<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/NCT03773536</url>
  </required_header>
  <id_info>
    <org_study_id>Aco V</org_study_id>
    <nct_id>NCT03773536</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Artesunate + Amodiaquine With SLD of Primaquine for Treatment of Falciparum Malaria in Zanzibar</brief_title>
  <acronym>AcoV</acronym>
  <official_title>Efficacy and Safety of Artesunate + Amodiaquine Combined With a Single Low Dose of Primaquine (0.25 mg/kg) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Zanzibar</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Professor Anders Björkman</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health and Social Welfare, Zanzibar</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Zanzibar Malaria Elimination Programme</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Uppsala University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Karolinska Institutet</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The general objective of this study is to assess the therapeutic efficacy and safety of&#xD;
      artesunate + amodiaquine combined with a single low dose of primaquine (0.25 mg/kg) for the&#xD;
      treatment of uncomplicated P. falciparum malaria patients in Zanzibar.&#xD;
&#xD;
      The specific objectives are:&#xD;
&#xD;
        -  To determine the clinical and parasitological efficacy of artesunate + amodiaquine and&#xD;
           primaquine in the treatment of uncomplicated Plasmodium falciparum infection.&#xD;
&#xD;
        -  To differentiate recurrent infections during follow-up, i.e. recrudescence from new&#xD;
           infections, by polymerase chain reaction (PCR).&#xD;
&#xD;
        -  To evaluate the incidence of adverse events, particularly with regards to potential&#xD;
           hematological adverse events of primaquine.&#xD;
&#xD;
        -  To determine the polymorphism of molecular markers associated with artesunate +&#xD;
           amodiaquine tolerance/resistance.&#xD;
&#xD;
        -  To formulate recommendations, which will enable the Zanzibar Ministry of Health to make&#xD;
           informed decisions about whether the current national antimalarial treatment guidelines&#xD;
           should be updated or not.&#xD;
&#xD;
        -  To determine efficacy rate of the first line treatment compared to the first efficacy&#xD;
           trial thirteen years ago.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aim of this study is to provide policymakers with updated efficacy and safety data of&#xD;
      artesunate + amodiaquine in combination with a single low dose of primaquine (0.25 mg/kg) and&#xD;
      data on genetic markers of tolerance/resistance to artemisinin based combination therapies&#xD;
      (ACTs), proposed as an early warning system for development and spread of antimalarial drug&#xD;
      resistance, in Zanzibar. The study protocol is based on the new WHO guidelines for&#xD;
      surveillance of antimalarial drug efficacy (WHO 2014).&#xD;
&#xD;
      This surveillance study was designed as a one-arm prospective evaluation of the clinical and&#xD;
      parasitological responses to directly observed treatment for uncomplicated malaria.&#xD;
      Participants were recruited from febrile patients, i.e. documented axillary temperature ≥37.5&#xD;
      °C or history of fever during the past 48 hours, of 3 months and older, presenting at primary&#xD;
      health care facilities in Zanzibar, with microscopy confirmed uncomplicated P. falciparum&#xD;
      infection. Enrolled patients received directly observed treatment with artesunate +&#xD;
      amodiaquine once daily for 3 consecutive days according to the national malaria treatment&#xD;
      guidelines. A single low dose of primaquine (0.25 mg/kg) was administered together with the&#xD;
      first artesunate + amodiaquine dose. Clinical and parasitological as well as safety&#xD;
      parameters were monitored over a 28-day follow-up period. The follow-up consisted of a fixed&#xD;
      schedule of check-up visits and corresponding clinical and laboratory examinations. On the&#xD;
      basis of the results of these assessments, the patients were classified as having therapeutic&#xD;
      failure (early or late) or an adequate response. Blood samples from patients experiencing&#xD;
      therapeutic failure during the follow-up period were used to estimate the efficacy of the&#xD;
      study drugs based on PCR analysis to distinguish between recrudescence (treatment failures)&#xD;
      and reinfection (new infections).&#xD;
&#xD;
      A standard physical examination was performed at baseline (day 0 before drug administration)&#xD;
      and on days 1, 2, 3, 7, 14, 21, and 28 ,or any other day if the patient returned&#xD;
      spontaneously and parasitological reassessment was required. This examination included&#xD;
      measuring axillary temperature, with a thermometer that has a precision of 0.1 °C, as well as&#xD;
      conducting a thick film for asexual and gametocyte counts and species identification.&#xD;
      Haemoglobin was assessed systematically on all participants on days 0, 3, 7, 14 and 28 using&#xD;
      Hemocue, and at any time in case of clinical suspicion of anaemia, i.e. pallor, according to&#xD;
      standard case management of malaria in Zanzibar.&#xD;
&#xD;
      In order to differentiate a recrudescence (treatment failure/same parasite strain) from a&#xD;
      newly acquired infection (reinfection/different parasite strain) among recurrent parasitemias&#xD;
      found during follow-up, a genotype analysis was to be conducted. This analysis was based on&#xD;
      the extensive diversity in the following P. falciparum genes: the merozoite surface protein 1&#xD;
      (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic&#xD;
      profiles of pre- and post-parasite strains were to be compared in a stepwise manner to&#xD;
      distinguish recrudescence from reinfection. In order to minimize discomfort to the patient&#xD;
      due to repeated finger pricks, two to three drops of blood will be collected on a 3MM&#xD;
      (Whatman) filter paper during screening or enrollment and each time blood smears are required&#xD;
      according to the protocol from day 7.&#xD;
&#xD;
