<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/NCT01710397</url>
  </required_header>
  <id_info>
    <org_study_id>H-31880</org_study_id>
    <secondary_id>1U01AI100015-01</secondary_id>
    <nct_id>NCT01710397</nct_id>
  </id_info>
  <brief_title>Rapid Initiation of Antiretroviral Therapy to Promote Early HIV/AIDS Treatment in South Africa (RapIT Study)</brief_title>
  <acronym>RapIT</acronym>
  <official_title>Rapid Initiation of Antiretroviral Therapy to Promote Early HIV/AIDS Treatment in South Africa (RapIT Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Witwatersrand, South Africa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Boston University</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>
      One of the most serious challenges facing antiretroviral therapy (ART) programs for HIV/AIDS&#xD;
      in resource-constrained settings is the failure of ART-eligible patients to complete the&#xD;
      steps required to initiate treatment. The high rate of loss to care of patients who are&#xD;
      treatment-eligible at HIV diagnosis may be due in part to the large number of steps required&#xD;
      between receiving an HIV diagnosis and obtaining the first dose of antiretrovirals (ARVs). In&#xD;
      South Africa, these steps usually require approximately four clinic visits over a period of&#xD;
      2-8 weeks before a patient can start treatment. One strategy proposed for reducing losses&#xD;
      among those eligible for ART is to simplify and condense the steps required for starting&#xD;
      treatment. This is now possible because new, point-of-care (POC) tests for CD4 counts and&#xD;
      tuberculosis (TB) diagnosis are available. These technologies can be combined with changes to&#xD;
      clinic schedules to allow all steps required for ART initiation under South African&#xD;
      guidelines (lab tests, physical exam, education) to take place on the day the patient&#xD;
      presents for an HIV test.&#xD;
&#xD;
      This study is a randomized strategy evaluation of the feasibility, effectiveness, and&#xD;
      cost-effectiveness of rapid ART initiation. Outpatient, non-pregnant, HIV-positive adults who&#xD;
      come to a South African clinic for an HIV test, consent to study participation, and are&#xD;
      eligible for ART will be randomized 1:1 to rapid ART initiation or to standard care. Those&#xD;
      who are assigned to rapid ART initiation will have the possibility of receiving their first&#xD;
      dose of ARVs as early as the same day, while those who are assigned to standard care will&#xD;
      follow the clinic's usual procedures for starting ART. Rapid ART initiation for HIV-positive&#xD;
      pregnant women, which has recently become the standard of care in South Africa, will also be&#xD;
      assessed in a programmatic evaluation conducted alongside the randomized evaluation, with a&#xD;
      retrospective comparison group. The primary study outcome for non-pregnant adults will be&#xD;
      remaining alive, in care and virally suppressed 10 months after having a positive HIV test at&#xD;
      the study site or making a first HIV-related visit. The primary study outcome for pregnant&#xD;
      women will be adherence to ART until delivery. The cost effectiveness of the rapid initiation&#xD;
      strategy will be assessed as the cost per patient achieving the primary outcome for each&#xD;
      population.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2013</start_date>
  <completion_date type="Actual">June 30, 2018</completion_date>
  <primary_completion_date type="Actual">July 2015</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion non-pregnant subjects virally suppressed at routine six-month viral load</measure>
    <time_frame>10 months after study enrollment</time_frame>
    <description>The primary outcome for non-pregnant adults is the proportion of subjects in each group alive, in care and virally suppressed at the routine six-month monitoring visit within 10 months of a positive HIV test or initial HIV care visit if previously diagnosed. The analysis period will start at study enrollment and continue through the earlier of the patient's six-month viral load or 10 months after the patient's HIV test.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of pregnant subjects who adhere to ART or the prior PMTCT regimen until delivery</measure>
    <time_frame>Up to 9 months after study enrollment</time_frame>
    <description>The primary outcome for pregnant women is the proportion of subjects in each group who adhere to ART or the prior prevention of mother-to-child transmission (PMTCT) regimen until delivery. The number of weeks a pregnant woman is on ART before delivery is the most important predictor of perinatal HIV transmission7. The guideline change to immediate ART initiation for pregnant women is likely to lead to earlier initiation for most pregnant women, but the intervention will be effective only if patients adhere to ART through the duration of pregnancy. Adherence will be measured as making monthly medication pickups to allow a continuous supply of ARVs through delivery. The analysis period for the primary outcome will start on the day of study enrollment, which is the date of a positive HIV test or the first antenatal visit of the current pregnancy, for women previously diagnosed, and end at the actual or estimated delivery date.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Average cost per non-pregnant patient who is alive, in care, and virally suppressed within 10 months of study enrollment</measure>
    <time_frame>10 months after study enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average cost per pregnant patient who initiates ART within 4 weeks</measure>
    <time_frame>3 months after study enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion virally suppressed at six-month intervals and final date of data censoring</measure>
    <time_frame>24 months after enrollment</time_frame>
