<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/NCT04500873</url>
  </required_header>
  <id_info>
    <org_study_id>222972553501</org_study_id>
    <secondary_id>222972553501</secondary_id>
    <nct_id>NCT04500873</nct_id>
  </id_info>
  <brief_title>Performance of RPA-LF for Cutaneous Leishmaniasis</brief_title>
  <acronym>RPA-LF</acronym>
  <official_title>Diagnostic Performance of a Recombinant Polymerase Amplification Test - Lateral Flow (RPA-LF) for Cutaneous Leishmaniasis in an Endemic Setting of Colombia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Internacional de Entrenamiento e Investigaciones Médicas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Texas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centro Internacional de Entrenamiento e Investigaciones Médicas</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>
      CL is public health in the Americas, diagnostic confirmation is required to start treatment,&#xD;
      however current diagnostic methods have several limitations and its access is limited.&#xD;
&#xD;
      Technical requirements of conventional molecular diagnostics and costs preclude their routine&#xD;
      use in primary care facilities in rural areas. A recently developed method of Isothermal&#xD;
      Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, has shown&#xD;
      high accuracy in detecting Leishmania Viannia spp. We evaluated the diagnostic performance of&#xD;
      the RPA-LF test in a laboratory reference center and field scenario with community&#xD;
      participation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CL is public health in the Americas with an average of 55,000 cases per year between 2001 -&#xD;
      2018 in 17 countries, which mainly occur in rural areas with an average of 55,000 cases per&#xD;
      year between 2001 - 2018 in 17 countries. Diagnostic confirmation is required to start&#xD;
      treatment, however current diagnostic methods have several limitations, and sometimes it is&#xD;
      necessary to perform confirmatory tests that are not available in endemic areas.&#xD;
&#xD;
      Several molecular diagnostic tests have been developed for the diagnosis of CL, however, the&#xD;
      technical requirements and costs of sample processing by conventional or quantitative PCR&#xD;
      preclude their routine use in primary care facilities in resource-constrained settings. A&#xD;
      recently developed method of Isothermal Recombinase Polymerase Amplification (RPA) targeting&#xD;
      Leishmania kinetoplast DNA, coupled with lateral flow (LF) immunochromatographic strip has&#xD;
      shown high accuracy in detecting Leishmania Viannia spp. We evaluated the diagnostic&#xD;
      performance of RPA-LF test in two scenarios: laboratory reference center and field with&#xD;
      community participation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Actual">December 20, 2019</completion_date>
  <primary_completion_date type="Actual">December 20, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Performance of RPA-LF compared with the composite gold standard (smear, culture, histopathology, and q-PCR-18S) in two scenarios: reference laboratory and field.</measure>
    <time_frame>Feb 2018 - August 2020</time_frame>
    <description>Sensitivity, specificity, predictive values (positive and negative) and likelihood ratios with their corresponding 95% confidence intervals will be calculated in both scenarios. We define as true positive (TP) when at least one of the gold standard tests (smear, culture, histopathology or q-PCR-18S) and RPA-LF are positive. A patient was considered true negative (TN) when at least smear, q-PCR-18S were negative and, culture and RPA-LF also resulted in negative.&#xD;
Reference lab scenario refers to when the samples are obtained by highly trained technicians (auxiliary nurses) in urban areas localized in Tumaco in a Primary Health facility and send to the reference center in Cali to be processed. In Reference center samples are taken and processed by an expert microbiologist.&#xD;
