Study of Imupret Application in the Technology of Delayed Prescription of Antibiotics in Patients With Acute Tonsillitis
Condition: Acute Tonsillitis
MeSH terms: Tonsillitis; Peritonsillar Abscess
Study type: Interventional

Summary: 
      The problem of acute tonsillitis (AT) is one of the most urgent in modern clinical medicine.
      The prevalence of pathology ranges from 2 to 15% of the total population.

      AT (ICD J03.0-J03.9) in most cases is due to viral infections. Bacterial acute tonsillitis
      occurs in immunocompetent children in 20-30% of cases.

      To determine the indications for antibacterial therapy, the Mclsaac scale is a commonly used
      tool for decision. This scale is used to classify patients according to their symptoms and to
      determine the patients for whom antibiotic therapy is not indicated.

      Thus, in most cases of acute tonsillitis (even if there are 4-5 points according to the
      scale), it has to be taken into account that there is a low probability of the presence of
      GABS. Therefore, there are no unconditional indications for the prescription of antibiotics.
      Unjustified antibiotic therapy of AT plays a significant role in the formation of antibiotic
      resistance.

      To prevent unjustified prescription of antibiotics, a therapeutic concept of delayed
      administration is proposed. A patient with AT is prescribed treatment with antibiotics in a
      delayed manner. In the absence of a positive effect within 36-48 hours from the beginning of
      treatment with Imupret, the antibacterial therapy is started. The advantage of deferred
      antibiotic prescription is, that a higher number of patients and doctors, awaiting antibiotic
      therapy, may be more agreeable with this way of treatment than with a complete rejection of
      the antibiotic's prescription. So delayed use of antibiotics is an important treatment
      strategy to reduce the number of unreasonable prescriptions of antibiotics.

      Considering this fact, it becomes necessary to use drugs with a complex effect and
      evidence-based efficacy base for acute tonsillitis. At the moment, there is an insignificant
      evidence base for the application of the phytoneering drug Imupret in acute tonsillitis. The
      spectrum of its pharmacological properties includes antiviral, antibacterial,
      anti-inflammatory, and immunomodulating effects. The combination of these properties makes it
      possible to influence practically all parts of acute tonsillitis. The already existing
      studies were not conducted under GCP conditions. Confirmation of the high effectiveness of
      Imupret in the treatment of acute tonsillitis would serve as a rationale for optimizing the
      treatment regimen of this nosology and recommendations for the inclusion of the drug in
      national guidelines.
    

Detailed description: 
      Study of Therapeutic Efficacy, Safety, and Tolerability of Imupret application in the
      therapeutic concept of delayed prescription of antibiotics in patients with severe acute
      tonsillitis in children, aged 6-12.

      Acute tonsillitis in most cases is due to viral infections. Bacterial tonsillitis occurs in
      immunocompetent children in 20-30% of cases, adults - in 5-15%, and the most frequent cause
      of it is β-hemolytic streptococcus group A (GABS).

      Acute tonsillitis is defined as the sudden appearance of the following symptoms: sore throat,
      hyperemia, edema of the tonsils, increase in swollen lymph nodes, and non-specific additional
      symptoms like fever, weakness, and joint pain. There are no pathognomonic symptoms of
      bacterial tonsillitis. To assess the patient's condition and to determine the indications for
      antibacterial therapy, the Mclsaac scale is a commonly used tool for decision. This scale is
      used to classify patients according to their symptoms and to determine the patients for whom
      antibiotic therapy is not indicated.

      McIsaac scale (sum of scores) The probability of the identification of β-hemolytic
      streptococcus in a smear from pharynx -1 or 0 - 1% 1-10% 2 ~17% 3 ~35% 4 or 5 ~50% Thus, in
      most cases of acute tonsillitis (even if there are 4-5 points according to the scale), it
      must be considered that there is a low probability of the presence of GABS. Therefore, there
      are no unconditional indications for the prescription of antibiotics.

      Unjustified antibiotic therapy of acute tonsillitis based on "sore throat" or "exudate
      (plaque) tonsils" only does not affect pain and lads the formation of antibiotic resistance.
      In order to avoid the irrational use of antibiotics, one should distinguish the desire of the
      patient or his parents to get rid of the pain, from the rational assessment of the doctor for
      all pros and cons about an antibacterial therapy.

      To prevent the unjustified prescription of antibiotics, a therapeutic concept of delayed
      administration is proposed. A patient with acute tonsillitis is prescribed treatment with
      antibiotics in a delayed manner. In the absence of positive dynamics within 36-48 hours from
      the beginning of treatment with Imupret the antibacterial therapy is started. The advantage
      of deferred antibiotic prescription is, that a higher number of patients and doctors,
      awaiting antibiotic therapy, may be more agreeable with this way of treatment than with a
      complete rejection of the antibiotic's prescription. Therefore, the delayed use of
      antibiotics is an important treatment strategy to reduce the number of unreasonable
      prescriptions of antibiotics.

      Considering this fact, it becomes necessary to use drugs with a complex effect on the main
      processes of pathogenesis and have an evidence-based efficacy for acute tonsillitis. Now,
      there is an insignificant evidence base for the application of the herbal drug Imupret in
      acute tonsillitis. The spectrum of its pharmacological properties includes antiviral,
      antibacterial, anti-inflammatory, and immunomodulating effects. Additionally, a good safety
      profile allows to consider Imupret as an adequate basic therapy for the treatment of acute
      tonsillitis in the therapeutic concept of delayed prescription of antibiotics. The already
      existing studies were not conducted under GCP conditions. Confirmation of the high
      effectiveness of Imupret in the treatment of acute tonsillitis would serve as a rationale for
      optimizing the treatment regimen of this nosology.

