<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/NCT01707199</url>
  </required_header>
  <id_info>
    <org_study_id>SPK</org_study_id>
    <nct_id>NCT01707199</nct_id>
  </id_info>
  <brief_title>SPK Study in Afghanistan</brief_title>
  <official_title>Efficacy and Safety of Artesunate+Sulphadoxine-Pyrimethamine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Malaria Control Center Asadabad in Kunar Province of Afghanistan</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>World Health Organization</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Oxford</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In Afghanistan, studies over the past 15 years have shown a high degree of Plasmodium&#xD;
      falciparum resistance to chloroquine. In 2003 the high failure rate of chloroquine against&#xD;
      falciparum malaria led the national malaria treatment programme to switch its recommended&#xD;
      first line drug treatment for uncomplicated Plasmodium falciparum malaria to&#xD;
      artemisinin-based combination therapy (ACT) in the form of&#xD;
      Artesunate/Sulphadoxine-Pyrimethamine (AS+SP). Second line drug treatment is oral quinine (7&#xD;
      days).&#xD;
&#xD;
      For operational reasons, prior to recent studies (manuscript in preparation) there have been&#xD;
      no molecular data on P. falciparum SP resistance markers from within the borders of&#xD;
      Afghanistan. These studies have revealed early evidence of increasing SP resistance&#xD;
      (resistance polymorphisms with double DHFR &amp; triple DHPS mutations). The aim of this study is&#xD;
      to conduct a focused, prospective study in Kunar for monitoring of the efficacy of the AS+SP&#xD;
      combination in this province, along with molecular studies of isolates from recruited&#xD;
      patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Afghanistan is a poor country that remains largely dependent on foreign aid. Life expectancy&#xD;
      remains in the order of 60 years, with 30% of mortality due to communicable diseases.&#xD;
&#xD;
      Malaria is a large health burden, and antimalarial drug resistance poses a considerable&#xD;
      threat to malaria control. Resistance to chloroquine was evident in Afghanistan by the&#xD;
      late-1990s, with failure rates more than 60% for the country as a whole and as high as 90%&#xD;
      for Jalalabad (Nangarhar province). The combination of artesunate with amodiaquine also&#xD;
      proved to have low efficacy. In 2004 failure rates for SP for the treatment of P. falciparum&#xD;
      were 10-15% consistent with comparable clinical data in Afghan refugees residing in Pakistan.&#xD;
      Given this efficacy, the Ministry of Public Health, in consultation with WHO and other&#xD;
      international partners, has implemented AS+SP as first-line treatment of slide confirmed P.&#xD;
      falciparum malaria in Afghanistan. Quinine (7 days po) is second line treatment. CQ+SP has&#xD;
      been the recommended treatment for patients with a presumptive diagnosis of malaria since&#xD;
      2003. Both artesunate and sulphadoxine-pyrimethamine are safe and well tolerated drugs and&#xD;
      there is no evidence of an interaction between them.&#xD;
&#xD;
      Artesunate (AS) has been reported to be associated with mild gastrointestinal disturbances,&#xD;
      dizziness and tinnitus although none of these associations are convincing. The only&#xD;
      potentially serious adverse effect that has been reported with the artemisinin class of drugs&#xD;
      in clinical trials is type I hypersensitivity reactions (about 1:3,000 patients). Transient&#xD;
      reticulocytopenia, neutropenia, and elevated liver enzyme values have been reported but none&#xD;
      have been clinically significant. The weight of evidence suggests these drugs have no&#xD;
      significant adverse cardiovascular effects. A variety of clinical, neurophysiological, and&#xD;
      pathologic studies in humans have not shown evidence of neurological toxicity. Because these&#xD;
      drugs have not been evaluated extensively in early pregnancy in humans, they should be&#xD;
      avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more&#xD;
      information is available (WHO guidelines 2006).&#xD;
&#xD;
      Sulphadoxine-pyrimethamine (SP) is a fixed combination of a long-acting sulfonamide and the&#xD;
      antifolate pyrimethamine. These are synergistic against sensitive parasites. Minor adverse&#xD;
      effects are unusual and serious sulfonamide toxicity is very unusual with a single-dose&#xD;
      treatment of malaria. The anti-folate properties of pyrimethamine rarely produce toxicity.&#xD;
&#xD;
      The combination of AS + SP has been evaluated extensively in adults and children with&#xD;
      uncomplicated malaria and is sufficiently efficacious in areas where 28-day cure rates with&#xD;
      sulphadoxine-pyrimethamine alone exceed 80%. This ACT is currently being used in parts of&#xD;
      South America, the Middle East, and South Asia where SP susceptibility remains high. Studies&#xD;
      conducted between 2004-2006 to evaluate the efficacy of artesunate plus&#xD;
      sulphadoxine-pyrimethamine (AS+SP) against P. falciparum showed high efficacy in terms of&#xD;
      adequate clinical and parasitological response (Afghanistan National Malaria Strategic Plan).&#xD;
&#xD;
      The genetic determinants of in vitro resistance to the two drug components of SP individually&#xD;
      are shown to be point mutations at seven sites in the dihydrofolate reductase gene (dhfr)&#xD;
      causing resistance to pyrimethamine and five sites in the dihydropteroate synthase (dhps)&#xD;
      gene causing resistance to sulphadoxine. Different combinations of mutations within each gene&#xD;
      confer differing degrees of insensitivity. Due to administrative instability, until recently&#xD;
      few molecular data relating to P. falciparum SP resistance markers have been available from&#xD;
      within the borders of Afghanistan. However the investigators have obtained recent (submitted)&#xD;
      data showing that in addition to two resistance polymorphisms in DHFR (C59R and S108N) that&#xD;
      are well known to be at high frequency in the region, a small number of parasites in the&#xD;
      Kunar province have three mutations (A437G, K540E and A581G) in DHPS.&#xD;
&#xD;
      This study is a prospective, open label, single arm clinical trial to test the PCR confirmed&#xD;