      The results of this study will be used to assist the Zanzibar Ministry of Health in assessing&#xD;
      the current national treatment guidelines for uncomplicated P. falciparum malaria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 9, 2017</start_date>
  <completion_date type="Actual">September 25, 2017</completion_date>
  <primary_completion_date type="Actual">September 25, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A one-armed prospective antimalarial drug efficacy trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PCR corrected cure rates for assessing efficacy of artesunate + amodiaquine given together with a single low dose primaquine in the treatment of uncomplicated Plasmodium falciparum infection</measure>
    <time_frame>42 days</time_frame>
    <description>PCR corrected cure rates were to be assessed by genotype analysis of the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of artesunate + amodiaquine and primaquine: Incidence of adverse events</measure>
    <time_frame>42 days</time_frame>
    <description>Incidence of adverse events, particularly with regards to potential hematological adverse events of primaquine.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Monitoring molecular markers of drug resistance</measure>
    <time_frame>42 days</time_frame>
    <description>Prevalence of genetic polymorphisms associated with artesunate + amodiaquine tolerance/resistance. I.e., prevalence of genetic markers in the P. falciparum chloroquine resistance transporter gene (pfcrt), the multidrug resistance gene 1 (pfmdr1), and in the Kelch 13 propeller region.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">146</enrollment>
  <condition>Plasmodium Falciparum Malaria</condition>
  <arm_group>
    <arm_group_label>ASAQ + SLD Primaquine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Artesunate + amodiaquine (WHO prequalified Artesunate/Amodiaquine Winthrop®) was administered orally as a fixed dose combination, at a dose of approximately artesunate 4 mg/kg + amodiaquine 10mg/kg once daily for 3 consecutive days. Primaquine was administered orally, as a single dose (0.25 mg/kg) together with the first artesunate + amodiaquine dose. All doses of medicine were administered under direct supervision. Any patient who vomited within a 30 minute observation period was re-treated with the same dose of medicine and observed for an additional 30 minutes. If the patient vomited again after the second study drug administration, he/she was withdrawn and offered rescue therapy (Artesunate IV).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artesunate-amodiaquine given with single low dose primaquine</intervention_name>
    <description>Three day treatment with ASAQ with SLD primaquine given with the first dose of ASAQ.</description>
    <arm_group_label>ASAQ + SLD Primaquine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 3 months and above;&#xD;
&#xD;
          -  P. falciparum infection detected by malaria rapid diagnostic test (mRDT) and confirmed&#xD;
             by microscopy;&#xD;
&#xD;
          -  Presence of P. falciparum malaria asexual parasitaemia (any level);&#xD;
&#xD;
          -  Presence of axillary ≥37.5 °C or history of fever during the past 48 hours&#xD;
&#xD;
          -  Ability to swallow oral medication;&#xD;
&#xD;
          -  Ability and willingness to comply with the study protocol for the duration of the&#xD;
             study and to comply with the study visit schedule; and&#xD;
&#xD;
          -  Informed consent from the patient or from a parent or guardian in the case of&#xD;
             children.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of general danger signs in children aged under 5 years or signs of severe&#xD;
             falciparum malaria according to the definitions of WHO (Appendix 1);&#xD;
&#xD;
          -  Mono-infection with a Plasmodium species other than P. falciparum detected by&#xD;
             microscopy;&#xD;
&#xD;
          -  Presence of febrile conditions other than malaria (e.g. measles, acute lower&#xD;
             respiratory tract infection, severe diarrhoea with dehydration) or other known&#xD;
             underlying chronic or severe diseases (e.g. severe malnutrition, cardiac, renal and&#xD;
             hepatic diseases, HIV/AIDS);&#xD;
&#xD;
          -  Regular medication, which may interfere with the study drugs;&#xD;
&#xD;
          -  History of hypersensitivity reactions or contraindications to any of the study&#xD;
             medicines; and&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mwinyi I Msellem</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mnazi mmoja hospital, Zanzibar Ministry of Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Abduallah S Ali</last_name>
    <role>Study Director</role>
    <affiliation>Zanzibar Malaria Elimination Programme</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Andreas Martensson</last_name>
    <role>Study Chair</role>
    <affiliation>Uppsala University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Micheweni, Bububu Jesheni, and Uzini</name>
      <address>
        <city>Zanzibar</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 12, 2018</study_first_posted>
  <last_update_submitted>December 10, 2018</last_update_submitted>
  <last_update_submitted_qc>December 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 12, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska Institutet</investigator_affiliation>
    <investigator_full_name>Professor Anders Björkman</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Artesunate-amodiaquine</keyword>
  <keyword>Single Low Dose Primaquine</keyword>
  <keyword>Zanzibar</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Falciparum</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Artesunate</mesh_term>
    <mesh_term>Primaquine</mesh_term>
    <mesh_term>Amodiaquine</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/36/NCT03773536/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03773536
org study id: Aco V
nct id: NCT03773536
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The general objective of this study is to assess the therapeutic efficacy and safety of
      artesunate + amodiaquine combined with a single low dose of primaquine (0.25 mg/kg) for the
      treatment of uncomplicated P. falciparum malaria patients in Zanzibar.

