<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/NCT02215265</url>
  </required_header>
  <id_info>
    <org_study_id>2014/VCC/0014</org_study_id>
    <nct_id>NCT02215265</nct_id>
  </id_info>
  <brief_title>Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS)</brief_title>
  <acronym>PATHOS</acronym>
  <official_title>A Phase III Trial of Risk-stratified, Reduced Intensity Adjuvant Treatment in Patients Undergoing Transoral Surgery for Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lisette Nixon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>UNICANCER</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AdventHealth</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Leipzig</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Princess Alexandra Hospital, Brisbane, Australia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Velindre NHS Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main objectives of the PATHOS study are:&#xD;
&#xD;
      To assess whether swallowing function can be improved following transoral resection of&#xD;
      HPV-positive OPSCC, by reducing the intensity of adjuvant treatment protocols. The aim is to&#xD;
      personalise treatment, based on disease biology (HPV status and pathology findings), to&#xD;
      optimise patient outcomes.&#xD;
&#xD;
      To demonstrate the non-inferiority of reducing the intensity of adjuvant treatment protocols&#xD;
      in terms of overall survival in the reduced intensity treatment arms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PATHOS is a multicentre, open-label, parallel-group Phase II/III randomised controlled trial&#xD;
      (RCT). The phase II target of 242 patients was reached in December 2018 and there was a&#xD;
      seamless transition into Phase III. The protocol was amended in September 2018 to incorporate&#xD;
      the changes associated with the phase III transition. The amendment included changes to the&#xD;
      outcome measures and sample size calculations.&#xD;
&#xD;
      Approximately 1100 patients will be recruited to the phase III study. Patients eligible for&#xD;
      the study must have biopsy proven oropharyngeal squamous cell carcinoma (OPSCC) clinically&#xD;
      staged T1T3 N0N2b. Their primary tumour, as judged by the local MDT, must be considered&#xD;
      resectable via a transoral approach. Having secured informed consent, patients with centrally&#xD;
      or locally determined HPV positive tumours will undergo baseline assessment of swallowing&#xD;
      function (includes; MDADI score, videofluoroscopy, PSSH&amp; N, 100 mL water swallow test) and&#xD;
      complete QOL questions (EORTC QLQC30 and EORTC QLQH&amp;N35) prior to surgery.&#xD;
&#xD;
      Transoral Laser Microsurgery, Transoral Robotic Surgery &amp; Endoscopically assisted Transoral&#xD;
      Surgery are all accepted transoral techniques for the study. A lateral oropharyngectomy&#xD;
      performed with monopolar cautery (The Huet Procedure) can also be used.&#xD;
&#xD;
      Following surgery and histopathological assessment of the primary tumour and neck dissection&#xD;
      surgical specimens, participants will be allocated into study groups based on the presence or&#xD;
      absence of pathological risk factors for recurrence as follows:&#xD;
&#xD;
      Group A: Participants with tumours which exhibit no adverse histological features.&#xD;
      Participants in this group will not receive any adjuvant treatment as per standard of care.&#xD;
&#xD;
      Group B: Participants with T3 tumours (or T1-T2 tumours with additional risk factors), TNM&#xD;
      7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b&#xD;
      (metastasis in multiple ipsilateral nodes &lt;61 mm diameter) disease, tumours with evidence of&#xD;
      perineural and/or vascular invasion, and/or a histologically normal tissue margin around the&#xD;
      primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. Patients&#xD;
      in this group will be randomised to PORT 60Gy in 30# over 6 weeks (Control Arm B1) or PORT&#xD;
      50Gy in 25# over 5 weeks (Test Arm B2).&#xD;
&#xD;
      Group C: Participants with tumours of any T or any N stage, which exhibit the following&#xD;
      high-risk pathological features will be included: A histologically normal tissue margin&#xD;
      around the primary tumour of &lt;1mm and, in the case of TLM, marginal biopsies free of tumour&#xD;
      and /or extracapsular spread (ECS) of nodal disease. Participants in this group will be&#xD;
      randomised to POCRT 60Gy in 30# over 6 weeks with concurrent Cisplatin (Control Arm C1) or&#xD;
      PORT 60Gy in 30# over 6 weeks without chemotherapy (Test Arm C2).&#xD;
&#xD;
      Participants in groups B and C will be stratified before randomisation by T stage, N stage,&#xD;
      smoking history and treating centre.&#xD;
&#xD;
      The same assessments as at baseline will be completed post-operatively prior to treatment and&#xD;
      then at four weeks and 6, 12 and 24 months post-treatment. The exception is videofluoroscopy&#xD;
      which will be repeated at post-surgery and 12 months only. Videofluroscopies are only&#xD;
      performed at UK sites.&#xD;
&#xD;
      Acute and late toxicity will be recorded weekly during treatment and again at 4 weeks and 6,&#xD;
      12 and 24 months post-treatment.&#xD;
&#xD;
      All study assessments, complications relating to surgery and adjuvant treatment, in&#xD;
      particular complications which necessitate a delay to the start of adjuvant treatment, will&#xD;
      all be recorded on the Case Report Form (CRF).&#xD;
&#xD;
      International sites have been initiated on Electronic Data Capture (EDC) and local UK sites&#xD;
      have transitioned to EDC for participants enrolled after implementation. Data entry needs to&#xD;
      be completed within four weeks of the study visit. In accordance with the principles of GCP,&#xD;
      the PI is responsible for ensuring accuracy, completeness, legibility and timeliness of the&#xD;
      data reported to the CTR in the CRFs. The CRF will be checked for missing, illegible or&#xD;
      unusual values (range checks) and consistency over time.&#xD;
&#xD;
      If missing or questionable data are identified, a data query will be raised on a data&#xD;
      clarification form and sent to the site for resolution. All answered data queries and&#xD;
      corrections should be signed off and dated by a delegated member of staff at the relevant&#xD;