Field refers when the samples are obtained by trained community health workers (CHW) and processed by a non-expert field technician in Tumaco in a primary health facility.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Performace of RPA-LF compared with 4 aditional reference standards in both scenarios.</measure>
    <time_frame>Feb 2018 - August 2020</time_frame>
    <description>Sensitivity, specificity , predictive values (positive and negative) and likelihood ratios and 95% confidence intervals will be also estimated using 4 reference tests 1)the same as the gold standard but without qPCR; 2) lesion smear microscopy and culture; 3) lesion smear microscopy read in reference lab and 4) lesion smear microscopy read in the primary health facility in both scenarios.</description>
  </secondary_outcome>
  <enrollment type="Actual">128</enrollment>
  <condition>Cutaneous Leishmaniasis (Diagnosis)</condition>
  <eligibility>
    <study_pop>
      <textblock>
        Participants with cutaneous lesions compatible with cutaneous leishmaniasis from South west&#xD;
        of Colombia&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men or women with 2 years of age and over of any ethnic group&#xD;
&#xD;
          -  Ulcerated skin lesions compatible with cutaneous leishmaniasis with two or more weeks&#xD;
             of duration&#xD;
&#xD;
          -  Approval of informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Mucosal leishmaniasis&#xD;
&#xD;
          -  Clinical presentations of cutaneous leishmaniasis different of ulcerated lesions&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Corporación Centro Internacional de entrenamiento e Investigaciónes Médicas</name>
      <address>
        <city>Cali</city>
        <state>Valle</state>
        <zip>5930</zip>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Colombia</country>
  </location_countries>
  <reference>
    <citation>Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M; WHO Leishmaniasis Control Team. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7(5):e35671. doi: 10.1371/journal.pone.0035671. Epub 2012 May 31.</citation>
    <PMID>22693548</PMID>
  </reference>
  <reference>
    <citation>Reveiz L, Maia-Elkhoury AN, Nicholls RS, Romero GA, Yadon ZE. Interventions for American cutaneous and mucocutaneous leishmaniasis: a systematic review update. PLoS One. 2013 Apr 29;8(4):e61843. doi: 10.1371/journal.pone.0061843. Print 2013.</citation>
    <PMID>23637917</PMID>
  </reference>
  <reference>
    <citation>Gomes CM, Paula NA, Morais OO, Soares KA, Roselino AM, Sampaio RN. Complementary exams in the diagnosis of American tegumentary leishmaniasis. An Bras Dermatol. 2014 Sep-Oct;89(5):701-9. doi: 10.1590/abd1806-4841.20142389.</citation>
    <PMID>25184908</PMID>
  </reference>
  <reference>
    <citation>Weigle KA, de Davalos M, Heredia P, Molineros R, Saravia NG, D'Alessandro A. Diagnosis of cutaneous and mucocutaneous leishmaniasis in Colombia: a comparison of seven methods. Am J Trop Med Hyg. 1987 May;36(3):489-96. doi: 10.4269/ajtmh.1987.36.489.</citation>
    <PMID>2437815</PMID>
  </reference>
  <reference>
    <citation>Boggild AK, Ramos AP, Espinosa D, Valencia BM, Veland N, Miranda-Verastegui C, Arevalo J, Low DE, Llanos-Cuentas A. Clinical and demographic stratification of test performance: a pooled analysis of five laboratory diagnostic methods for American cutaneous leishmaniasis. Am J Trop Med Hyg. 2010 Aug;83(2):345-50. doi: 10.4269/ajtmh.2010.09-0414.</citation>
    <PMID>20682880</PMID>
  </reference>
  <reference>
    <citation>Braz LMA. Tegumentary leishmaniasis diagnosis: what happened with MST (Montenegro Skin Test) in Brazil? Rev Inst Med Trop Sao Paulo. 2019 Mar 11;61:e17. doi: 10.1590/S1678-9946201961017. No abstract available.</citation>
    <PMID>30864622</PMID>
  </reference>
  <reference>
    <citation>Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016 Dec 15;63(12):e202-e264. doi: 10.1093/cid/ciw670. Epub 2016 Nov 14.</citation>
    <PMID>27941151</PMID>
  </reference>
  <reference>
    <citation>de Vries HJ, Reedijk SH, Schallig HD. Cutaneous leishmaniasis: recent developments in diagnosis and management. Am J Clin Dermatol. 2015 Apr;16(2):99-109. doi: 10.1007/s40257-015-0114-z.</citation>