      efficacy and tolerability of AS+SP for the treatment of uncomplicated falciparum malaria in&#xD;
      Afghanistan. Follow-up will be for 42 days, in order to sensitively detect recrudescence.&#xD;
      Recrudescence will be distinguished from re-infection by molecular techniques based on well&#xD;
      characterized microsatellite markers msp1, msp2 and glurp will be used. Baseline and any&#xD;
      recurrent parasites will be tested for DHFR and DHPS polymorphisms by RFLP as well as&#xD;
      sequencing if indicated. The proposed study will provide accurate data and accurate evidences&#xD;
      on efficacy of the current malaria treatment regimen in Afghanistan.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2012</start_date>
  <completion_date type="Actual">January 2014</completion_date>
  <primary_completion_date type="Actual">January 2014</primary_completion_date>
  <phase>N/A</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Adequate clinical and parasitological response (ACPR)</measure>
    <time_frame>42 days</time_frame>
    <description>WHO defined ACPR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>42 days</time_frame>
    <description>The incidence of any adverse event will be documented. All patients will be asked routinely about previous symptoms and about symptoms that have emerged since the previous follow-up visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Molecular markers for antimalarial drug resistance</measure>
    <time_frame>Baseline</time_frame>
    <description>To study polymorphisms in PfDHFR, PfDHPS and copy number of PfGCH1 which are considered as markers of resistance to Sulphadoxine-pyrimethamine (SP) components.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">83</enrollment>
  <condition>Uncomplicated P. Falciparum Malaria</condition>
  <arm_group>
    <arm_group_label>Artesunate + Sulphadoxine-pyrimethamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AS+SP will be administered according to the patient's age, based on a dose of 4mg artesunate/kg body weight once daily for 3 days plus SP at a dose of 25mg sulphadoxine/kg body weight single dose on the first day.&#xD;
One co-blister pack of Artecospe will be used per patient and obtained via WHO from Guilin Pharmaceutical Co. Ltd., Shanghai China, with appropriate expiry date.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artesunate + Sulphadoxine-pyrimethamine</intervention_name>
    <description>AS+SP will be administered according to the patient's age, based on a dose of 4mg artesunate/kg body weight once daily for 3 days plus SP at a dose of 25mg sulphadoxine/kg body weight single dose on the first day.&#xD;
One co-blister pack of Artecospe will be used per patient and obtained via WHO from Guilin Pharmaceutical Co. Ltd., Shanghai China, with appropriate expiry date.</description>
    <arm_group_label>Artesunate + Sulphadoxine-pyrimethamine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males: age over 4 months;&#xD;
&#xD;
          -  Females: age 4 months - 11 years inclusive, or 18 years or older;&#xD;
&#xD;
          -  Infection with P. falciparum detected by microscopy at a level of 500-150,000/µL&#xD;
             asexual forms;&#xD;
&#xD;
          -  Presence of axillary or tympanic temperature ≥ 37.5 °C or oral or rectal temperature&#xD;
             of ≥ 38 °C or history of fever during the past 24 h;&#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 children&#xD;
             under 16 years of age.&#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;
          -  Infection with another Plasmodium species detected by microscopy not mixed with&#xD;
             falciparum;&#xD;
&#xD;
          -  Females 18 years or older: a positive pregnancy test or absence of a negative&#xD;
             pregnancy test when a pregnancy test is not possible for cultural reasons;&#xD;
&#xD;
          -  Breastfeeding&#xD;
&#xD;
          -  Presence of severe malnutrition (defined as a child whose growth standard is below -3&#xD;
             z-score, has symmetrical oedema involving at least the feet or has a mid-upper arm&#xD;
             circumference &lt; 110 mm);&#xD;
&#xD;
          -  Presence of febrile conditions due to diseases other than malaria (e.g. measles, acute&#xD;
             lower respiratory tract infection, severe diarrhoea with dehydration) or other known&#xD;
             underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases,&#xD;
             HIV/AIDS);&#xD;
&#xD;
          -  Regular medication, which may interfere with antimalarial pharmacokinetics;&#xD;
&#xD;
          -  History of hypersensitivity reactions or contraindications to any of the study&#xD;
             medications;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ghulam Rahim Awab, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Research Dept. Ministry of Public Health (MoPH) Afghanistan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Narang, Asadabad, Watapoor district health centres</name>
      <address>
        <city>Kunar</city>
        <country>Afghanistan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Afghanistan</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>October 11, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 16, 2012</study_first_posted>
  <last_update_submitted>October 9, 2020</last_update_submitted>
  <last_update_submitted_qc>October 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>P. falciparum</keyword>
  <keyword>Sulphadoxine-pyrimethamine</keyword>
  <keyword>Artesunate</keyword>
  <keyword>Artemisinin Combination Therapy (ACT)</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>Pyrimethamine</mesh_term>
    <mesh_term>Sulfadoxine</mesh_term>
    <mesh_term>Fanasil, pyrimethamine drug combination</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01707199
org study id: SPK
nct id: NCT01707199
lead sponsor: 
collaborator: 
has dmc: No
In Afghanistan, studies over the past 15 years have shown a high degree of Plasmodium
      falciparum resistance to chloroquine. In 2003 the high failure rate of chloroquine against
      falciparum malaria led the national malaria treatment programme to switch its recommended
      first line drug treatment for uncomplicated Plasmodium falciparum malaria to
      artemisinin-based combination therapy (ACT) in the form of
      Artesunate/Sulphadoxine-Pyrimethamine (AS+SP). Second line drug treatment is oral quinine (7
      days).

