Randomized Double-blind Placebo-controlled Multicenter Clinical Trial of Bacterial Polyvalent Vaccine (BACTEK®), Administered Sublingually in COPD Patients, to Evaluate Efficacy, Safety, and Immunomodulatory Response.
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: Inmunotek S.L.

 
 
 CONFIDENTIAL 
PROTOCOL No.: MV130-SLG-001 
INMUNOTEK, S.L. 
EUDRACT No.: 2012-003253-28 
Madrid, Spain 
Medical Department 
Version: 08.2 
Date: 29/Dec/2017 
TITLE: PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PARALLEL, PLACEBO-CONTROLLED 
CLINICAL TRIAL EVALUATING THE SAFETY, CLINICAL EFFICACY, AND IMMUNOMODULATORY 
RESPONSE OF A POLYVALENT BACTERIAL VACCINE (BACTEK®) ADMINISTERED VIA THE 
SUBLINGUAL MUCOSA IN SUBJECTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE 
(COPD) 
Product:  
BACTEK® 
Indication: 
Chronic Obstructive Pulmonary Disease  
Country:  
Spain  
Route of administration:  
Sublingual mucosa 
Dosage: 
See protocol 
No. of subjects: 
180 
Trial duration: 
7 years (estimated)  
COORDINATING INVESTIGATOR 
MEDICAL DIRECTOR 
Dr. Eduardo Fernández-Cruz. 
Clinical Immunology Service 
Hospital General Universitario Gregorio Marañón  
Dr. Miguel Casanovas 
Inmunotek, S.L. 
 
Version 01: 01/Jun/2012. 
Version 02: this version incorporates clarifications from the Regional Clinical Research Ethics Committee 
(R-CREC) of the Autonomous Community of Madrid. 
Version 03: this version incorporates modifications of relevant Amendment 01. Dated 21/Jun/2013. 
Version 04: this version incorporates modifications of relevant Amendment 02. Dated 12/Feb/2014. 
Version 05: this version incorporates modifications of relevant Amendment 03. Dated 10/Mar/2014. 
Version 06: this version incorporates modifications of relevant Amendment 04. Dated 29/Oct/2014. 
Version 07: this version incorporates modifications of relevant Amendment 05. Dated 26/Oct/2015. 
Version 07.01: this version incorporates changes of the non-substantial modification. Dated 21/Jun/2016. 
Version 08: this version incorporates changes of substantial modification 06. Dated 09/Jan/2017. 
Version 08.1: this version incorporates changes of the non-substantial modification. Dated 21/Jun/2017. 
Version 08.2: this version incorporates changes of the non-substantial modification. Dated 29/Dec/2017. 
OWNERSHIP RIGHTS: INMUNOTEK, S.L. 

Inmunotek S.L. 
Clinical Research 
Protocol No.: MV130-SLG-001 
EudraCT No.: 2012-003253-28 
Version No.:  08.2 
Date: 29/Dec/2017 
 
 
Page 1 of 103 
SIGNATURE SHEET 
Protocol approval 
Sponsor: 
INMUNOTEK S.L 
C/Punto Mobi, 5, 28805 Alcalá de Henares, Madrid, Spain 
Telephone no.: 916 510 010   Fax no.: 916 639 732 
 
Sponsor’s signature 
Signature 
Date 
Dr. Miguel Casanovas 
[Illegible 
signature] 
29/Dec/2017 
Medical Director 
 
 
 
 

Inmunotek S.L. 
Clinical Research 
Protocol No.: MV130-SLG-001 
EudraCT No.: 2012-003253-28 
Version No.:  08.2 
Date: 29/Dec/2017 
 