    <description>Proportion of subjects in each track and group alive, on ART, and virally suppressed at six-month intervals and the final date of data censoring</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average time to ART initiation</measure>
    <time_frame>24 months after enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average gestational age at ART initiation and average duration on ART prior to delivery</measure>
    <time_frame>3 months after study enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-level predictors of treatment uptake, retention in care, and viral suppression</measure>
    <time_frame>10 months after enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of TB symptoms, confirmed TB, time to initiation of TB treatment, and time to initiation of ART among patients with TB</measure>
    <time_frame>10 months after enrollment</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Acceptance of rapid initiation strategy</measure>
    <time_frame>10 months after enrollment</time_frame>
    <description>Acceptance of rapid initiation strategy (% of patients offered rapid initiation who accept)</description>
  </other_outcome>
  <other_outcome>
    <measure>Time from HIV test to treatment</measure>
    <time_frame>10 months after enrollment</time_frame>
    <description>Average time elapsed (days) between HIV test and dispensing of first dose of ARVs</description>
  </other_outcome>
  <other_outcome>
    <measure>Cost to patients</measure>
    <time_frame>10 months after enrollment</time_frame>
    <description>Average cost to patients of initiating treatment, including travel and other out-of-pocket costs and time spent in clinic</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">531</enrollment>
  <condition>HIV</condition>
  <arm_group>
    <arm_group_label>Standard group, non-pregnant adults</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Comparison group (prospective enrollment)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard group, pregnant women</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Comparison group (retrospective record review)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rapid group, non-pregnant adults</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rapid ART initiation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rapid group, pregnant women</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rapid ART initiation</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Rapid ART initiation</intervention_name>
    <description>Subjects offered the intervention who are eligible for antiretroviral therapy under South African guidelines will be offered the opportunity to initiate ART immediately, if possible on the same day as testing positive for HIV. Rapid testing technologies and an accelerated schedule will be used to allow all steps required prior to initiating ART to take place in approximately a half-day period.</description>
    <arm_group_label>Rapid group, non-pregnant adults</arm_group_label>
    <arm_group_label>Rapid group, pregnant women</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients (&gt;18 years)&#xD;
&#xD;
          -  Tested HIV-positive at study site's outpatient testing service or antenatal clinic on&#xD;
             day of study enrollment or previously tested HIV-positive but making first visit to&#xD;
             study site for HIV-related care or antenatal care for the current pregnancy&#xD;
&#xD;
          -  Eligible for antiretroviral therapy under prevailing South African guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently or previously on ART (three-drug combination; previous PMTCT regimen&#xD;
             exposure for an earlier pregnancy is not an exclusion criterion)&#xD;
&#xD;
          -  Stated intention to seek further HIV or antenatal care at another site, not at the&#xD;
             study site&#xD;
&#xD;
          -  Not physically or emotionally able to participate in the study, in the opinion of the&#xD;
             investigators&#xD;
&#xD;
          -  Not willing or able to provide written informed consent to participate in the study&#xD;
&#xD;
          -  Previously screened for the same study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sydney Rosen</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Thuthukani Primary Health Clinic</name>
      <address>
        <city>Johannesburg</city>
        <state>Gauteng</state>
        <zip>2092</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Themba Lethu Clinic, Helen Joseph Hospital</name>
      <address>
        <city>Johannesburg</city>
        <state>Gauteng</state>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <link>
    <url>http://www.heroza.org</url>
    <description>Website of implementing organization in South Africa</description>
  </link>
  <results_reference>
    <citation>Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Rohr JK, Long L. Rapid ART initiation reduces loss between HIV testing and treatment: the RapIT trial. Abstract 1091, 21st Conference on Retroviruses and Opportunistic Infections (CROI 2015), Seattle, February 23-26, 2015.</citation>
  </results_reference>
  <results_reference>
    <citation>Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Bokaba D, Sauls C, Rohr J, Long L. Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016 May 10;13(5):e1002015. doi: 10.1371/journal.pmed.1002015. eCollection 2016 May. Erratum In: PLoS Med. 2016 Jun;13(6):e1002050.</citation>
    <PMID>27163694</PMID>
  </results_reference>
  <results_reference>
    <citation>Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Bokaba D, Sauls C, Rohr R, Long L. Initiating antiretroviral therapy for HIV at a patient's first clinic visit: the RapIT randomized controlled trial. Conference on Retroviruses and Opportunistic Infections (CROI) 2016, Boston, Feb 22-25 2016.</citation>
  </results_reference>
  <results_reference>
    <citation>Long LC, Maskew M, Brennan AT, Mongwenyana C, Nyoni C, Malete G, Sanne I, Fox MP, Rosen S. Initiating antiretroviral therapy for HIV at a patient's first clinic visit: a cost-effectiveness analysis of the rapid initiation of treatment randomized controlled trial. AIDS. 2017 Jul 17;31(11):1611-1619. doi: 10.1097/QAD.0000000000001528.</citation>
