Clinical trial NCT02787863: Clinical and Immunological Efficiency of Bacterial Vaccines at Adult Patients With Bronchopulmonary Pathology
Official title: Pathogenetic Justification and Clinical and Immunological Efficiency of Application Bacterial Vaccines at Adult Patients With Bronchopulmonary Pathology
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease
Asthma
Pneumococcal Infections
Keywords: Pneumococcal vaccines
Lead sponsor: Russian Academy of Medical Sciences
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2016-06-01
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Goal: to to examine the formation of postvaccination immunity and evaluate the therapeutic effect of bacterial vaccines in patients with inflammation diseases of bronchopulmonary system. Objectives of the study: assessment of microbiocenosis mucous membranes of the upper respiratory tract in patients with bronchopulmonary pathology before and after use of bacterial vaccines. Identification of mayor lymphocytes subpopulations in patients in the dynamics of the vaccination process. Study the profile of humoral immune response in patients under different schemes of vaccination. Assessment of the clinic and functional status bronchopulmonary system in the immunized patients.

Detailed description: Methods:

1. Immunoglobulin G (IgG)-antibodies against Streptococcus pneumoniae (S. pneumoniae) - solid-phase enzyme-linked immunoelectrodiffusion essay (ELISA).
2. General levels of Immunoglobulin A (IgA), Immunoglobulin M (IgM), IgG, Immunoglobulin E (IgE) in sera - radial immunodiffusion.
3. Phagocytic activity (granulocytes, monocytes), nitroblue tetrazolium test; T-lymphocytes, T-helpers (cluster of differentiation, CD3+CD4+), cytotoxic T-lymphocytes (СD3+CD8+), B-lymphocytes (CD19+); NK-cells (CD3-CD16+CD56+), NKT-cells (CD3+CD16+CD56+), activated T-cells (human leucocyte antigens, CD3+HLA DR+), CD3-HLA DR+.
4. Microbiological examination of sputum.
5. Determining the clinical effectiveness of vaccination.

   * the number of exacerbations of chronic bronchopulmonary pathology for the year prior to vaccination and during the first and fourth years after vaccination;
   * the number of courses of antibiotic therapy a year prior to vaccination and during the first and fourth years after immunization;
   * the number of hospitalizations for acute exacerbations of chronic bronchopulmonary disease during the year prior to vaccination and during the first and fourth years after immunization.
6. Method of estimating quality of life associated with health in patients with chronic bronchopulmonary pathology (asthma control questionnaire (ACQ-5), COPD assessment test (CAT)).

Characteristics of variables (arms 1-8).

1. The age of patients (years): mean (standard deviation) \[min; median; max\] for normally distributed variables; median \[Q25; Q75\] - for variables with distribution different from normal.
2. Gender: male/female.
3. Indicators of immune status

   * IgG antibodies to S. pneumoniae
   * IgA, g/l \[0,4-3,5\]
   * IgM, g/l \[0,7-2,8\]
   * IgG, g/l \[8-18\]
   * IgE, IU/ml \[\< 100\]
   * Phagocytic index (granulocyte), % \[82-90\]
   * Phagocytic index (monocytes), % \[75-85\]
   * The participation rate of spontaneous NBT-test (neutrophils), % with intensity of 0.2.e. \[7-14\]
   * The index of activity induced NBT-test (neutrophils), % if intensity \>of 0.36.e. \[\>28\]
   * The percentage of NBT-positive cells in spontaneous test, % \[2-19\]
   * Circulating immune complexes (CEC) cond. units \[0,055-0,11\]
   * CD3+, % \[55-80\]
   * CD3+CD4+, % \[31-49\]
   * CD3+CD8+, % \[12-30\]
   * CD19+, % \[5-19\]
   * CD3-CD16+CD56+, % \[6-20\]
   * CD3+CD16+CD56+, % \[\<10\]
   * CD3-HLA DR+, % \[5-20\]
   * CD3+HLA DR+, % \[\<12\]
   * CD45RO. The reference value = 0,2.
4. Microbiological examination of sputum: frequency of selection of certain microorganisms are presented as absolute number of cases and % in the respective groups.
5. Evaluation of early post-vaccination period