 
Page 2 of 103 
Dr. Eduardo Fernández-Cruz 
Clinical Immunology Service 
Hospital General Universitario Gregorio Marañón  
Hereby declares: 
That he has evaluated the protocol of clinical trial titled: “PROSPECTIVE, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL, PLACEBO-CONTROLLED CLINICAL TRIAL EVALUATING THE SAFETY, 
CLINICAL EFFICACY, AND IMMUNOMODULATORY RESPONSE OF A POLYVALENT BACTERIAL 
VACCINE (BACTEK®) ADMINISTERED VIA THE SUBLINGUAL MUCOSA IN SUBJECTS WITH CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE (COPD)”. 
Sponsor’s code: MV130-SLG-001 
EudraCT No.: 2012-003253-28 
Version: 08.2 
Date: 29/Dec/2017 
Sponsored by INMUNOTEK, S.L. 
That the clinical trial respects the ethical standards applicable to this type of clinical trial. 
That he agrees to participate in this clinical trial as the coordinating investigator. 
That he has the necessary materials and human resources to carry out the clinical trial, without 
this interfering with the conduct of other types of trials or other tasks that are usually entrusted 
to him. 
That he undertakes that each subject be treated and monitored in accordance with the provisions 
of the protocol, which was issued a favorable opinion by the Clinical Research Ethics Committee 
and authorized by the Spanish Agency of Medicines and Medical Devices (AEMPS, Agencia 
Española de Medicamentos y Productos Sanitarios). 
That he will respect the ethical and legal standards applicable to this type of trial and will follow 
the Good Clinical Practice guidelines when conducting the trial. 
That the collaborators that he needs to conduct the proposed clinical trial are suitable. 
Signed in MADRID, Spain, on 29 December 2017 
Signed: [Illegible signature] 
Eduardo Fernández-Cruz: Coordinating Investigator 
  

Inmunotek S.L. 
Clinical Research 
Protocol No.: MV130-SLG-001 
EudraCT No.: 2012-003253-28 
Version No.:  08.2 
Date: 29/Dec/2017 
 
 
Page 3 of 103 
TABLE OF ABBREVIATIONS 
AE 
Adverse Event 
ARs 
Adverse Reactions 
COPD 
HGUGM 
HCSC 
Chronic Obstructive Pulmonary Disease 
Hospital General Universitario Gregorio Marañón 
Hospital Clínico San Carlos 
CRF 
CAT 
Case Report Form 
COPD ASSESMENT TEST 
ELISA 
Enzyme Linked ImmunoSorbent Assay 
GCP 
Good Clinical Practice     
IgAs 
Secretory Immunoglobulin A 
LNs 
Local/regional mucosa-draining lymph Nodes 
MALT 
Mucosa-Associated Lymphoid Tissue 
NKs 
PHA 
Natural Killer cells 
Phytohemagglutinin 
PIDs 
RRTIs 
Primary ImmunoDeficiencies 
Recurrent Respiratory Tract Infections 
SAE 
Serious Adverse Event 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
 

Inmunotek S.L. 
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Protocol No.: MV130-SLG-001 
EudraCT No.: 2012-003253-28 
Version No.:  08.2 
Date: 29/Dec/2017 
 
 
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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................. 4 
2. 
GENERAL INFORMATION ...................................................................................................... 9 
2.1. 
PROTOCOL TITLE, IDENTIFICATION NUMBER, AND DATE ................................................... 9 
2.2. 
NAME AND ADDRESS OF THE SPONSOR AND MONITOR .................................................... 9 
2.3. 
NAME AND ADDRESS OF THE PERSON AUTHORIZED BY THE SPONSOR TO SIGN THE 
PROTOCOL AND THE PROTOCOL MODIFICATIONS .............................................................. 9 
2.4. 
NAME, TITLE, ADDRESS, AND TELEPHONE NUMBERS OF THE MEDICAL EXPERTS OF THE 
TRIAL’S SPONSOR ................................................................................................................ 10 
2.5. 
NAME AND POSITION OF ALL THE INVESTIGATORS RESPONSIBLE FOR CONDUCTING THE 
TRIAL, AND ADDRESS AND TELEPHONE NUMBERS OF THE TRIAL SITES ........................... 10 
2.6. 
NAME, TITLE, ADDRESS, AND TELEPHONE NUMBER OF THE PERSON RESPONSIBLE FOR 
MAKING THE MEDICAL DECISIONS RELATING TO THE TRIAL SITE ..................................... 17 
2.7. 
NAME AND ADDRESS OF THE CLINICAL LABORATORY AND OTHER MEDICAL AND/OR 
TECHNICAL DEPARTMENTS AND/OR INSTITUTIONS INVOLVED IN THE TRIAL ................. 19 
3. 
RATIONALE ........................................................... ¡ERROR! MARCADOR NO DEFINIDO. 
3.1. 
INTRODUCTION ................................................................................................................... 21 
3.2. 
BACKGROUND OF THE DISEASE AND CURRENT TREATMENT MODALITIES ...................... 23 
3.3. 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ...................................... 27 
3.4. 
SUMMARY OF FINDINGS OF POTENTIAL CLINICAL SIGNIFICANCE OBTAINED IN NON-
CLINICAL TRIALS AND OF FINDINGS RELEVANT TO THE CURRENT TRIAL OBTAINED IN 
CLINICAL TRIALS .................................................................................................................. 28 
3.4.1. 
NON-CLINICAL STUDIES ....................................................................................................... 28 
3.4.2. 
CLINICAL STUDIES ................................................................................................................ 32 
3.5. 
SUMMARY OF THE KNOWN BENEFITS FOR HUMAN SUBJECTS ........................................ 43 