    <PMID>28463879</PMID>
  </results_reference>
  <results_reference>
    <citation>Maskew M, Jamieson L, Mohomi G, Long L, Mongwenyana C, Nyoni C, Mokaba D, Fox MP, Sanne I, Rosen S. Implementation of Option B and a fixed-dose combination antiretroviral regimen for prevention of mother-to-child transmission of HIV in South Africa: A model of uptake and adherence to care. PLoS One. 2018 Aug 30;13(8):e0201955. doi: 10.1371/journal.pone.0201955. eCollection 2018.</citation>
    <PMID>30161147</PMID>
  </results_reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>September 7, 2012</study_first_submitted>
  <study_first_submitted_qc>October 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 19, 2012</study_first_posted>
  <last_update_submitted>January 3, 2019</last_update_submitted>
  <last_update_submitted_qc>January 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 4, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston University</investigator_affiliation>
    <investigator_full_name>Sydney Rosen</investigator_full_name>
    <investigator_title>Prinicipal Investigator</investigator_title>
  </responsible_party>
  <keyword>Antiretroviral therapy</keyword>
  <keyword>South Africa</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be made publicly available in the Dryad repository (http://www. datadryad.org/) after the protocol has been closed (anticipated closure December 2018).</ipd_description>
  </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/NCT01710397
org study id: H-31880
secondary id: 1U01AI100015-01
nct id: NCT01710397
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
One of the most serious challenges facing antiretroviral therapy (ART) programs for HIV/AIDS
      in resource-constrained settings is the failure of ART-eligible patients to complete the
      steps required to initiate treatment. The high rate of loss to care of patients who are
      treatment-eligible at HIV diagnosis may be due in part to the large number of steps required
      between receiving an HIV diagnosis and obtaining the first dose of antiretrovirals (ARVs). In
      South Africa, these steps usually require approximately four clinic visits over a period of
      2-8 weeks before a patient can start treatment. One strategy proposed for reducing losses
      among those eligible for ART is to simplify and condense the steps required for starting
      treatment. This is now possible because new, point-of-care (POC) tests for CD4 counts and
      tuberculosis (TB) diagnosis are available. These technologies can be combined with changes to
      clinic schedules to allow all steps required for ART initiation under South African
      guidelines (lab tests, physical exam, education) to take place on the day the patient
      presents for an HIV test.

      This study is a randomized strategy evaluation of the feasibility, effectiveness, and
      cost-effectiveness of rapid ART initiation. Outpatient, non-pregnant, HIV-positive adults who
      come to a South African clinic for an HIV test, consent to study participation, and are
      eligible for ART will be randomized 1:1 to rapid ART initiation or to standard care. Those
      who are assigned to rapid ART initiation will have the possibility of receiving their first
      dose of ARVs as early as the same day, while those who are assigned to standard care will
      follow the clinic's usual procedures for starting ART. Rapid ART initiation for HIV-positive
      pregnant women, which has recently become the standard of care in South Africa, will also be
      assessed in a programmatic evaluation conducted alongside the randomized evaluation, with a
      retrospective comparison group. The primary study outcome for non-pregnant adults will be
      remaining alive, in care and virally suppressed 10 months after having a positive HIV test at
      the study site or making a first HIV-related visit. The primary study outcome for pregnant
      women will be adherence to ART until delivery. The cost effectiveness of the rapid initiation
      strategy will be assessed as the cost per patient achieving the primary outcome for each
      population.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Health Services Research
masking: None (Open Label)
measure: Proportion non-pregnant subjects virally suppressed at routine six-month viral load
time frame: 10 months after study enrollment
description: The primary outcome for non-pregnant adults is the proportion of subjects in each group alive, in care and virally suppressed at the routine six-month monitoring visit within 10 months of a positive HIV test or initial HIV care visit if previously diagnosed. The analysis period will start at study enrollment and continue through the earlier of the patient's six-month viral load or 10 months after the patient's HIV test.
measure: Proportion of pregnant subjects who adhere to ART or the prior PMTCT regimen until delivery
time frame: Up to 9 months after study enrollment
description: The primary outcome for pregnant women is the proportion of subjects in each group who adhere to ART or the prior prevention of mother-to-child transmission (PMTCT) regimen until delivery. The number of weeks a pregnant woman is on ART before delivery is the most important predictor of perinatal HIV transmission7. The guideline change to immediate ART initiation for pregnant women is likely to lead to earlier initiation for most pregnant women, but the intervention will be effective only if patients adhere to ART through the duration of pregnancy. Adherence will be measured as making monthly medication pickups to allow a continuous supply of ARVs through delivery. The analysis period for the primary outcome will start on the day of study enrollment, which is the date of a positive HIV test or the first antenatal visit of the current pregnancy, for women previously diagnosed, and end at the actual or estimated delivery date.