      Proposed trial design: open-label, exploratory, comparative, multicenter, randomized,
      prospective, parallel-group study.

      Treatment:

      The comparison group (n = 100): soft diet; elimination of factors that irritate the mucous
      membrane of the pharynx (thermal, chemical); local NSAIDs - benzydamine hydrochloride (Tantum
      Verde); acetaminophen as antipyretic if necessary.

      The main group (n=100): soft diet; elimination of factors that irritate the mucous membrane
      of the pharynx (thermal, chemical); local NSAIDs - benzydamine hydrochloride; Imupret oral
      drops in the age-related dosage of 6 times per day for 6 days with the subsequent transition
      to the regime of 15 drops / 3 times in a day according to the patient's condition;
      acetaminophen as antipyretic, if necessary.

      Schedule of visits. During the study, 3 planned visits: Visit 1 (The 1-st day): screening,
      randomization, and treatment; evaluation by Mc Isaac Score scale; LTM Scale (Local
      Tonsillitis Manifestation Scale): (5 symptoms: Sore throat at swallowing (0 - absent, 1 -
      mild, 2 - moderate, 3 - severe / pronounced); Sore throat at rest; Throat irritation at rest;
      Palatine tonsils hyperemia; Palatine tonsils edema); Patients self-assessment (VAS; 0-10).
      Visit 2 (3rd±1 day): intermediate evaluation of the effectiveness of treatment -
      clarification of the patient's condition, the need to prescribe an antibiotic; evaluation by
      LTM Scale, patients' self-assessment (VAS; 0-10). Visit 3: intermediate evaluation of the
      effectiveness of treatment (day 5-day ±1) via telephone (or visit if necessary); patients'
      self-assessment (VAS; 0-10). Visit 4: final (10th day ±1 day). Evaluation by LTM Scale
      (0-15), patients' self-assessment (VAS; 0-10). 5 Follow up; day 28: evaluation of the
      long-term effects of treatment.

      An unscheduled visit can be made if the patient's condition worsens (according to the patient
      and/or the researcher, including if the symptoms of the disease persist or worsen, including
      but not limited to an increase in the temperature in the armpit above 38.0 ° C at the 3rd
      and/or subsequent days of treatment).

      The total duration of the treatment: 10 days. The total duration of the study for one patient
      is no longer than 38 days.

      Objectives of the study: To investigate the influence of Imupret prescriptions in the
      therapeutic concept of delayed prescription of antibiotics to:

        -  need for antibiotics;

        -  regression of the tonsillitis symptoms;

        -  duration of antipyretics administration.

      Proposed parameters of interest:

        -  The severity of symptoms of tonsillitis, on the Visit 2 compared to the Visit 1. -
           Indications for prescribing antibiotics (no positive dynamics or worsening of the
           patient's condition).

        -  The decrease in the total score (the sum of scores for each symptom) according to the
           LTM Scale (0-15), - Patients self-assessment (VAS; 0-10) scale of local manifestations
           of tonsillitis at the V 2, V 3 and V 4 in comparison with the 1-st visit. - Decrease in
           temperature in the armpit at the V 2 and V 3 compared to the Visit 1. - Self-evaluation
           of the patient's quality of life. - Duration of NSAID administration

      Statistical endpoints:

      The main criterion (main variable):

      - the decrease in the severity of each symptom (complaint) that is part of the scale of
      tonsillitis manifestations, up to 1 point or less. This variable is dichotomous, with the
      categories "treatment effective" and "treatment not effective": Treatment is effective -
      reducing the severity of each symptom (complaint) that is part of the Local Tonsillitis
      Manifestation Scale (0-15),of tonsillitis manifestations, up to 1 point or less in the
      evaluation stages. Absence of indications for prescribing antibacterial therapy Treatment is
      not effective - the condition is given for the category "therapy is effective" is not met.

      Secondary variables:

        -  The decrease in the severity of the symptoms of the underlying disease, at the V 2, V 3
           and V 4 visits compared to the 1-st visit.

        -  The decrease in the total score (the sum of scores for each symptom) according to the
           scale of local manifestations of tonsillitis at the V 2, V 3 and V 4 in comparison with
           the 1-st visit.

        -  Decrease in temperature in the armpit at the 2-nd and 3-rd visits compared to the 1-st
           visit.

        -  Patient's self-assessment of the quality of life (every day).

        -  Duration of antipyretics administration. Statistical analysis is performed by a
           statistician and includes descriptions of patients (included, completed and withdrawn),
           adverse events and reactions, analysis of efficacy in each group, comparison of efficacy
           between groups, safety assessment, and tolerability in each group. It is planned to use
           the criteria of Shapiro-Wilk, Mann-Whitney (U).

      Biometry: Patients with acute tonsillitis (N = 200): Age: 6-12 years old. The main group (n =
      100). The control group (n = 100).
    

Intervention name(s): Imupret in addition to local NAID; Local NAID (Benzydamin)
Intervention type(s): Drug; Drug
Intervention description(s): Additional prescription of Imupret oral drops to conventional therapy with local NAID (Benzydamine hydrochloridy), elimination of irritating factors in the diet and acetaminophen (if necessary); (Benzydamine hydrochloridy) and acetaminophen (if necessary), elimination of irritating factors in the diet
Other intervention name(s): BNO 1030 extract from 7 plants (active substance of Imupret); Tantum Verde
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute tonsillitis; antibiotics; phytotherapy