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3.6. 
DESCRIPTION AND RATIONALE OF THE ROUTE OF ADMINISTRATION, DOSAGE, AND 
TREATMENT PERIODS ......................................................................................................... 46 
3.6.1. 
DESCRIPTION AND RATIONALE OF THE ROUTE OF ADMINISTRATION .............................. 46 
3.6.2. 
DOSAGE ............................................................................................................................... 50 
3.6.3. 
TREATMENT PERIOD ........................................................................................................... 50 
3.7. 
DESCRIPTION OF THE STUDY POPULATION ....................................................................... 53 
3.8. 
REFERENCES TO THE LITERATURE AND DATA RELEVANT TO THE TRIAL PROVIDING 
BACKGROUND INFORMATION ABOUT THE TRIAL ............................................................. 53 
4. 
OBJECTIVE AND PURPOSE OF THE TRIAL ............................................................................ 59 
4.1. 
PRIMARY OBJECTIVE OF THE TRIAL .................................................................................... 59 
5. 
TRIAL DESIGN ...................................................................................................................... 62 
5.1. 
DESCRIPTION OF THE PRIMARY AND SECONDARY VARIABLES ......................................... 62 
5.2. 
DESCRIPTION OF THE TRIAL TYPE/DESIGN ......................................................................... 65 
5.2.1. 
OVERVIEW OF THE TRIAL DESIGN, PROCEDURES, AND PHASES ....................................... 66 
5.3. 
DESCRIPTION OF THE MEASURES TAKEN TO MINIMIZE/AVOID BIAS ............................... 72 
5.3.1. 
RANDOMIZATION ............................................................................................................... 72 
5.3.2. 
BLINDING ............................................................................................................................. 72 
5.3.3. 
DESCRIPTION OF THE TRIAL TREATMENT........................................................................... 73 
5.3.4. 
DESCRIPTION OF THE DOSES AND DOSAGE REGIMEN OF THE INVESTIGATIONAL 
MEDICINAL PRODUCT ......................................................................................................... 74 
5.3.5. 
DESCRIPTION OF THE PHARMACEUTICAL FORM, PACKAGING, AND LABELING OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT .......................................................................... 75 
5.4. 
EXPECTED DURATION OF THE TRIAL. DESCRIPTION OF THE SEQUENCE AND DURATION OF 
THE TRIAL PERIODS, INCLUDING FOLLOW-UP ................................................................... 77 
5.5. 
DESCRIPTION OF THE SUBJECT “TERMINATION CRITERIA” AND “DISCONTINUATION 
CRITERIA” DURING THE ENTIRE TRIAL OR PARTS OF IT ..................................................... 77 