   * The General condition (satisfactory/unsatisfactory)
   * Local reactions: pain (n/%), redness (n/%, cm), consolidation (n/%, cm)
   * General reactions:

     * Temperature 37,0-37,5 (n/%)
     * Temperature of 37.6-38,5 (n/%)
     * A temperature of 38.6 and \> (n/%)
     * Headache (n/%)
     * Malaise, fatigue (n/%)
     * Joint pain (n/%)
     * Muscle pain (n/%)
6. Health related quality of life (HRQoL): CAT-test (for Chronic obstructive pulmonary disease (COPD) patients), ACQ-5 (for asthma patients).

Eligibility criteria: Inclusion Criteria:

* Individuals of both sexes from 18 years with a diagnosis of COPD or Bronchial Asthma;
* The presence of signed and dated informed consent to participate in a clinical study;
* The ability to perform the requirements of the Protocol;
* For women of childbearing age is a negative result of a pregnancy test before vaccination.

Diagnostic criteria for:

- COPD: dyspnea: progressive (worsens over time), increases with exertion, persistent; chronic cough (may appear sporadically and may be unproductive); chronic expectoration; the impact of risk factors in the medical history (Smoking, occupational dust pollutants and chemicals); widespread wheeze on auscultation of the chest and/or distant wheezing in the chest; family history of COPD; spirometric data confirming the presence of fixed bronchial obstruction.

Exclusion Criteria:

* Vaccination against pneumococcal infection in anamnesis;
* Application of preparations of immune globulin or blood transfusion within last three months prior to clinical studies;
* Prolonged use (more than 14 days) immunosuppressants or other immunosuppressive drugs within 6 months prior to the start of the study;
* Any confirmed or suspected immunosuppressive or immunodeficient condition, including Human Immunodeficiency Virus (HIV) infection;
* A history or currently hematologic and other cancers;
* A positive reaction for HIV infection, viral hepatitis B and hepatitis C;
* The presence of respiratory, cardio-vascular insufficiency, impaired liver and kidney function, established during a physical examination at visit number 1;
* Pronounced congenital defects or serious chronic diseases in the acute stage, including any clinically important exacerbation of chronic diseases of the liver, kidney, cardiovascular, nervous system, mental diseases or metabolic disorders, confirmed by the history or objective examination (pulmonary: cystic fibrosis, lung abscess, empyema, active tuberculosis; extra-pulmonary: congestive heart failure, malabsorption, chronic renal and hepatic failure, cirrhosis, malignancy, immunodeficiency, cirrhosis of the liver);
* Severe allergic reactions in anamnesis, autoimmune disease;
* The presence of acute infectious and/or communicable illnesses within 1 month prior to study;
* History of chronic alcohol abuse and/or drug use;
* Exacerbation of chronic diseases;
* Breastfeeding;
* Pregnancy;
* Participation in any other clinical study within the last 3 months.