      participating site.&#xD;
&#xD;
      The CTR will send reminders for any overdue data. It is the site's responsibility to submit&#xD;
      complete and accurate data in a timely manner.&#xD;
&#xD;
      Quality assurance: The clinical trial risk assessment has been used to determine the&#xD;
      intensity and focus of central and on-site monitoring activity in the PATHOS trial.&#xD;
      Monitoring levels will be employed and are fully documented in the trial monitoring plan.&#xD;
      Investigators should agree to allow trial-related monitoring, including audits and regulatory&#xD;
      inspections, by providing direct access to source data/documents as required. Patient consent&#xD;
      for this will be obtained.&#xD;
&#xD;
      Registration: All sites have transitioned to an electronic database and the registration and&#xD;
      randomisation process is completed online. Participants will be randomised using minimisation&#xD;
      with a random element. This will ensure balanced treatment allocation by clinically important&#xD;
      stratification factors. Randomisation will have an allocation ratio of 1:1.&#xD;
&#xD;
      Statistical analyses:&#xD;
&#xD;
      Primary outcome measure&#xD;
&#xD;
      MDADI/Overall survival co-primary endpoint&#xD;
&#xD;
      Secondary outcome measures&#xD;
&#xD;
        -  Swallowing panel including qualitative and quantitative swallowing assessments (100ml&#xD;
           Water Swallow Test, Videofluoroscopy, Performance Status Scale-Head &amp; Neck)&#xD;
&#xD;
        -  QOL (using validated EORTC QLQ C30 and HN35 questionnaires, Appendix 6)&#xD;
&#xD;
        -  Acute and late toxicity using CTACE version 4.03&#xD;
&#xD;
        -  Disease-Free Survival*&#xD;
&#xD;
        -  Locoregional control*&#xD;
&#xD;
        -  Distant Metastases* *Determined by clinical follow-up as per standard guidelines (no&#xD;
           trial-specific imaging required)&#xD;
&#xD;
      The co-primary endpoint of the Phase III will be MDADI and overall survival (time to event).&#xD;
&#xD;
      We will use linear regression to estimate the treatment arm effect on MDADI at 12 months and&#xD;
      will include the randomisation stratification variables and baseline MDADI in the model. Both&#xD;
      OS and MDADI endpoints will be used to define study success so no adjustment for multiplicity&#xD;
      is planned. A detailed statistical analysis plan will be developed before the analyses are&#xD;
      conducted.&#xD;
&#xD;
      The data will be reviewed (approximately six-monthly) by an Independent Data Monitoring&#xD;
      Committee (IDMC), consisting of at least two Clinicians (not entering patients into the&#xD;
      trial) and an independent Statistician. The IDMC will be asked to recommend whether the&#xD;
      accumulated data from the trial, together with results from other relevant trials, justifies&#xD;
      continuing recruitment of further patients. A decision to discontinue recruitment, in all&#xD;
      patients or selected subgroups, will be made only if the result is likely to convince a broad&#xD;
      range of Clinicians including PIs in the trial and the general clinical community. If a&#xD;
      decision is made to continue, the IDMC will advise on the frequency of future reviews of the&#xD;
      data based on accrual and event rates.&#xD;
&#xD;
      Sub-group statistical analyses:&#xD;
&#xD;
      For swallowing endpoints, subgroup analysis by T stage and tumour subsite (tonsil, soft&#xD;
      palate, tongue base) and surgery technique will be carried out, as the most likely relevant&#xD;
      clinical co-variables affecting swallowing function.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 2015</start_date>
  <completion_date type="Anticipated">April 2027</completion_date>
  <primary_completion_date type="Anticipated">October 2026</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>MDADI/Overall survival co-primary endpoint</measure>
    <time_frame>At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Swallowing panel including qualitative and quantitative swallowing assessments</measure>
    <time_frame>Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.</time_frame>
    <description>Water swallow test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QOL (using validated EORTC QLQ C30 and HN35 questionnaires)</measure>
    <time_frame>Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.</time_frame>
    <description>Quality of Life (QOL) questions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute and late toxicity using CTACE version 4.03</measure>
    <time_frame>Weekly during RT and at end of treatment; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks), 6 months (+/- 4 weeks), 12 months (+/- 4 weeks), and 24 months (+/- 8 weeks) post treatment.</time_frame>
    <description>Toxicity assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Free Survival</measure>
    <time_frame>6 months intervals</time_frame>
    <description>Determined by clinical follow up as per standard guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Locoregional control</measure>
    <time_frame>6 months intervals</time_frame>
    <description>Determined by clinical follow up as per standard guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant Metastases</measure>
    <time_frame>6 months intervals</time_frame>
    <description>Determined by clinical follow up as per standard guidelines</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">1100</enrollment>
  <condition>Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer</condition>
  <arm_group>
    <arm_group_label>A: No adjuvant treatment</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Group A Patients with tumours which exhibit no adverse histological features. Patients in this group will not receive any adjuvant treatment as per standard of care.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B1: Postoperative radiotherapy 60 Gray</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Arm B1: postoperative radiotherapy (PORT) at a dose of 60 Gray (Gy) in 30 fractions over 6 weeks.&#xD;
Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes &lt;61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B2: Postoperative radiotherapy 50 Gray</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm B2: Postoperative radiotherapy (PORT) at a dose 50 Gray in 25 fractions over 5 weeks.&#xD;
Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes &lt;61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>C1: Postoperative radiotherapy 60 Gray with Cisplatin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice.&#xD;
Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of &lt;1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease</description>
  </arm_group>
  <arm_group>
    <arm_group_label>C2: Postoperative radiotherapy 60 Gray without chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm C2: Postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks without chemotherapy (Test Arm C2).&#xD;
Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of &lt;1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Chemotherapy</description>
    <arm_group_label>C1: Postoperative radiotherapy 60 Gray with Cisplatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Postoperative radiotherapy</intervention_name>
    <description>Postoperative radiotherapy (PORT)</description>
    <arm_group_label>B1: Postoperative radiotherapy 60 Gray</arm_group_label>
    <arm_group_label>B2: Postoperative radiotherapy 50 Gray</arm_group_label>
    <arm_group_label>C1: Postoperative radiotherapy 60 Gray with Cisplatin</arm_group_label>
    <arm_group_label>C2: Postoperative radiotherapy 60 Gray without chemotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed or suspected squamous cell carcinoma of the oropharynx.&#xD;
&#xD;
          -  UICC/AJCC TNM 7th edition stage T1-T3, N0-N2b (or UICC TNM 8th edition stage T1-T3,&#xD;
             N0-N1) disease.&#xD;
&#xD;
          -  Multidisciplinary team (MDT) decision to treat with primary transoral resection and&#xD;
             neck dissection.&#xD;
&#xD;
          -  Patients considered fit for surgery and adjuvant radiotherapy&#xD;
&#xD;
          -  Aged 18 or over.&#xD;
&#xD;
          -  Written informed consent provided.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known HPV negative squamous cell carcinomas of the head and neck: A negative result&#xD;
             for p16 Immunohistochemistry automatically excludes a patient from the trial. If&#xD;
             initial p16 testing is positive but High Risk HPV (HR HPV) In-Situ Hybridization&#xD;
             (ISH)/Polymerase Chain Reaction (PCR) does not demonstrate the presence of HR HPV DNA,&#xD;
             the patient will also be excluded. Patients who are p16+ may complete swallowing&#xD;
             assessments, excluding videofluoroscopy, and surgery whilst HR HPV DNA status is being&#xD;
             determined (with recourse to central concordance testing, if appropriate, for UK&#xD;
             centres). HPV positivity, as determined by p16 and the demonstration of HR HPV DNA is&#xD;
             essential before patients undergo videofluoroscopy or randomisation.&#xD;
&#xD;
          -  T4 and/or T1-T3 tumours where transoral surgery is considered not feasible.&#xD;
&#xD;
          -  UICC/AJCC TNM 7th edition N2c-N3 nodal disease (or UICC/AJCC TNM 8th edition N2-N3&#xD;
             nodal disease).&#xD;
&#xD;
          -  Patients for whom transoral surgery and neck dissection is not considered the primary&#xD;
             treatment modality.&#xD;
&#xD;
          -  Current smokers with clinically staged N2b disease (including smokers up to 6 months&#xD;
             before diagnosis), even if HPV-positive. Vaping is permitted and should be considered&#xD;
             as non-smoking status.&#xD;
&#xD;
          -  Any pre-existing medical condition likely to impair swallowing function and/ or a&#xD;
             history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer.&#xD;
&#xD;
          -  Patients with distant metastatic disease as determined by routine pre-operative&#xD;
             staging radiological investigations e.g., CT thorax and upper abdomen or PET-CT.&#xD;
&#xD;
          -  Patients with a history of malignancy in the last 5 years, except basal cell carcinoma&#xD;
             of the skin or carcinoma in-situ of the cervix.&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding and fertile women who will not be using&#xD;
             contraception during the trial.&#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>Mererid Evans, MBBch, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Velindre NHS Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Terrence Jones, MBBS,MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Aintree University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Board of Trustees of the Leland Stanford Junior University</name>
      <address>
        <city>Redwood City</city>
        <state>California</state>
        <zip>94063</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michelle Chen</last_name>
      <phone>650-723-5957</phone>
      <email>nbedi@stanford.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Advent Health</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32803</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bruce Haughey</last_name>
      <phone>407-303-0409</phone>
      <email>bruce.haughey.md@flhosp.org</email>
    </contact>
    <contact_backup>
      <last_name>Sara Guyler</last_name>
      <phone>407-543-4000</phone>
      <phone_ext>1203655</phone_ext>
      <email>Sara.Guyler@AdventHealth.com</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Centre</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Metro South Health</name>
      <address>
        <city>Brisbane</city>
        <zip>QLD 4113</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ben Panizza, Prof</last_name>
      <email>ben@panizza.com.au</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Unicancer</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Haitham Mirghani (National Coordinator)</last_name>
      <email>haitham.mirghani@aphp.fr</email>
    </contact>
    <investigator>
      <last_name>Pierre Blanchard</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Vincent Gregoire</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Franchel-Rais Obongo-Anga</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ovidiu Veresezan</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Wassila Boukhelif</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Alexandre Villeneuve</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Florence Huguet</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sylvain Moriniere</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Guillaume Chambon</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Philippe Ceruse</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Vivantes Klinikum</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Volker Schilling</last_name>