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5.6. 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTING PROCEDURES ........................... 78 
5.7. 
MAINTENANCE OF THE RANDOMIZATION CODES AND CODE UNLOCKING PROCEDURES
 ............................................................................................................................................. 79 
5.8. 
IDENTIFICATION OF ANY DATUM TO BE RECORDED DIRECTLY IN THE CRFS AND TO BE 
CONSIDERED AS AN ORIGINAL DATUM ............................................................................. 79 
6. 
SCREENING AND WITHDRAWAL OF TRIAL SUBJECTS ........................................................ 79 
6.1. 
SUBJECT INCLUSION CRITERIA ............................................................................................ 80 
6.2. 
SUBJECT EXCLUSION CRITERIA ........................................................................................... 81 
6.3. 
SUBJECT WITHDRAWAL CRITERIA AND PROCEDURES ....................................................... 84 
6.3.1. 
WHEN AND HOW TO WITHDRAW SUBJECTS FROM THE TRIAL/INVESTIGATIONAL 
PRODUCT ............................................................................................................................. 84 
6.3.2. 
TYPE OF DATA THAT WILL BE COLLECTED FROM THE WITHDRAWN SUBJECTS ................ 85 
6.3.3. 
WHETHER AND HOW SUBJECTS ARE TO BE REPLACED ...................................................... 86 
6.3.4. 
FOLLOW-UP OF DROPOUTS/WITHDRAWN SUBJECTS ....................................................... 86 
7. 
TREATMENT OF SUBJECTS .................................................................................................. 87 
7.1. 
TREATMENT TO BE ADMINISTERED, INCLUDING THE NAME OF ALL PRODUCTS AND DOSES
 ............................................................................................................................................. 87 
7.1.1. 
TREATMENTS AND DOSES TO BE ADMINISTERED ............................................................. 87 
7.1.2. 
TREATMENT ADMINISTRATION SCHEDULE ........................................................................ 87 
7.1.3. 
ROUTE/MODE OF ADMINISTRATION OF THE TREATMENTS TO BE ADMINISTERED ........ 88 
7.1.4. 
TREATMENT PERIODS, INCLUDING THE FOLLOW-UP PERIOD ........................................... 88 
7.2. 
MEDICATION/TREATMENTS PERMITTED (INCLUDING RESCUE MEDICATION) AND NOT 
PERMITTED BEFORE AND/OR DURING THE TRIAL ............................................................. 88 
7.3. 
PROCEDURES FOR MONITORING SUBJECT COMPLIANCE ................................................. 89 
8. 
EFFICACY ASSESSMENT ....................................................................................................... 90 

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8.1. 
SPECIFICATION OF EFFICACY PARAMETERS ....................................................................... 90 
8.2. 
METHODS USED TO ASSESS, RECORD, AND ANALYZE THE EFFICACY PARAMETERS ........ 91 
9. 
SAFETY ASSESSMENT .......................................................................................................... 94 
9.1. 
SPECIFICATION OF SAFETY PARAMETERS .......................................................................... 94 
9.2. 
METHODS AND SCHEDULE USED TO ASSESS, RECORD, AND ANALYZE THE SAFETY 
PARAMETERS ...................................................................................................................... 95 
9.3. 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS AND INTERCURRENT 
DISEASES, AND FOR SUBMITTING THEIR REPORTS ............................................................ 98 
9.4. 
TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER AN ADVERSE EVENT ..... 99 
9.4.1. 
FOLLOW-UP OF NON-SERIOUS AES .................................................................................... 99 
9.4.2. 
FOLLOW-UP OF SERIOUS AES ........................................................................................... 100 
10. 
STATISTICS ......................................................................................................................... 100 
10.1. 
DESCRIPTION OF THE STATISTICAL METHODS TO BE USED, INCLUDING THE SCHEDULE OF 
ANY PLANNED INTERIM ANALYSIS ................................................................................... 100 
10.2. 
NUMBER OF ANTICIPATED SUBJECTS AND RATIONALE. CALCULATION METHOD USED FOR 
DETERMINING THE SAMPLE SIZE AND DATA USED FOR SUCH PURPOSE ....................... 102 
10.3. 
SIGNIFICANCE LEVEL TO BE USED ..................................................................................... 102 
10.4. 
TRIAL TERMINATION CRITERIA ......................................................................................... 102 
10.5. 
PROCEDURES TO JUSTIFY MISSING, UNUSUAL, OR FALSE DATA .................................... 102 
10.6. 
PROCEDURES FOR REPORTING ANY DEVIATION FROM THE ORIGINAL STATISTICAL PLAN
 ........................................................................................................................................... 103 
10.7. 
SELECTION OF SUBJECTS TO BE INCLUDED IN THE ANALYSIS .......................................... 103 
11. 
DIRECT ACCESS TO THE SOURCE DATA/DOCUMENTS ..................................................... 104 
12. 
QUALITY CONTROL AND ASSURANCE .............................................................................. 105 
13. 
ETHICAL ASPECTS RELATED TO THE TRIAL........................................................................ 107 