      The specific objectives are:

        -  To determine the clinical and parasitological efficacy of artesunate + amodiaquine and
           primaquine in the treatment of uncomplicated Plasmodium falciparum infection.

        -  To differentiate recurrent infections during follow-up, i.e. recrudescence from new
           infections, by polymerase chain reaction (PCR).

        -  To evaluate the incidence of adverse events, particularly with regards to potential
           hematological adverse events of primaquine.

        -  To determine the polymorphism of molecular markers associated with artesunate +
           amodiaquine tolerance/resistance.

        -  To formulate recommendations, which will enable the Zanzibar Ministry of Health to make
           informed decisions about whether the current national antimalarial treatment guidelines
           should be updated or not.

        -  To determine efficacy rate of the first line treatment compared to the first efficacy
           trial thirteen years ago.
The aim of this study is to provide policymakers with updated efficacy and safety data of
      artesunate + amodiaquine in combination with a single low dose of primaquine (0.25 mg/kg) and
      data on genetic markers of tolerance/resistance to artemisinin based combination therapies
      (ACTs), proposed as an early warning system for development and spread of antimalarial drug
      resistance, in Zanzibar. The study protocol is based on the new WHO guidelines for
      surveillance of antimalarial drug efficacy (WHO 2014).

      This surveillance study was designed as a one-arm prospective evaluation of the clinical and
      parasitological responses to directly observed treatment for uncomplicated malaria.
      Participants were recruited from febrile patients, i.e. documented axillary temperature ≥37.5
      °C or history of fever during the past 48 hours, of 3 months and older, presenting at primary
      health care facilities in Zanzibar, with microscopy confirmed uncomplicated P. falciparum
      infection. Enrolled patients received directly observed treatment with artesunate +
      amodiaquine once daily for 3 consecutive days according to the national malaria treatment
      guidelines. A single low dose of primaquine (0.25 mg/kg) was administered together with the
      first artesunate + amodiaquine dose. Clinical and parasitological as well as safety
      parameters were monitored over a 28-day follow-up period. The follow-up consisted of a fixed
      schedule of check-up visits and corresponding clinical and laboratory examinations. On the
      basis of the results of these assessments, the patients were classified as having therapeutic
      failure (early or late) or an adequate response. Blood samples from patients experiencing
      therapeutic failure during the follow-up period were used to estimate the efficacy of the
      study drugs based on PCR analysis to distinguish between recrudescence (treatment failures)
      and reinfection (new infections).