      <email>volker.schilling@vivantes.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Asklepios Kliniken</name>
      <address>
        <city>Hamburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Silke Tribius</last_name>
      <email>silke@tribius.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitat Leipzig</name>
      <address>
        <city>Leipzig</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Susanne Wiegand</last_name>
      <email>Susanne.Wiegand@medizin.uni-leipzig.de</email>
    </contact>
    <investigator>
      <last_name>Silke Tribius</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ernst von Bergmann Klinikum</name>
      <address>
        <city>Potsdam</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Markus Jungehulsing</last_name>
      <phone>0331/241-36007</phone>
      <email>mjungehuelsing@klinikumevb.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinikum Solingen</name>
      <address>
        <city>Solingen</city>
        <zip>42653</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>A.M Sesterhenn</last_name>
      <phone>00492125472738</phone>
      <email>sesterhenn@klinikumsolingen.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Ulm</name>
      <address>
        <city>Ulm</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Simon Laban</last_name>
      <phone>0731 500 59543</phone>
      <email>Simon.laban@uniklinik-ulm.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospitals Dorset NHS Foundation</name>
      <address>
        <city>Poole</city>
        <state>Dorset</state>
        <zip>BH15 2JB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emma King, Dr</last_name>
      <email>emmabarker@doctors.org.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal United Hospitals Bath NHS Foundation Trust</name>
      <address>
        <city>Bath</city>
        <zip>BA1 3NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emma De Winton, Dr</last_name>
      <email>emma.dewinton@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <zip>B15 2TH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrew Hartley, Dr</last_name>
      <email>andrew.hartley@uhb.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Blackburn Hospital</name>
      <address>
        <city>Blackburn</city>
        <zip>BB2 3HH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Panayiotis Kyzas, Mr</last_name>
      <email>Panayiotis.Kyzas@elht.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Sussex County Hospital</name>
      <address>
        <city>Brighton</city>
        <zip>BN2 5BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Katy Bradley</last_name>
      <phone>01273 696955</phone>
      <phone_ext>63911</phone_ext>
      <email>katy.bradley2@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Katy Bradley</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospitals Bristol NHS Foundation Trust</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8ED</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthew Beasley, Dr</last_name>
      <email>Matthew.Beasley@UHBristol.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cambridge University Hospitals NHS Foundation Trust</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Irune Ekpemi, Miss</last_name>
      <email>ekpemi.irune@addenbrookes.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kent and Canterbury Hospital</name>
      <address>
        <city>Canterbury</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Robert Hone</last_name>
      <email>rhone@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>HPV Research Group Section of Pathology Cardiff University ,School of Medicine</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Ned Powell, Dr</last_name>
      <email>PowellNG@cardiff.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cardiff and Vale University Local Health Board</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sandeep Berry, Mr</last_name>
      <email>Sandeep.Berry@wales.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre for Trials Research</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4YS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Chris Hurt</last_name>
      <phone>02920687471</phone>
      <email>HurtCN@cardiff.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Velindre NHS Trust</name>
      <address>
        <city>Cardiff</city>
        <zip>CF142TL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mererid Evans, Professor</last_name>
      <email>Mererid.Evans@wales.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Castle Hill Hospital</name>
      <address>
        <city>Cottingham</city>
        <zip>HU16 5JQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lorcan O'Toole, Dr</last_name>
      <email>lorcan.otoole@hey.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Derby Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Derby</city>
        <zip>DE22 3DT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sean Mortimore, Mr</last_name>
      <email>sean.mortimore@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Western General Hospital</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH4 2XU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Iain Nixon, Mr</last_name>
      <email>iain.nixon@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Devon University Health Care NHS Foundation Trust</name>
      <address>
        <city>Exeter</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joel Smith</last_name>
      <email>joel.smith2@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Surrey County Hospital</name>
      <address>
        <city>Guildford</city>
        <zip>GU2 7XX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stephen Derbyshire, Mr</last_name>
      <email>stephen.derbyshire2@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>St James University Hospital</name>
      <address>
        <city>Leeds</city>
        <zip>LS9 7TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kate Cardale, Dr</last_name>
      <email>kate.cardale@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Liverpool Head and Neck Centre</name>
      <address>
        <city>Liverpool</city>
        <zip>L3 9TA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Terry Jones, Professor</last_name>
      <email>T.M.Jones@liverpool.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Liverpool</name>