    <PMID>25687688</PMID>
  </reference>
  <reference>
    <citation>Adams ER, Gomez MA, Scheske L, Rios R, Marquez R, Cossio A, Albertini A, Schallig H, Saravia NG. Sensitive diagnosis of cutaneous leishmaniasis by lesion swab sampling coupled to qPCR. Parasitology. 2014 Dec;141(14):1891-7. doi: 10.1017/S0031182014001280. Epub 2014 Aug 11.</citation>
    <PMID>25111885</PMID>
  </reference>
  <reference>
    <citation>Motazedian H, Karamian M, Noyes HA, Ardehali S. DNA extraction and amplification of leishmania from archived, Giemsa-stained slides, for the diagnosis of cutaneous Leishmaniasis by PCR. Ann Trop Med Parasitol. 2002 Jan;96(1):31-4. doi: 10.1179/000349802125000484.</citation>
    <PMID>11989531</PMID>
  </reference>
  <reference>
    <citation>Jara M, Adaui V, Valencia BM, Martinez D, Alba M, Castrillon C, Cruz M, Cruz I, Van der Auwera G, Llanos-Cuentas A, Dujardin JC, Arevalo J. Real-time PCR assay for detection and quantification of Leishmania (Viannia) organisms in skin and mucosal lesions: exploratory study of parasite load and clinical parameters. J Clin Microbiol. 2013 Jun;51(6):1826-33. doi: 10.1128/JCM.00208-13. Epub 2013 Apr 3.</citation>
    <PMID>23554201</PMID>
  </reference>
  <reference>
    <citation>Weigle KA, Labrada LA, Lozano C, Santrich C, Barker DC. PCR-based diagnosis of acute and chronic cutaneous leishmaniasis caused by Leishmania (Viannia). J Clin Microbiol. 2002 Feb;40(2):601-6. doi: 10.1128/JCM.40.2.601-606.2002.</citation>
    <PMID>11825977</PMID>
  </reference>
  <reference>
    <citation>Faber WR, Oskam L, van Gool T, Kroon NC, Knegt-Junk KJ, Hofwegen H, van der Wal AC, Kager PA. Value of diagnostic techniques for cutaneous leishmaniasis. J Am Acad Dermatol. 2003 Jul;49(1):70-4. doi: 10.1067/mjd.2003.492.</citation>
    <PMID>12833011</PMID>
  </reference>
  <reference>
    <citation>Bensoussan E, Nasereddin A, Jonas F, Schnur LF, Jaffe CL. Comparison of PCR assays for diagnosis of cutaneous leishmaniasis. J Clin Microbiol. 2006 Apr;44(4):1435-9. doi: 10.1128/JCM.44.4.1435-1439.2006.</citation>
    <PMID>16597873</PMID>
  </reference>
  <reference>
    <citation>Saldarriaga OA, Castellanos-Gonzalez A, Porrozzi R, Baldeviano GC, Lescano AG, de Los Santos MB, Fernandez OL, Saravia NG, Costa E, Melby PC, Travi BL. An Innovative Field-Applicable Molecular Test to Diagnose Cutaneous Leishmania Viannia spp. Infections. PLoS Negl Trop Dis. 2016 Apr 26;10(4):e0004638. doi: 10.1371/journal.pntd.0004638. eCollection 2016 Apr.</citation>
    <PMID>27115155</PMID>
  </reference>
  <reference>
    <citation>Drain PK, Hyle EP, Noubary F, Freedberg KA, Wilson D, Bishai WR, Rodriguez W, Bassett IV. Diagnostic point-of-care tests in resource-limited settings. Lancet Infect Dis. 2014 Mar;14(3):239-49. doi: 10.1016/S1473-3099(13)70250-0. Epub 2013 Dec 10.</citation>
    <PMID>24332389</PMID>
  </reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>August 3, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>August 3, 2020</last_update_submitted>
  <last_update_submitted_qc>August 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 5, 2020</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>Leishmaniasis</mesh_term>
    <mesh_term>Leishmaniasis, Cutaneous</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04500873
org study id: 222972553501
secondary id: 222972553501
nct id: NCT04500873
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
CL is public health in the Americas, diagnostic confirmation is required to start treatment,
      however current diagnostic methods have several limitations and its access is limited.

      Technical requirements of conventional molecular diagnostics and costs preclude their routine
      use in primary care facilities in rural areas. A recently developed method of Isothermal
      Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, has shown
      high accuracy in detecting Leishmania Viannia spp. We evaluated the diagnostic performance of
      the RPA-LF test in a laboratory reference center and field scenario with community
      participation.