measure: Average cost per non-pregnant patient who is alive, in care, and virally suppressed within 10 months of study enrollment
time frame: 10 months after study enrollment
measure: Average cost per pregnant patient who initiates ART within 4 weeks
time frame: 3 months after study enrollment
measure: Proportion virally suppressed at six-month intervals and final date of data censoring
time frame: 24 months after enrollment
description: Proportion of subjects in each track and group alive, on ART, and virally suppressed at six-month intervals and the final date of data censoring
measure: Average time to ART initiation
time frame: 24 months after enrollment
measure: Average gestational age at ART initiation and average duration on ART prior to delivery
time frame: 3 months after study enrollment
measure: Patient-level predictors of treatment uptake, retention in care, and viral suppression
time frame: 10 months after enrollment
measure: Prevalence of TB symptoms, confirmed TB, time to initiation of TB treatment, and time to initiation of ART among patients with TB
time frame: 10 months after enrollment
measure: Acceptance of rapid initiation strategy
time frame: 10 months after enrollment
description: Acceptance of rapid initiation strategy (% of patients offered rapid initiation who accept)
measure: Time from HIV test to treatment
time frame: 10 months after enrollment
description: Average time elapsed (days) between HIV test and dispensing of first dose of ARVs
measure: Cost to patients
time frame: 10 months after enrollment
description: Average cost to patients of initiating treatment, including travel and other out-of-pocket costs and time spent in clinic
arm group label: Standard group, non-pregnant adults
arm group type: No Intervention
description: Comparison group (prospective enrollment)
arm group label: Standard group, pregnant women
arm group type: No Intervention
description: Comparison group (retrospective record review)
arm group label: Rapid group, non-pregnant adults
arm group type: Experimental
description: Rapid ART initiation
arm group label: Rapid group, pregnant women
arm group type: Experimental
description: Rapid ART initiation
intervention type: Other
intervention name: Rapid ART initiation
description: Subjects offered the intervention who are eligible for antiretroviral therapy under South African guidelines will be offered the opportunity to initiate ART immediately, if possible on the same day as testing positive for HIV. Rapid testing technologies and an accelerated schedule will be used to allow all steps required prior to initiating ART to take place in approximately a half-day period.
arm group label: Rapid group, non-pregnant adults
arm group label: Rapid group, pregnant women
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sydney Rosen
role: Principal Investigator
affiliation: Boston University
facility: 
facility: 
country: South Africa
url: http://www.heroza.org
description: Website of implementing organization in South Africa
citation: Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Rohr JK, Long L. Rapid ART initiation reduces loss between HIV testing and treatment: the RapIT trial. Abstract 1091, 21st Conference on Retroviruses and Opportunistic Infections (CROI 2015), Seattle, February 23-26, 2015.
citation: Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Bokaba D, Sauls C, Rohr J, Long L. Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016 May 10;13(5):e1002015. doi: 10.1371/journal.pmed.1002015. eCollection 2016 May. Erratum In: PLoS Med. 2016 Jun;13(6):e1002050.
PMID: 27163694
citation: Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Bokaba D, Sauls C, Rohr R, Long L. Initiating antiretroviral therapy for HIV at a patient's first clinic visit: the RapIT randomized controlled trial. Conference on Retroviruses and Opportunistic Infections (CROI) 2016, Boston, Feb 22-25 2016.
citation: Long LC, Maskew M, Brennan AT, Mongwenyana C, Nyoni C, Malete G, Sanne I, Fox MP, Rosen S. Initiating antiretroviral therapy for HIV at a patient's first clinic visit: a cost-effectiveness analysis of the rapid initiation of treatment randomized controlled trial. AIDS. 2017 Jul 17;31(11):1611-1619. doi: 10.1097/QAD.0000000000001528.
PMID: 28463879
citation: Maskew M, Jamieson L, Mohomi G, Long L, Mongwenyana C, Nyoni C, Mokaba D, Fox MP, Sanne I, Rosen S. Implementation of Option B and a fixed-dose combination antiretroviral regimen for prevention of mother-to-child transmission of HIV in South Africa: A model of uptake and adherence to care. PLoS One. 2018 Aug 30;13(8):e0201955. doi: 10.1371/journal.pone.0201955. eCollection 2018.
PMID: 30161147
responsible party type: Principal Investigator
investigator affiliation: Boston University
investigator full name: Sydney Rosen
investigator title: Prinicipal Investigator
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
sharing ipd: Yes
ipd description: Data will be made publicly available in the Dryad repository (http://www. datadryad.org/) after the protocol has been closed (anticipated closure December 2018).