      <address>
        <city>Liverpool</city>
        <zip>L69 3GB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Joanne Patterson, Prof</last_name>
      <email>Joanne.Patterson@liverpool.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cwm Taf Bro Morganwg</name>
      <address>
        <city>Llantrisant</city>
        <zip>CF72 8XR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Richard Webster, Dr</last_name>
      <email>Richard.Webster@wales.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University College London Hospitals NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW1 2BU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jonathan Hughes, Mr</last_name>
      <email>jonathan.hughes1@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Guys and St Thomas's NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SE1 9RT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Asit Arora, Mr</last_name>
      <email>Asit.Arora@gstt.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>St Georges University Hospital</name>
      <address>
        <city>London</city>
        <zip>SW17 0QT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Enyinnaya Ofo</last_name>
      <phone>0208 725 2052</phone>
      <email>enyinnaya.ofo@stgeorges.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Imperial College Healthcare NHS Trust</name>
      <address>
        <city>London</city>
        <zip>SW7 2AZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zaid Awad, Mr</last_name>
      <email>zawad@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Central Manchester University Hospital NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jarrod Homer, Professor</last_name>
      <email>jarrod.j.homer@manchester.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Christie NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M20 4BX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Thomson, Dr</last_name>
      <email>david.thomson@christie.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Pennine Acute Hospital Trust</name>
      <address>
        <city>Manchester</city>
        <zip>OL1 2JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kapil Java, Mr</last_name>
      <email>kapil.java@mft.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>The James Cook University Hospital</name>
      <address>
        <city>Middlesbrough</city>
        <zip>TS4 3BW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shane Lester, Mr</last_name>
      <email>shanelester@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Victoria Infirmary</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <zip>NE1 4LP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Max Robinson, Dr</last_name>
      <email>max.robinson@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Newcastle upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <zip>NE7 7DN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>James O'Hara, Mr</last_name>
      <email>James.Ohara@nuth.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Aneurin Bevan University Health Board</name>
      <address>
        <city>Newport</city>
        <zip>NP18 3XQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carl Passant, Mr</last_name>
      <email>Carl.Passant@wales.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Nottingham City Hospital</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Neeraj Sethi</last_name>
      <email>Neeraj.Sethi@nuh.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Oxford University Hospitals NHS Foundation Trust</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 7LD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stuart Winter, Mr</last_name>
      <email>stuart.winter@ouh.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Plymouth</name>
      <address>
        <city>Plymouth</city>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Richard Williams, Mr</last_name>
      <email>richard.williams8@nhs.net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Queen Alexandra Hospital</name>
      <address>
        <city>Portsmouth</city>
        <zip>PO6 3LY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Costa Repanos, Mr</last_name>
      <email>costa.repanos@porthosp.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Preston Hospital</name>
      <address>
        <city>Preston</city>
        <zip>PR2 9HT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sharan Jayaram</last_name>
      <phone>01772522074</phone>
      <email>Sharan.ChakkyathJayaram@LTHTR.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Berkshire Hospital</name>
      <address>
        <city>Reading</city>
        <zip>RG1 5AN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nicola Dallas, Dr</last_name>
      <email>Nicola.Dallas@royalberkshire.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Satish Harinarayanan, Dr</last_name>
      <email>sathish.harinarayanan@uhs.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>City Hospitals Sunderland NHS Foundation Trust</name>
      <address>
        <city>Sunderland</city>
        <zip>SR4 7TP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helen Cocks, Dr</last_name>
      <email>helen.cocks@chsft.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Swansea Bay University Local Health Board</name>
      <address>
        <city>Swansea</city>
        <zip>SA2 8QA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Conor Marnane, Mr</last_name>
      <email>conor.marnane@wales.nhs.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>France</country>
    <country>Germany</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Belgium</country>
  </removed_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>July 19, 2023</last_update_submitted>
  <last_update_submitted_qc>July 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Velindre NHS Trust</investigator_affiliation>
    <investigator_full_name>Lisette Nixon</investigator_full_name>
    <investigator_title>Trial Manager</investigator_title>
  </responsible_party>
  <keyword>Human papillomavirus HPV positive oropharyngeal cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Oropharyngeal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</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/NCT02215265
org study id: 2014/VCC/0014
nct id: NCT02215265
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The main objectives of the PATHOS study are:

      To assess whether swallowing function can be improved following transoral resection of
      HPV-positive OPSCC, by reducing the intensity of adjuvant treatment protocols. The aim is to
      personalise treatment, based on disease biology (HPV status and pathology findings), to
      optimise patient outcomes.

      To demonstrate the non-inferiority of reducing the intensity of adjuvant treatment protocols
      in terms of overall survival in the reduced intensity treatment arms.
PATHOS is a multicentre, open-label, parallel-group Phase II/III randomised controlled trial
      (RCT). The phase II target of 242 patients was reached in December 2018 and there was a
      seamless transition into Phase III. The protocol was amended in September 2018 to incorporate
      the changes associated with the phase III transition. The amendment included changes to the
      outcome measures and sample size calculations.

      Approximately 1100 patients will be recruited to the phase III study. Patients eligible for
      the study must have biopsy proven oropharyngeal squamous cell carcinoma (OPSCC) clinically
      staged T1T3 N0N2b. Their primary tumour, as judged by the local MDT, must be considered
      resectable via a transoral approach. Having secured informed consent, patients with centrally
      or locally determined HPV positive tumours will undergo baseline assessment of swallowing
      function (includes; MDADI score, videofluoroscopy, PSSH& N, 100 mL water swallow test) and
      complete QOL questions (EORTC QLQC30 and EORTC QLQH&N35) prior to surgery.