      For operational reasons, prior to recent studies (manuscript in preparation) there have been
      no molecular data on P. falciparum SP resistance markers from within the borders of
      Afghanistan. These studies have revealed early evidence of increasing SP resistance
      (resistance polymorphisms with double DHFR & triple DHPS mutations). The aim of this study is
      to conduct a focused, prospective study in Kunar for monitoring of the efficacy of the AS+SP
      combination in this province, along with molecular studies of isolates from recruited
      patients.
Afghanistan is a poor country that remains largely dependent on foreign aid. Life expectancy
      remains in the order of 60 years, with 30% of mortality due to communicable diseases.

      Malaria is a large health burden, and antimalarial drug resistance poses a considerable
      threat to malaria control. Resistance to chloroquine was evident in Afghanistan by the
      late-1990s, with failure rates more than 60% for the country as a whole and as high as 90%
      for Jalalabad (Nangarhar province). The combination of artesunate with amodiaquine also
      proved to have low efficacy. In 2004 failure rates for SP for the treatment of P. falciparum
      were 10-15% consistent with comparable clinical data in Afghan refugees residing in Pakistan.
      Given this efficacy, the Ministry of Public Health, in consultation with WHO and other
      international partners, has implemented AS+SP as first-line treatment of slide confirmed P.
      falciparum malaria in Afghanistan. Quinine (7 days po) is second line treatment. CQ+SP has
      been the recommended treatment for patients with a presumptive diagnosis of malaria since
      2003. Both artesunate and sulphadoxine-pyrimethamine are safe and well tolerated drugs and
      there is no evidence of an interaction between them.

      Artesunate (AS) has been reported to be associated with mild gastrointestinal disturbances,
      dizziness and tinnitus although none of these associations are convincing. The only
      potentially serious adverse effect that has been reported with the artemisinin class of drugs
      in clinical trials is type I hypersensitivity reactions (about 1:3,000 patients). Transient
      reticulocytopenia, neutropenia, and elevated liver enzyme values have been reported but none
      have been clinically significant. The weight of evidence suggests these drugs have no
      significant adverse cardiovascular effects. A variety of clinical, neurophysiological, and
      pathologic studies in humans have not shown evidence of neurological toxicity. Because these
      drugs have not been evaluated extensively in early pregnancy in humans, they should be
      avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more
      information is available (WHO guidelines 2006).

