Echinaforce Study to Investigate Explorative Pharmacology and Effectiveness to Prevent From Enveloped Virus Infections
Condition: Respiratory Tract Infections; Common Cold
MeSH terms: Infections; Communicable Diseases; Virus Diseases; Respiratory Tract Infections; Common Cold
Study type: Interventional
Phase: Phase 4

Summary: 
      It is a single-center, randomized, open-label, phase IV study for the explorative
      investigation of the pharmacological mode-of-action of Echinaforce® extract in the form of
      Echinaforce® Chewable tablets"- Further, it is aimed to evaluate the effectiveness of the
      study product for the prevention and treatment of respiratory tract infections in generally
      healthy adults following a real-life setting. The study covers 2x2 + 1 month of prevention in
      120 randomized participants following a tight sampling set-up for sensitive detection of
      viral infections by RT-qPCR analysis of nasal swabs and seroconversion of SARS-CoV2 IgG/IgM
      in serum samples.
    

Detailed description: 
      It is a single-center, randomized, open-label, phase IV study for the explorative
      investigation of the pharmacological mode-of-action of Echinaforce® extract in the form of
      Echinaforce® Chewable tablets"- Further, it is aimed to evaluate the effectiveness of the
      study product for the prevention and treatment of respiratory tract infections in generally
      healthy adults following a real-life setting. The study covers 2x2 + 1 month of prevention in
      120 randomized participants following a tight sampling set-up for sensitive detection of
      viral infections by RT-qPCR analysis of nasal swabs and seroconversion of SARS-CoV2 IgG/IgM
      in serum samples.

      Study flyers are presented in waiting rooms at GPs/hospitals locally and study information is
      forwarded via the study centre network to attract interest of potential participants.
      Altogether, 140 participants shall be recruited (screened) by the study. Interested persons
      shall be invited to the study centre for first informative visit 1 (V1). Participants
      encountering acute symptoms during screening and/or run-in phase can be included as well. The
      number of recurrences that can be treated and documented per participant during the time of
      observation in this study is in principal unlimited. Participants are equipped with study
      product and study diaries sufficient to encounter a max of 3 individual respiratory tract
      infections "RTI".

      The commercially available study product "Echinaforce Chewable "EC" tablets shall be compared
      to no treatment in study participants that were randomized equally to the two study groups:
      1) "Treatment group" and 2) "no-treatment group". Participants assigned to the "treatment
      group" are instructed to perform 2 consecutive prevention periods taking 3x2 EC tablets daily
      for 2x2 months followed by a voluntary, 1 month follow up prevention in frame of this study.
      After each 2 month prevention phase, participant interrupted prevention for 1 week before
      starting with a new phase. Intake of regular preventive supplements is recorded as per eCRF
      entries (V1-V7) and intake of co-medication to treat acute RTI symptoms as per study diary
      entries. Participants should contact the study coordinator as soon as possible upon first
      signs of acute cold-/flu like symptoms. The study coordinator confirms the symptoms and
      instructs participants to start taking 5x2 instead of 3x2 EC tablets daily immediately.

      Quality assurance:

      Informed Consent Forms, individual e-CRFs accounts and paper study diaries, investigator
      records, medical test results, and study product must be accessible at all times to study
      monitors commissioned by the CRO (CONVEX CRO Ltd.) on behalf of and mandated by the sponsor.

      The monitor will review the data of the participants and the declared and signed informed
      consent forms as well as all other study relevant notifications according to procedures
      defined in the monitoring manual of this study. The monitor will also have access to the
      source data and undertakes to maintain confidentiality at any time with special regard to
      reviewed personal, de-anonymized participant data. The monitor assesses protocol deviations
      of any kind and reports to responsible A. Vogel Clinical trial project manager (CTPM).

      In this study, generally, healthy volunteers are to be included and the pharmacological
      mode-of-action and effectiveness of the test medication, which is Echinaforce Chewable
      tablets "EC", to prevent from RTIs during phases of prevention assessed with regard to
      self-diagnosed, usually self-limiting common colds/flu-like infections including infections
      with SARS-CoV2. Additionally, asymptomatic courses of RTIs are assessed to give a more
      comprehensive picture of preventive effectiveness. For most of the participants no medical
      history at the trial center exists and due to the study design, a complete cross-section
      comparison of e-CRF and participant files waived at the family doctor. With regard to the
      exclusion criteria (e.g. existence of serious diseases such as autoimmune diseases or
      degenerative diseases, it is assumed that the participants are aware of them and can name
      correctly during screening at visit 1). Despite this, no additional comparison between the
      participant's medical history stored at his doctors place and study centre filed e-CRF
      accounts/printouts of e-CRF will take place (and vice versa). This also includes relevant
      AEs/ADRs during the study as well as newly-diagnosed exclusion criteria (accompanying
      illnesses) during the study period.

      The study will be monitored by the executing CRO's representative as specified in the
      monitoring manual. The monitor will perform an initiation visit before the first participant
      is screened, have regular contacts with the study site, including routine visits conducted
      to:

        -  Provide information and support to the Investigator(s).

        -  Assure compliance with the study protocol.

        -  Verify that the research facilities, including laboratories and equipment, are adequate
           to safely and properly conduct the study.

        -  Verify that the investigational product is stored properly and under the proper
           conditions, is in sufficient supply, and that receipt, use, and return of
           investigational product are controlled and documented adequately.

        -  Verify that written informed consent was obtained before any protocol-specific screening
           procedures are performed solely for the purpose of determining eligibility for the
           clinical study and/or prior to the provision of study product.

        -  Review the CRFs and source documents to ensure that reported study data are accurate,
           complete, and verifiable transferred from source documents.

        -  Ensure that adequate records of clinical trial supplies are maintained.

