last name: Edna O Kara, MD
role: Study Chair
affiliation: World Health Organization
last name: Melanie M Taylor, MD
phone: +41 22 791 2172
email: mtaylor@who.int
last name: Edna O Kara, MD
phone: +41 22 791 2649
email: karae@who.int
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
country: Brazil
citation: Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1-137. Erratum In: MMWR Recomm Rep. 2015 Aug 28;64(33):924.
PMID: 26042815
citation: WHO. WHO guidelines for the treatment of Treponema pallidum (syphilis). http://wwwwhoint/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/. 2016.
citation: Liang Z, Chen YP, Yang CS, Guo W, Jiang XX, Xu XF, Feng SX, Liu YQ, Jiang G. Meta-analysis of ceftriaxone compared with penicillin for the treatment of syphilis. Int J Antimicrob Agents. 2016 Jan;47(1):6-11. doi: 10.1016/j.ijantimicag.2015.10.020. Epub 2015 Nov 23.
PMID: 26724187
citation: Norris SJ, Cox DL, Weinstock GM. Biology of Treponema pallidum: correlation of functional activities with genome sequence data. J Mol Microbiol Biotechnol. 2001 Jan;3(1):37-62.
PMID: 11200228
citation: Faulkner RD, Fernandez P, Lawrence G, Sia LL, Falkowski AJ, Weiss AI, Yacobi A, Silber BM. Absolute bioavailability of cefixime in man. J Clin Pharmacol. 1988 Aug;28(8):700-6. doi: 10.1002/j.1552-4604.1988.tb03203.x.
PMID: 3216036
citation: Faulkner RD, Bohaychuk W, Haynes JD, Desjardins RE, Yacobi A, Silber BM. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol. 1988;34(5):525-8. doi: 10.1007/BF01046715.
PMID: 3203716
citation: Barbee LA, Nayak SU, Blumer JL, O'Riordan MA, Gray W, Zenilman JM, Golden MR, Griffiss JM. A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx. Sex Transm Dis. 2018 Oct;45(10):677-683. doi: 10.1097/OLQ.0000000000000844.
PMID: 29624558
citation: Rafal'skii VV, Dovgan' EV, Kozyrev IuV, Gustovarova TA, Khlybova SV, Novoselova AV, Filippenko NG, Likhikh DG. [The efficacy and safety of cefixime and amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women: a randomized, prospective, multicenter study]. Urologiia. 2013 Sep-Oct;(5):24, 26-8. Russian.
PMID: 24437236
citation: Nurse-Findlay S, Taylor MM, Savage M, Mello MB, Saliyou S, Lavayen M, Seghers F, Campbell ML, Birgirimana F, Ouedraogo L, Newman Owiredu M, Kidula N, Pyne-Mercier L. Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews. PLoS Med. 2017 Dec 27;14(12):e1002473. doi: 10.1371/journal.pmed.1002473. eCollection 2017 Dec.
PMID: 29281619
citation: U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 . https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf
citation: Hook EW 3rd, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC, Martin D, Langley C, McNeil L, Wolff M. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010 Jun 1;201(11):1729-35. doi: 10.1086/652239.
PMID: 20402591
citation: Cao Y, Su X, Wang Q, Xue H, Zhu X, Zhang C, Jiang J, Qi S, Gong X, Zhu X, Pan M, Ren H, Hu W, Wei Z, Tian M, Liu W. A Multicenter Study Evaluating Ceftriaxone and Benzathine Penicillin G as Treatment Agents for Early Syphilis in Jiangsu, China. Clin Infect Dis. 2017 Oct 30;65(10):1683-1688. doi: 10.1093/cid/cix611.
PMID: 29020150
responsible party type: Principal Investigator
investigator affiliation: World Health Organization
investigator full name: Melanie Taylor
investigator title: Medical Offier
mesh term: Syphilis
mesh term: Penicillins
mesh term: Cefixime
mesh term: Penicillin G Benzathine
mesh term: Penicillin G
mesh term: Penicillin G Procaine
sharing ipd: Yes
ipd description: Beginning 9 months and ending 24 months following article publication, the supporting information that will be shared for IPD are all data that underlie the results in the publication.
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: Beginning 9 months and ending 24 months following article publication,
ipd access criteria: Access will be provided to investigators whose proposed use of data has been approved by an independent review committee identified for this purpose
Data whose goal is to achieve aims in the approved proposal
The way proposals should be submitted will be decided and informed after WHO standard operating procedure (in development) for this purpose is complete.