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14. 
DATA PROCESSING AND FILING ........................................................................................ 107 
15. 
FINANCING AND INSURANCE ........................................................................................... 109 
16. 
PUBLICATION POLICY ........................................................................................................ 109 
17. 
ANNEXES ........................................................................................................................... 110 
18. 
REFERENCES ...................................................................................................................... 110 
 
 

Inmunotek S.L. 
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Protocol No.: MV130-SLG-001 
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Date: 29/Dec/2017 
 
 
Page 9 of 103 
2. 
GENERAL INFORMATION 
2.1. 
Protocol Title, Identification Number, and Date 
• PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PARALLEL, PLACEBO-CONTROLLED 
CLINICAL 
TRIAL 
EVALUATING 
THE 
SAFETY, 
CLINICAL 
EFFICACY, 
AND 
IMMUNOMODULATORY RESPONSE OF A POLYVALENT BACTERIAL VACCINE 
(BACTEK®) ADMINISTERED VIA THE SUBLINGUAL MUCOSA IN SUBJECTS WITH 
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 
• Identification number: MV130-SLG-001 
• Date: 29/Dec/2017 
• Version: 08.2 
• EudraCT No.: 2012-003253-28 
2.2. 
Name and Address of the Sponsor and Monitor  
• Name: Inmunotek, S.L. 
• Address: Punto Mobi, 5, 28805 Alcalá de Henares, Madrid, Spain. 
2.3. 
Name and Address of the Person Authorized by the Sponsor to Sign the Protocol 
and the Protocol Modifications  
• Name: Dr. Miguel Casanovas. 
• Position: Medical Director. 
• Address: Punto Mobi, 5, 28805 Alcalá de Henares, Madrid, Spain. 

Inmunotek S.L. 
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2.4. 
Name, Title, Address, and Telephone Numbers of the Medical Experts of the Trial’s 
Sponsor 
• Name: Dr. José Luís Subiza.  Immunologist. 
- Position:  General Director.  
- Address: Inmunotek, S.L. Punto Mobi, no. 5. 28805 Alcalá de Henares, Madrid, 
Spain. 
- Telephone no.: 916 510 010. 
• Name: Dr. Miguel Casanovas. Allergologist.  
- Position: Medical Director. 
- Address: Inmunotek, S.L. Punto Mobi, no. 5. 28805 Alcalá de Henares, Madrid, 
Spain. 
- Telephone no.: 916 510 010. 
2.5. 
Name and Position of All the Investigators Responsible for Conducting the Trial, and 
Address and Telephone Numbers of the Trial Sites  
• HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑÓN (HGUGM) 
- Name: Dr. Eduardo Fernández-Cruz.  
• 
Coordinating Investigator. 
• 
Title: Head of the Clinical Immunology Service of Hospital General 
Universitario Gregorio Marañón (HGUGM). 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 

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- Name: Dr. Javier de Miguel Díez. 
• 
Principal Investigator of HGUGM. 
• 
Title: Head of the Pulmonology Section of Hospital General Universitario 
Gregorio Marañón (HGUGM). 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Luís Puente Maestú.  
• 
Associate-Coordinating Investigator of HGUGM. 
• 
Title: Head of the Respiratory Function Tests and Endoscopies Section. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Julia García de Pedro. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Segismudo Solano Reina. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Pilar Sanz Sanz. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 

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Page 12 of 103 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. María Jesús Chillón Martín. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Gema Sánchez Muñóz. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Fernando Pedraza Serrano. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Marta Fuentes Alonso. 
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Javier Carbone Campoverde.  
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Clinical Immunology Unit of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 

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• 
Telephone no.: 91 586 80 00. 
- Name: Dr. Paola Benedetti.  
• 
Associate Investigator of HGUGM. 
• 
Title: Area Specialist of the Pulmonology Service of HGUGM. 
• 
Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• 
Telephone no.: 91 586 80 00. 
• HOSPITAL UNIVERSITARIO CLÍNICO SAN CARLOS MADRID 
- Name: Dr. José Luís Álvarez-Sala. 
• 
Principal Investigator. 
• 
Title: Head of the Pulmonology Service of Hospital Universitario Clínico de 
San Carlos of Madrid.  
• 
Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
• 
Telephone no.: 913 303 045. 
- Name: Dr. Miriam Calle Rubio.  
• 
Associate-Coordinating Investigator. 
• 
Title: Associate Pulmonologist of Hospital Clínico San Carlos of Madrid. 
• 
Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
• 
Telephone no.: 913 303 045. 
- Dr. María Jesús Gómez Nebreda.  
• 
Associate Investigator. 
• 
Title: Associate Pulmonologist of Hospital Clínico San Carlos of Madrid. 
• 
Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
• 
Telephone no.: 913 303 045. 