      Transoral Laser Microsurgery, Transoral Robotic Surgery & Endoscopically assisted Transoral
      Surgery are all accepted transoral techniques for the study. A lateral oropharyngectomy
      performed with monopolar cautery (The Huet Procedure) can also be used.

      Following surgery and histopathological assessment of the primary tumour and neck dissection
      surgical specimens, participants will be allocated into study groups based on the presence or
      absence of pathological risk factors for recurrence as follows:

      Group A: Participants with tumours which exhibit no adverse histological features.
      Participants in this group will not receive any adjuvant treatment as per standard of care.

      Group B: Participants with T3 tumours (or T1-T2 tumours with additional risk factors), TNM
      7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b
      (metastasis in multiple ipsilateral nodes <61 mm diameter) disease, tumours with evidence of
      perineural and/or vascular invasion, and/or a histologically normal tissue margin around the
      primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. Patients
      in this group will be randomised to PORT 60Gy in 30# over 6 weeks (Control Arm B1) or PORT
      50Gy in 25# over 5 weeks (Test Arm B2).

      Group C: Participants with tumours of any T or any N stage, which exhibit the following
      high-risk pathological features will be included: A histologically normal tissue margin
      around the primary tumour of <1mm and, in the case of TLM, marginal biopsies free of tumour
      and /or extracapsular spread (ECS) of nodal disease. Participants in this group will be
      randomised to POCRT 60Gy in 30# over 6 weeks with concurrent Cisplatin (Control Arm C1) or
      PORT 60Gy in 30# over 6 weeks without chemotherapy (Test Arm C2).

      Participants in groups B and C will be stratified before randomisation by T stage, N stage,
      smoking history and treating centre.

      The same assessments as at baseline will be completed post-operatively prior to treatment and
      then at four weeks and 6, 12 and 24 months post-treatment. The exception is videofluoroscopy
      which will be repeated at post-surgery and 12 months only. Videofluroscopies are only
      performed at UK sites.

      Acute and late toxicity will be recorded weekly during treatment and again at 4 weeks and 6,
      12 and 24 months post-treatment.

      All study assessments, complications relating to surgery and adjuvant treatment, in
      particular complications which necessitate a delay to the start of adjuvant treatment, will
      all be recorded on the Case Report Form (CRF).

      International sites have been initiated on Electronic Data Capture (EDC) and local UK sites
      have transitioned to EDC for participants enrolled after implementation. Data entry needs to
      be completed within four weeks of the study visit. In accordance with the principles of GCP,
      the PI is responsible for ensuring accuracy, completeness, legibility and timeliness of the
      data reported to the CTR in the CRFs. The CRF will be checked for missing, illegible or
      unusual values (range checks) and consistency over time.

      If missing or questionable data are identified, a data query will be raised on a data
      clarification form and sent to the site for resolution. All answered data queries and
      corrections should be signed off and dated by a delegated member of staff at the relevant
      participating site.

      The CTR will send reminders for any overdue data. It is the site's responsibility to submit
      complete and accurate data in a timely manner.

      Quality assurance: The clinical trial risk assessment has been used to determine the
      intensity and focus of central and on-site monitoring activity in the PATHOS trial.
      Monitoring levels will be employed and are fully documented in the trial monitoring plan.
      Investigators should agree to allow trial-related monitoring, including audits and regulatory
      inspections, by providing direct access to source data/documents as required. Patient consent
      for this will be obtained.

      Registration: All sites have transitioned to an electronic database and the registration and
      randomisation process is completed online. Participants will be randomised using minimisation
      with a random element. This will ensure balanced treatment allocation by clinically important
      stratification factors. Randomisation will have an allocation ratio of 1:1.

      Statistical analyses:

      Primary outcome measure

      MDADI/Overall survival co-primary endpoint

      Secondary outcome measures

        -  Swallowing panel including qualitative and quantitative swallowing assessments (100ml
           Water Swallow Test, Videofluoroscopy, Performance Status Scale-Head & Neck)

        -  QOL (using validated EORTC QLQ C30 and HN35 questionnaires, Appendix 6)

        -  Acute and late toxicity using CTACE version 4.03

        -  Disease-Free Survival*

        -  Locoregional control*

        -  Distant Metastases* *Determined by clinical follow-up as per standard guidelines (no
           trial-specific imaging required)

      The co-primary endpoint of the Phase III will be MDADI and overall survival (time to event).