      A standard physical examination was performed at baseline (day 0 before drug administration)
      and on days 1, 2, 3, 7, 14, 21, and 28 ,or any other day if the patient returned
      spontaneously and parasitological reassessment was required. This examination included
      measuring axillary temperature, with a thermometer that has a precision of 0.1 °C, as well as
      conducting a thick film for asexual and gametocyte counts and species identification.
      Haemoglobin was assessed systematically on all participants on days 0, 3, 7, 14 and 28 using
      Hemocue, and at any time in case of clinical suspicion of anaemia, i.e. pallor, according to
      standard case management of malaria in Zanzibar.

      In order to differentiate a recrudescence (treatment failure/same parasite strain) from a
      newly acquired infection (reinfection/different parasite strain) among recurrent parasitemias
      found during follow-up, a genotype analysis was to be conducted. This analysis was based on
      the extensive diversity in the following P. falciparum genes: the merozoite surface protein 1
      (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic
      profiles of pre- and post-parasite strains were to be compared in a stepwise manner to
      distinguish recrudescence from reinfection. In order to minimize discomfort to the patient
      due to repeated finger pricks, two to three drops of blood will be collected on a 3MM
      (Whatman) filter paper during screening or enrollment and each time blood smears are required
      according to the protocol from day 7.

      The results of this study will be used to assist the Zanzibar Ministry of Health in assessing
      the current national treatment guidelines for uncomplicated P. falciparum malaria.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A one-armed prospective antimalarial drug efficacy trial.
primary purpose: Treatment
masking: None (Open Label)
measure: PCR corrected cure rates for assessing efficacy of artesunate + amodiaquine given together with a single low dose primaquine in the treatment of uncomplicated Plasmodium falciparum infection
time frame: 42 days
description: PCR corrected cure rates were to be assessed by genotype analysis of the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection.
measure: Safety of artesunate + amodiaquine and primaquine: Incidence of adverse events
time frame: 42 days
description: Incidence of adverse events, particularly with regards to potential hematological adverse events of primaquine.
measure: Monitoring molecular markers of drug resistance
time frame: 42 days
description: Prevalence of genetic polymorphisms associated with artesunate + amodiaquine tolerance/resistance. I.e., prevalence of genetic markers in the P. falciparum chloroquine resistance transporter gene (pfcrt), the multidrug resistance gene 1 (pfmdr1), and in the Kelch 13 propeller region.
arm group label: ASAQ + SLD Primaquine
arm group type: Experimental
description: Artesunate + amodiaquine (WHO prequalified Artesunate/Amodiaquine Winthrop®) was administered orally as a fixed dose combination, at a dose of approximately artesunate 4 mg/kg + amodiaquine 10mg/kg once daily for 3 consecutive days. Primaquine was administered orally, as a single dose (0.25 mg/kg) together with the first artesunate + amodiaquine dose. All doses of medicine were administered under direct supervision. Any patient who vomited within a 30 minute observation period was re-treated with the same dose of medicine and observed for an additional 30 minutes. If the patient vomited again after the second study drug administration, he/she was withdrawn and offered rescue therapy (Artesunate IV).
intervention type: Drug
intervention name: Artesunate-amodiaquine given with single low dose primaquine
description: Three day treatment with ASAQ with SLD primaquine given with the first dose of ASAQ.
arm group label: ASAQ + SLD Primaquine
criteria: 
gender: All
minimum age: 3 Months
maximum age: N/A
healthy volunteers: No
last name: Mwinyi I Msellem
role: Principal Investigator
affiliation: Mnazi mmoja hospital, Zanzibar Ministry of Health
last name: Abduallah S Ali
role: Study Director
affiliation: Zanzibar Malaria Elimination Programme
last name: Andreas Martensson
role: Study Chair
affiliation: Uppsala University
facility: 
country: Tanzania
responsible party type: Sponsor-Investigator
investigator affiliation: Karolinska Institutet
investigator full name: Professor Anders Björkman
investigator title: Professor
mesh term: Malaria
mesh term: Malaria, Falciparum
mesh term: Artesunate
mesh term: Primaquine
mesh term: Amodiaquine
provided document: 