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- Dr. Juan Luís Rodríguez Hermosa.  
• 
Associate Investigator. 
• 
Title: Associate Pulmonologist and Head of the Fibrobronchoscopy Unit of 
Hospital Universitario Clínico San Carlos of Madrid. 
• 
Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
• 
Telephone no.: 913 303 045. 
• HOSPITAL INFANTA LEONOR DE MADRID 
- Name: Dr. María Jesús Buendía García.  
• 
Principal Investigator. 
• 
Title: Department Head of the Pulmonology Service of Hospital Infanta 
Leonor of Madrid.  
• 
Address: Av. Gran Vía del Este, 80 28032 Madrid, Spain. 
• 
Telephone no.: 91 191 80 00. 
- Name: Dr. Julio Hernández Vázquez. 
• 
Associate Investigator. 
• 
Title: Area Specialist of the Pulmonology Service of Hospital Infanta Leonor 
of Madrid.  
• 
Address: Av. Gran Vía del Este, 80 28032 Madrid, Spain. 
• 
Telephone no.: 91 191 80 00. 
• HOSPITAL UNIVERSITARIO DE TORREJÓN 
- Name: Dr. Soledad Alonso Viteri. 
• 
Principal Investigator. 
• 
Title: Department Head of the Pulmonology Service of Hospital Universitario 
de Torrejón. 
• 
Address: C/ Mateo Inurria, s/n, 28850 Torrejón de Ardoz, Madrid, Spain. 
• 
Telephone no.: 91 626 26 00. 

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- Name: Dr. Francisco Muñiz González. 
• 
Associate Investigator. 
• 
Title: Area Specialist of the Pulmonology Service of Hospital Universitario de 
Torrejón de Ardoz. 
• 
Address: C/ Mateo Inurria, s/n, 28850 Torrejón de Ardoz, Madrid, Spain. 
• 
Telephone no.: 91 626 26 00. 
• HOSPITAL UNIVERSITARIO 12 DE OCTUBRE 
- Name: Dr. Carlos José Álvarez Martínez. 
• 
Principal Investigator. 
• 
Title: Associate Pulmonologist of Hospital 12 de Octubre. 
• 
Address: C/ Avd. de Córdoba, s/n, 28041 Madrid, Spain. 
• 
Telephone no.: 913 90 80 00. 
- Name: Dr. Gonzalo Segrellés Calvo. 
• 
Associate Investigator. 
• 
Title: Associate Pulmonologist of Hospital Universitario 12 de Octubre. 
• 
Address: C/ Avd. de Córdoba, s/n, 28041 Madrid, Spain. 
• 
Telephone no.: 913 90 80 00. 
- Name: Dr. Pedro Daniel Benavides Mañas. 
• 
Associate Investigator. 
• 
Title: Medical Area Specialist of the Pulmonology Service of Hospital 
Universitario 12 de Octubre. 
• 
Address: C/ Avd. de Córdoba, s/n, 28041 Madrid, Spain. 
• 
Telephone no.: 913 90 80 00. 

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• HOSPITAL UNIVERSITARIO LA PAZ 
- Name: Dr. Francisco García Río. 
• 
Principal Investigator. 
• 
Pulmonology Service. 
• 
Address: Paseo de la Castellana, 261, 28046 Madrid, Spain. 
• 
Telephone no.: 917 27 70 00. 
- Name: Dr. Raquel Casitas Mateo. 
• 
Associate Investigator. 
• 
Pulmonology Service. 
• 
Address: Paseo de la Castellana, 261, 28046 Madrid, Spain. 
• 
Telephone no.: 917 27 70 00. 
- Name: Dr. Elisabeth Martínez Cerón. 
• 
Associate Investigator. 
• 
Pulmonology Service. 
• 
Address: Paseo de la Castellana, 261, 28046 Madrid, Spain. 
• 
Telephone no.: 917 27 70 00. 
• HOSPITAL UNIVERSITARIO DE VIC 
- Name: Dr. Joan Serra Battles. 
• 
Principal Investigator. 
• 
Pulmonology Service. 
• 
Address: Carrer de Francesc Pla el Vigatà, 1, 08500 Vic, Barcelona, Spain. 
• 
Telephone no.: 938 89 11 11. 