CL is public health in the Americas with an average of 55,000 cases per year between 2001 -
      2018 in 17 countries, which mainly occur in rural areas with an average of 55,000 cases per
      year between 2001 - 2018 in 17 countries. Diagnostic confirmation is required to start
      treatment, however current diagnostic methods have several limitations, and sometimes it is
      necessary to perform confirmatory tests that are not available in endemic areas.

      Several molecular diagnostic tests have been developed for the diagnosis of CL, however, the
      technical requirements and costs of sample processing by conventional or quantitative PCR
      preclude their routine use in primary care facilities in resource-constrained settings. A
      recently developed method of Isothermal Recombinase Polymerase Amplification (RPA) targeting
      Leishmania kinetoplast DNA, coupled with lateral flow (LF) immunochromatographic strip has
      shown high accuracy in detecting Leishmania Viannia spp. We evaluated the diagnostic
      performance of RPA-LF test in two scenarios: laboratory reference center and field with
      community participation.
observational model: Other
time perspective: Cross-Sectional
measure: Performance of RPA-LF compared with the composite gold standard (smear, culture, histopathology, and q-PCR-18S) in two scenarios: reference laboratory and field.
time frame: Feb 2018 - August 2020
description: Sensitivity, specificity, predictive values (positive and negative) and likelihood ratios with their corresponding 95% confidence intervals will be calculated in both scenarios. We define as true positive (TP) when at least one of the gold standard tests (smear, culture, histopathology or q-PCR-18S) and RPA-LF are positive. A patient was considered true negative (TN) when at least smear, q-PCR-18S were negative and, culture and RPA-LF also resulted in negative.
Reference lab scenario refers to when the samples are obtained by highly trained technicians (auxiliary nurses) in urban areas localized in Tumaco in a Primary Health facility and send to the reference center in Cali to be processed. In Reference center samples are taken and processed by an expert microbiologist.
Field refers when the samples are obtained by trained community health workers (CHW) and processed by a non-expert field technician in Tumaco in a primary health facility.
measure: Performace of RPA-LF compared with 4 aditional reference standards in both scenarios.
time frame: Feb 2018 - August 2020
description: Sensitivity, specificity , predictive values (positive and negative) and likelihood ratios and 95% confidence intervals will be also estimated using 4 reference tests 1)the same as the gold standard but without qPCR; 2) lesion smear microscopy and culture; 3) lesion smear microscopy read in reference lab and 4) lesion smear microscopy read in the primary health facility in both scenarios.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 2 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Colombia
citation: Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M; WHO Leishmaniasis Control Team. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7(5):e35671. doi: 10.1371/journal.pone.0035671. Epub 2012 May 31.
PMID: 22693548
citation: Reveiz L, Maia-Elkhoury AN, Nicholls RS, Romero GA, Yadon ZE. Interventions for American cutaneous and mucocutaneous leishmaniasis: a systematic review update. PLoS One. 2013 Apr 29;8(4):e61843. doi: 10.1371/journal.pone.0061843. Print 2013.
PMID: 23637917
citation: Gomes CM, Paula NA, Morais OO, Soares KA, Roselino AM, Sampaio RN. Complementary exams in the diagnosis of American tegumentary leishmaniasis. An Bras Dermatol. 2014 Sep-Oct;89(5):701-9. doi: 10.1590/abd1806-4841.20142389.
PMID: 25184908
citation: Weigle KA, de Davalos M, Heredia P, Molineros R, Saravia NG, D'Alessandro A. Diagnosis of cutaneous and mucocutaneous leishmaniasis in Colombia: a comparison of seven methods. Am J Trop Med Hyg. 1987 May;36(3):489-96. doi: 10.4269/ajtmh.1987.36.489.
PMID: 2437815
citation: Boggild AK, Ramos AP, Espinosa D, Valencia BM, Veland N, Miranda-Verastegui C, Arevalo J, Low DE, Llanos-Cuentas A. Clinical and demographic stratification of test performance: a pooled analysis of five laboratory diagnostic methods for American cutaneous leishmaniasis. Am J Trop Med Hyg. 2010 Aug;83(2):345-50. doi: 10.4269/ajtmh.2010.09-0414.