        -  Verify that the Investigator and study site personnel are adequately qualified
           throughout the study.

        -  Verify that the safety information and amendments are submitted to the relevant
           authorities and to sponsors.

      All checks that the data given in the eCRF complies with the source document will be carried
      out in accordance with the study specific monitoring manual.

      The monitor will be available between visits if the Investigator(s) or other staff at the
      centre needs information and advice about the study conduct.

      After the data base lock and approval from the Sponsor a close-out visit will be performed in
      order to close the study at the site.

      The corresponding SOPs of the executing CRO as well as a study specific monitoring manual set
      the guidelines applicable for carrying out the monitoring.

      The sponsor or a delegate on his behalf, local authorities (Bulgarian drugs administration,
      BDA) or the responsible ethics committee may inspect this study to reassure quality. The
      inspectors must be granted access to all medical documents, study documents, correspondence
      and declarations of consent of participants, which are deemed relevant. All parties involved
      are to uphold the confidentiality regarding all de-anonymized participant data.

      Source data/SDV:

      Source data are the original records of all variables collected for the clinical
      investigation. They include:

        -  Signed informed consent

        -  Original printouts of laboratory reports.

        -  Progress notes, Follow-up notes.

        -  All filled-out S/AE forms.

        -  Filled study diaries.

        -  Descriptions of interventions done to the participants in the study.

        -  Original Data Records kept at the pharmacy, laboratory or any other 3rd party vendor
           involved in this study

        -  Evaluation checklists

        -  Study product related records (dispensation, return, replacement, compliance, etc.).

        -  Documentation of sample storage, processing and shipment. The Investigator must allow
           the monitor access to all documents in the participant's study file to confirm their
           consistency with the eCRF entries. All study data will be handled confidentially. No
           information about participant identity on these documents will be allowed to leave the
           study site.

      It is the responsibility of the Investigator to maintain a comprehensive and centralized
      filing system of all relevant documentation.

      • Investigators will be instructed to retain all study records required by the Sponsor and
      regulatory authorities in a secure and safe facility with limited access for one of the
      following time periods based on notification from the Sponsor:

        -  For a period of at least 2 years from the last marketing approval worldwide or for at
           least 25 years, whichever is the greater

        -  Or a period of at least two years after discontinuation of clinical development of the
           investigational product as confirmed by the Sponsor

        -  For a longer period if required by local regulations The Investigator will be instructed
           to consult with the Sponsor before disposal of any study records and to provide written
           notification to the Sponsor of any change in the location, disposition, or custody of
           the study files.

      The sponsor or its representative may visit the study facilities at any time in order to
      maintain current and personal knowledge of the study through review of the records,
      comparison with source documents, observation and discussion of the conduct and progress of
      the study. The investigator will permit trial-related monitoring, audits, EC review and
      regulatory inspections, providing direct access to source data and study documents

      Data coding:

      The full details of procedures for data handling will be documented in the Data Management
      Plan (DMP).

      AEs and medical history will be coded using the Medical Dictionary for Regulatory Activities
      (MedDRA, version 17.1GE). Concomitant medications will be coded using the World Health
      Organization (WHO) Drug Dictionary.

      Unique numbers will identify the participant and the biological material obtained from the
      participant. Appropriate measures such as encryption or deletion will be enforced to protect
      the identity of human participants in all presentations and publications as required by
      local/regional/national requirements.

      Sample size assessment:

      A sample size calculation has been conducted on the main study parameter, which is the
      incidence of RTIs during the time of observation. A difference between both study groups of
      at least 20.5% will be recognized as significant clinically relevant (two-group Chi-square
      test with a 0.05 two sided significance level) with a power of 80% with an incidence rate of
      10% seen under active treatment and at least 60 participants included evaluable per study
      group (chi²-test, nquery advisor 7.0). In addition, for the pharmacological parameters
      assessed in the study it is estimated that 80% power is achieved with cross-sectional and
      longitudinal sampling to detect CpG DNA methylation differences of 20%.Amendments to the
      protocol

      SAP:

      For planning the statistical analysis and reporting in this clinical study the ICH guidelines
      for "biostatistical methodology in clinical trials" are taken into account. The details of
      the statistical methodology (including the handling of missing and incorrect data) are
      presented in detail in a separate statistical analysis plan (SAP).

      Descriptive parameters are determined for assessed clinical variables. In addition to the
      absolute and relative frequencies of the score values, the arithmetic mean, median, first and
      third quartile (Q1 or Q3), standard deviation, minimum and maximum of the current value and
      the changes in comparison between "treatment group" and "no treatment group", are calculated.
      All assessed target variables are exploratory evaluated using suitable test methods
      (Mantel-Haenszel test for ordinal variables, Fisher's exact/Chi-Square test for dichotomous
      or categorical variables and t-test or analysis of variance for quantitative target
      variables) in the "treatment group" compared to "no treatment group".

      The safety assessment is based on the recording of adverse events (AEs), adverse drug
      reactions (ADRs) as per entries in the e-CRF and ultimately the subjective assessment of
      tolerability and acceptance by the study investigators and participants.
    

Intervention name(s): Echinaforce Chewable tablets
Intervention type(s): Drug
Intervention description(s): Preventive treatment: 3X2 EC tablets daily during 2 + 2 months of prevention after run-in of 1 week and intermittent treatment break of 1 week without treatment + 1 month of voluntary follow-up prevention.
Acute treatment: 5 X 2 EC tablets daily for max. 10 days per individual vRTI or until symptom resolution.
Other intervention name(s): Echinacea; Echinaforce; Echinaforce Junior tablets
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Monocentric, 2-armed, randomized, open-label, no-treatment-controlled,
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: SARS-CoV2; Prevention of Respiratory tract infections; Prospective; Controlled; Randomized; Open