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2.6. 
Name, Title, Address, and Telephone Number of the Person Responsible for Making 
the Medical Decisions Relating to the Trial Site  
• Name: Dr. Javier de Miguel Díez. 
− Principal Investigator of HGUGM. 
− Title: Head of the Pulmonology Section of Hospital General Universitario 
Gregorio Marañón (HGUGM). 
− Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
− Telephone no.: 91 586 80 00. 
• Name: Dr. José Luís Álvarez-Sala. 
− Principal Investigator of Hospital Universitario Clínico San Carlos of Madrid. 
− Title: Head of the Pulmonology Service of Hospital Clínico de San Carlos of 
Madrid.  
− Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
− Telephone no.: 913 303 045. 
• Name: Dr. María Jesús Buendía García.  
− Principal Investigator of Hospital Infanta Leonor of Madrid. 
− Title: Department Head of the Pulmonology Service of Hospital Infanta Leonor 
of Madrid.  
− Address: Av. Gran Vía del Este, 80 28032 Madrid, Spain. 
− Telephone no.: 91 191 80 00. 
• Name: Dr. Soledad Alonso Viteri. 
− Principal Investigator of Hospital Universitario de Torrejón de Ardoz. 
− Title: Head of Department of the Pulmonology Service of Hospital Universitario 
de Torrejón. 
− Address: C/ Mateo Inurria, s/n, 28850 Torrejón de Ardoz, Madrid, Spain. 
− Telephone no.: 91 626 26 00. 

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• HOSPITAL UNIVERSITARIO 12 DE OCTUBRE 
- Name: Dr. Carlos José Álvarez Martínez. 
• 
Principal Investigator. 
• 
Title: Associate Medical Pulmonologist of Hospital 12 de Octubre. 
• 
Address: C/ Avd. de Córdoba, s/n, 28041 Madrid, Spain. 
• 
Telephone no.: 913 90 80 00. 
• HOSPITAL UNIVERSITARIO LA PAZ 
- Name: Dr. Francisco García Río. 
• 
Principal Investigator. 
• 
Pulmonology Service. 
• 
Address: Paseo de la Castellana, 261, 28046 Madrid, Spain. 
• 
Telephone no.: 917 27 70 00. 
• HOSPITAL UNIVERSITARIO DE VIC 
- Name: Dr. Joan Serra Battles. 
• 
Principal Investigator. 
• 
Pulmonology Service. 
• 
Address: Carrer de Francesc Pla el Vigatà, 1, 08500 Vic, Barcelona, Spain. 
• 
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2.7. 
Name and Address of the Clinical Laboratory and Other Medical and/or Technical 
Departments and/or Institutions Involved in the Trial 
• Laboratory of Clinical Molecular Immunogenetics. Clinical Immunology Service of 
Hospital General Universitario Gregorio Marañón (HGUGM). Dr. Carmen 
Rodríguez Sainz. 
− Address: C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. 
• Clinical Diagnosis Laboratory. Immunology Service. Hospital Universitario Clínico 
San Carlos of Madrid. Dr. Lourdes Hernández Cillero. 
− Address: C/ Profesor Martín Lagos s/n 28040 Madrid, Spain. 
 
The following tasks will be carried out: 
Assessment of the following immunological parameters in patients participating 
in the study protocol, the “Immunological Substudy”, and/or the induced sputum 
substudy (change between months 0, 1, 3, 6, and 12, as well as in comparison with 
the placebo) in the following immunological parameters:  
General Immunological Studies: 
− Specific humoral response (IgG serum concentration against Bactek® 
bacterial antigens;  IgA concentration in patients’ saliva and induced 
sputum against Bactek® antigens). 
− Specific 
cellular 
response 
(specific 
CD4+ 
T-cell 
response 
in 
peripheral-blood mononuclear cells [PBMCs]) by means of a 
carboxyfluorescein diacetate succinimidyl ester (CFSE) assay after 
stimulation with the bacterial antigens that comprise Bactek®. 