      We will use linear regression to estimate the treatment arm effect on MDADI at 12 months and
      will include the randomisation stratification variables and baseline MDADI in the model. Both
      OS and MDADI endpoints will be used to define study success so no adjustment for multiplicity
      is planned. A detailed statistical analysis plan will be developed before the analyses are
      conducted.

      The data will be reviewed (approximately six-monthly) by an Independent Data Monitoring
      Committee (IDMC), consisting of at least two Clinicians (not entering patients into the
      trial) and an independent Statistician. The IDMC will be asked to recommend whether the
      accumulated data from the trial, together with results from other relevant trials, justifies
      continuing recruitment of further patients. A decision to discontinue recruitment, in all
      patients or selected subgroups, will be made only if the result is likely to convince a broad
      range of Clinicians including PIs in the trial and the general clinical community. If a
      decision is made to continue, the IDMC will advise on the frequency of future reviews of the
      data based on accrual and event rates.

      Sub-group statistical analyses:

      For swallowing endpoints, subgroup analysis by T stage and tumour subsite (tonsil, soft
      palate, tongue base) and surgery technique will be carried out, as the most likely relevant
      clinical co-variables affecting swallowing function.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: MDADI/Overall survival co-primary endpoint
time frame: At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.
measure: Swallowing panel including qualitative and quantitative swallowing assessments
time frame: Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.
description: Water swallow test
measure: QOL (using validated EORTC QLQ C30 and HN35 questionnaires)
time frame: Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.
description: Quality of Life (QOL) questions.
measure: Acute and late toxicity using CTACE version 4.03
time frame: Weekly during RT and at end of treatment; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks), 6 months (+/- 4 weeks), 12 months (+/- 4 weeks), and 24 months (+/- 8 weeks) post treatment.
description: Toxicity assessment
measure: Disease Free Survival
time frame: 6 months intervals
description: Determined by clinical follow up as per standard guidelines
measure: Locoregional control
time frame: 6 months intervals
description: Determined by clinical follow up as per standard guidelines
measure: Distant Metastases
time frame: 6 months intervals
description: Determined by clinical follow up as per standard guidelines
arm group label: A: No adjuvant treatment
arm group type: No Intervention
description: Group A Patients with tumours which exhibit no adverse histological features. Patients in this group will not receive any adjuvant treatment as per standard of care.
arm group label: B1: Postoperative radiotherapy 60 Gray
arm group type: Active Comparator
description: Arm B1: postoperative radiotherapy (PORT) at a dose of 60 Gray (Gy) in 30 fractions over 6 weeks.
Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes <61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.
arm group label: B2: Postoperative radiotherapy 50 Gray
arm group type: Experimental
description: Arm B2: Postoperative radiotherapy (PORT) at a dose 50 Gray in 25 fractions over 5 weeks.
Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes <61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.
arm group label: C1: Postoperative radiotherapy 60 Gray with Cisplatin
arm group type: Active Comparator
description: Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice.
Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of <1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease
arm group label: C2: Postoperative radiotherapy 60 Gray without chemotherapy
arm group type: Experimental
description: Arm C2: Postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks without chemotherapy (Test Arm C2).
Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of <1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease
intervention type: Drug
intervention name: Cisplatin
description: Chemotherapy
arm group label: C1: Postoperative radiotherapy 60 Gray with Cisplatin
intervention type: Radiation
intervention name: Postoperative radiotherapy
description: Postoperative radiotherapy (PORT)
arm group label: B1: Postoperative radiotherapy 60 Gray
arm group label: B2: Postoperative radiotherapy 50 Gray
arm group label: C1: Postoperative radiotherapy 60 Gray with Cisplatin
arm group label: C2: Postoperative radiotherapy 60 Gray without chemotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mererid Evans, MBBch, PhD
role: Principal Investigator
affiliation: Velindre NHS Trust
last name: Terrence Jones, MBBS,MD
role: Principal Investigator
affiliation: Aintree University Hospital
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country: Australia
country: France
country: Germany
country: United Kingdom
country: United States
country: Belgium
responsible party type: Sponsor-Investigator
investigator affiliation: Velindre NHS Trust
investigator full name: Lisette Nixon
investigator title: Trial Manager
mesh term: Oropharyngeal Neoplasms
mesh term: Cisplatin