      Sulphadoxine-pyrimethamine (SP) is a fixed combination of a long-acting sulfonamide and the
      antifolate pyrimethamine. These are synergistic against sensitive parasites. Minor adverse
      effects are unusual and serious sulfonamide toxicity is very unusual with a single-dose
      treatment of malaria. The anti-folate properties of pyrimethamine rarely produce toxicity.

      The combination of AS + SP has been evaluated extensively in adults and children with
      uncomplicated malaria and is sufficiently efficacious in areas where 28-day cure rates with
      sulphadoxine-pyrimethamine alone exceed 80%. This ACT is currently being used in parts of
      South America, the Middle East, and South Asia where SP susceptibility remains high. Studies
      conducted between 2004-2006 to evaluate the efficacy of artesunate plus
      sulphadoxine-pyrimethamine (AS+SP) against P. falciparum showed high efficacy in terms of
      adequate clinical and parasitological response (Afghanistan National Malaria Strategic Plan).

      The genetic determinants of in vitro resistance to the two drug components of SP individually
      are shown to be point mutations at seven sites in the dihydrofolate reductase gene (dhfr)
      causing resistance to pyrimethamine and five sites in the dihydropteroate synthase (dhps)
      gene causing resistance to sulphadoxine. Different combinations of mutations within each gene
      confer differing degrees of insensitivity. Due to administrative instability, until recently
      few molecular data relating to P. falciparum SP resistance markers have been available from
      within the borders of Afghanistan. However the investigators have obtained recent (submitted)
      data showing that in addition to two resistance polymorphisms in DHFR (C59R and S108N) that
      are well known to be at high frequency in the region, a small number of parasites in the
      Kunar province have three mutations (A437G, K540E and A581G) in DHPS.

      This study is a prospective, open label, single arm clinical trial to test the PCR confirmed
      efficacy and tolerability of AS+SP for the treatment of uncomplicated falciparum malaria in
      Afghanistan. Follow-up will be for 42 days, in order to sensitively detect recrudescence.
      Recrudescence will be distinguished from re-infection by molecular techniques based on well
      characterized microsatellite markers msp1, msp2 and glurp will be used. Baseline and any
      recurrent parasites will be tested for DHFR and DHPS polymorphisms by RFLP as well as
      sequencing if indicated. The proposed study will provide accurate data and accurate evidences
      on efficacy of the current malaria treatment regimen in Afghanistan.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Adequate clinical and parasitological response (ACPR)
time frame: 42 days
description: WHO defined ACPR
measure: Adverse events
time frame: 42 days
description: The incidence of any adverse event will be documented. All patients will be asked routinely about previous symptoms and about symptoms that have emerged since the previous follow-up visit.
measure: Molecular markers for antimalarial drug resistance
time frame: Baseline
description: To study polymorphisms in PfDHFR, PfDHPS and copy number of PfGCH1 which are considered as markers of resistance to Sulphadoxine-pyrimethamine (SP) components.
arm group label: Artesunate + Sulphadoxine-pyrimethamine
arm group type: Experimental
description: AS+SP will be administered according to the patient's age, based on a dose of 4mg artesunate/kg body weight once daily for 3 days plus SP at a dose of 25mg sulphadoxine/kg body weight single dose on the first day.
One co-blister pack of Artecospe will be used per patient and obtained via WHO from Guilin Pharmaceutical Co. Ltd., Shanghai China, with appropriate expiry date.
intervention type: Drug
intervention name: Artesunate + Sulphadoxine-pyrimethamine
description: AS+SP will be administered according to the patient's age, based on a dose of 4mg artesunate/kg body weight once daily for 3 days plus SP at a dose of 25mg sulphadoxine/kg body weight single dose on the first day.
One co-blister pack of Artecospe will be used per patient and obtained via WHO from Guilin Pharmaceutical Co. Ltd., Shanghai China, with appropriate expiry date.
arm group label: Artesunate + Sulphadoxine-pyrimethamine
criteria: 
gender: All
minimum age: 4 Months
maximum age: N/A
healthy volunteers: No
last name: Ghulam Rahim Awab, MD
role: Principal Investigator
affiliation: Research Dept. Ministry of Public Health (MoPH) Afghanistan
facility: 
country: Afghanistan
responsible party type: Sponsor
mesh term: Malaria
mesh term: Malaria, Falciparum
mesh term: Artesunate
mesh term: Pyrimethamine
mesh term: Sulfadoxine
mesh term: Fanasil, pyrimethamine drug combination