PMID: 20682880
citation: Braz LMA. Tegumentary leishmaniasis diagnosis: what happened with MST (Montenegro Skin Test) in Brazil? Rev Inst Med Trop Sao Paulo. 2019 Mar 11;61:e17. doi: 10.1590/S1678-9946201961017. No abstract available.
PMID: 30864622
citation: Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016 Dec 15;63(12):e202-e264. doi: 10.1093/cid/ciw670. Epub 2016 Nov 14.
PMID: 27941151
citation: de Vries HJ, Reedijk SH, Schallig HD. Cutaneous leishmaniasis: recent developments in diagnosis and management. Am J Clin Dermatol. 2015 Apr;16(2):99-109. doi: 10.1007/s40257-015-0114-z.
PMID: 25687688
citation: Adams ER, Gomez MA, Scheske L, Rios R, Marquez R, Cossio A, Albertini A, Schallig H, Saravia NG. Sensitive diagnosis of cutaneous leishmaniasis by lesion swab sampling coupled to qPCR. Parasitology. 2014 Dec;141(14):1891-7. doi: 10.1017/S0031182014001280. Epub 2014 Aug 11.
PMID: 25111885
citation: Motazedian H, Karamian M, Noyes HA, Ardehali S. DNA extraction and amplification of leishmania from archived, Giemsa-stained slides, for the diagnosis of cutaneous Leishmaniasis by PCR. Ann Trop Med Parasitol. 2002 Jan;96(1):31-4. doi: 10.1179/000349802125000484.
PMID: 11989531
citation: Jara M, Adaui V, Valencia BM, Martinez D, Alba M, Castrillon C, Cruz M, Cruz I, Van der Auwera G, Llanos-Cuentas A, Dujardin JC, Arevalo J. Real-time PCR assay for detection and quantification of Leishmania (Viannia) organisms in skin and mucosal lesions: exploratory study of parasite load and clinical parameters. J Clin Microbiol. 2013 Jun;51(6):1826-33. doi: 10.1128/JCM.00208-13. Epub 2013 Apr 3.
PMID: 23554201
citation: Weigle KA, Labrada LA, Lozano C, Santrich C, Barker DC. PCR-based diagnosis of acute and chronic cutaneous leishmaniasis caused by Leishmania (Viannia). J Clin Microbiol. 2002 Feb;40(2):601-6. doi: 10.1128/JCM.40.2.601-606.2002.
PMID: 11825977
citation: Faber WR, Oskam L, van Gool T, Kroon NC, Knegt-Junk KJ, Hofwegen H, van der Wal AC, Kager PA. Value of diagnostic techniques for cutaneous leishmaniasis. J Am Acad Dermatol. 2003 Jul;49(1):70-4. doi: 10.1067/mjd.2003.492.
PMID: 12833011
citation: Bensoussan E, Nasereddin A, Jonas F, Schnur LF, Jaffe CL. Comparison of PCR assays for diagnosis of cutaneous leishmaniasis. J Clin Microbiol. 2006 Apr;44(4):1435-9. doi: 10.1128/JCM.44.4.1435-1439.2006.
PMID: 16597873
citation: Saldarriaga OA, Castellanos-Gonzalez A, Porrozzi R, Baldeviano GC, Lescano AG, de Los Santos MB, Fernandez OL, Saravia NG, Costa E, Melby PC, Travi BL. An Innovative Field-Applicable Molecular Test to Diagnose Cutaneous Leishmania Viannia spp. Infections. PLoS Negl Trop Dis. 2016 Apr 26;10(4):e0004638. doi: 10.1371/journal.pntd.0004638. eCollection 2016 Apr.
PMID: 27115155
citation: Drain PK, Hyle EP, Noubary F, Freedberg KA, Wilson D, Bishai WR, Rodriguez W, Bassett IV. Diagnostic point-of-care tests in resource-limited settings. Lancet Infect Dis. 2014 Mar;14(3):239-49. doi: 10.1016/S1473-3099(13)70250-0. Epub 2013 Dec 10.
PMID: 24332389
responsible party type: Sponsor
mesh term: Leishmaniasis
mesh term: Leishmaniasis, Cutaneous
sharing ipd: Undecided