Primary outcomes:
measure: Number of Patients Without Exacerbations of the Underlying Disease, Antibiotic Use and Hospitalisation.
timeFrame: Baseline (1 year prior to vaccination), 1 year after vaccination, 4 years after vaccination
measure: The Number of Exacerbations of the Underlying Disease, Antibiotic Use and Hospitalisation
timeFrame: Baseline (1 year prior to vaccination), 1 year after vaccination, 4 years after vaccination
Secondary outcomes:
measure: Seeding Frequency S. Pneumoniae From Sputum in Patients With COPD
timeFrame: Baseline, after 1 and 4 years after vaccination
measure: Average CAT (COPD) and ACQ-5 (Asthma) Score
timeFrame: Baseline, after 1 and 4 years after vaccination
measure: Phagocytic Activity in Patients With COPD at Baseline, 1, 2, and 6 Weeks After PCV13 and PPV13 Vaccination
timeFrame: Baseline, 1, 2, 6 weeks after PCV13 and PPV13 vaccination
measure: Immunophenotype of Blood Lymphocytes in Patients With COPD
timeFrame: Baseline, 1, 2, 6 weeks after PCV13 and PPV13 vaccination
measure: IgA, IgM, IgG, IgE, Circulating Immune Complexes (CIC)
timeFrame: Baseline, 1, 2, 6 weeks after PCV13 and PPV13 vaccination in COPD
measure: CD45RO
timeFrame: Baseline, 1 and 4 years after vaccination
measure: Specific IgG Levels in Vaccinated Patients With COPD to S. Pneumoniae Serotypes
timeFrame: Baseline, 1 and 12 months after vaccination
Other outcomes:
Locations:
city: Samara
country: Russian Federation
facility: Samara State Medical Univercity
state: Samara Region
city: Moscow
country: Russian Federation
facility: Institute of Sera and Vaccines RAS
Study officials:
affiliation: Samara State Medical University
name: Andrei D Protasov, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Sera and Vaccines RAS, Moscow
name: Mikhael P Kostinov, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Sera and Vaccines RAS, Moscow
name: Mikhael P Kostinov, Professor
role: STUDY_CHAIR
affiliation: Samara State Medical University
name: Aleksander V Zhestkov, Professor
role: STUDY_CHAIR
References:
citation: Protasov AD. Pneumococcal vaccination in patients with chronic broncho-pulmonary disease (literature review). The Bulletin of Contemporary Clinical Medicine. 6(2): 60-65, 2013.
citation: Protasov AD, Zhestkov AV, Kostinov MP. First results of 13-valent pneumococcal conjugate vaccine treatment in patients with chronic bronchopulmonary diseases: evaluation safety and tolerability. Russian Allergology Journal 4: 18-23, 2013.
citation: Protasov AD.COMPARATIVE EVALUATION OF THE EFFECTIVENESS OF PNEUMOCOCCAL VACCINATION WITH 13-VALENT CONJUGATE AND 23-VALENT POLYSACCHARIDE VACCINE IN PATIENTS WITH COPD. Russian Allergology Journal 4: 12-17, 2014.
citation: Kostinov MP, Protasov AD, Zhestkov AV, Polishuk VB. Promising data with pneumococcal 13-valent conjugate vaccine in adult patients with chronic bronchopulmonary pathology. Pulmonology 4: 57-63, 2014
citation: Protasov AD. Comparative evaluation of the effectiveness of vaccination against pneumococcal infection in patients with bronchial asthma with the use of 13-valent conjugate and 23-valent polysaccharide vaccine. Pulmonology. 5: 52-56, 2014
citation: Kostinov MP, Zhestkov AV, Protasov AD, Kostinova TA, Pakhomov DV, Chebykina AV, Magarshak OO.Comparative analysis of dynamics of indicators of quality of life in patients with chronic obstructive pulmonary disease on the background of vaccination against pneumococcal disease using the 13-valent conjugate and 23-valent polysaccharide vaccine. Pulmonology 25(2): 163-166, 2015
citation: Protasov AD, Kostinov MP, Zhestkov AV, Shteiner ML, Magarshak OO, Kostinova TA, Ryzhov AA, Pakhomov DV, Blagovidov DA, Panina MI. [Choice of optimal vaccination tactics against pneumococcal infection from immunological and clinical standpoints in patients with chronic obstructive pulmonary disease]. Ter Arkh. 2016;88(5):62-69. doi: 10.17116/terarkh201688562-69. Russian.
citation: Protasov AD, Zhestkov AV, Kostinov MP, Shteiner ML, Tezikov YV, Lipatov IS, Yastrebova NE, Kostinova AM, Ryzhov AA, Polishchuk VB. [Analysis of the effectiveness and long-term results of formation of adaptive immunity in the use of various medications and vaccination schemes against pneumococcal infection in patients with chronic obstructive pulmonary disease]. Ter Arkh. 2017;89(12. Vyp. 2):165-174. doi: 10.17116/terarkh20178912165-174. Russian.
citation: Protasov AD, Zhestkov AV, Kostinov MP, Korymasov EA, Shteyner ML, Tezikov YV, Lipatov IS, Reshetnikova VP, Lavrent'yeva NE. Long-term clinical efficacy and a possible mechanism of action of different modes of pneumococcal vaccination in asthma patients. Pulmonology 28(2): 193-199, 2018.