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• Genomics and Microarrays Unit. Hospital Clínico San Carlos of Madrid. Dr. Beatriz 
Pérez-Villamil and Laboratory of Clinical Molecular Immunogenetics. Clinical 
Immunology Service of HGUGM. Dr. Carmen Rodríguez Sainz. 
− Address: C/ Profesor Martín Lagos s/n 28040 Madrid, Spain. 
 
The following tasks will be carried out: 
− Assessment of messenger RNA (mRNA) and micro-RNA (miRNA) in PBMCs 
and induced sputum (change between the baseline level and months 1 
and 12, as well as in comparison with the placebo).  
− Proteomics studies using the isobaric tags for relative and absolute 
quantification (iTRAQ) technique. 
− Phenotypic markers of leukocyte populations. 
− Neutrophil function studies: phagocytosis (Phagotest) and bacteriophage 
capacity of the neutrophils (oxidative burst). 
• Statistics: Dr. Cristina Fernández: 
- Title: Head of the Clinical Epidemiology and Clinical Research Methodology 
Unit of Health Research Institute Hospital Universitario Clínico San Carlos. 
- Address: Calle del Profesor Martín Lagos 28040, Madrid, Spain. 
- Telephone no.: 913 303 045. 
The following tasks will be performed: 
− Epidemiological counseling. 
− Preparation and custody of the randomization list. 

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− Entry of the data into the trial’s database. 
− Certification of the database lock. 
− Preparation of the statistical plan. 
− Statistical analysis. 
− Preparation of the statistical report. 
3. RATIONALE 
3.1. 
Introduction 
Healthcare focused on chronic infectious diseases involves a high consumption of the 
time of healthcare professionals and of the budget assigned by the Public 
Administration to the National Health System (NHS).  Chronic obstructive pulmonary 
disease (COPD) is the most prevalent condition among such diseases, as recent 
epidemiological studies have estimated that over 10% of the adult population 
between the ages of 40 and 80 years is affected by this illness.1, 2  
Approximately 85% of all cases of COPD are caused by smoking, and it is estimated 
that 15% of all smokers will develop COPD. Furthermore, because of the persistence 
of smoking among young people, the World Health Organization (WHO) considers 
that COPD will go from being the fourth cause of death worldwide to the third cause 
in 2020, following cerebrovascular disease and ischemic heart disease.3  
 
 

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Chronic obstructive pulmonary disease is a chronic and progressive disease 
characterized by frequent exacerbations during its clinical evolution. Flare-ups or 
exacerbations of COPD can be caused by a variety of risk factors, with recurrent 
bacterial and, predominantly, viral infections of the respiratory tract being most 
commonly associated with this condition and one of the most frequent causes of 
consultations in Primary Care centers and the hospital services of the NHS.4 
This illness currently affects millions of people worldwide and is one of the leading 
causes of death with an increasing incidence.5 In the USA, of the six most frequent 
causes of death, only the incidence of those due to COPD has risen constantly since 
the 1970s, which makes this condition the main cause of morbidity, mortality, and 
disability in this country3 (Fig. 1). Although diagnosing this condition is not difficult, it 
is an underdiagnosed disease, particularly in the case of its milder and more treatable 
forms.6 In 1993, the direct medical costs resulting from this disease in the USA 
summed up to 14.7 billion dollars, and the indirect costs related to its morbidity (e.g., 
loss of work days and productivity) were 9.2 billion dollars.6 
Figure 1. Deaths per 100,000 USA inhabitants resulting from the six most frequent 
causes of mortality throughout the 1970-2002 period. 

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In Spain, COPD affects 9% of people over the age of 40 and 20% of those over the age 
of 65.7, 8 In a 2001 publication,8 the authors estimated that, in Spain, COPD caused 
approximately 10-12% of consultations in primary care centers, 35-40% of 
pulmonology consultations, and 35% of permanent occupational disabilities. 
Moreover, the same authors indicated that COPD was responsible for 7% of hospital 
admissions 
and 
the 
fourth 
leading 
cause 
of 
death 
(33 deaths/100,000 inhabitants/year) in our country. The costs resulting from this 
disease were estimated to amount to 2% of the annual budget of the Spanish Ministry 
of Health and Consumer Affairs (Ministerio de Sanidad y Consumo) and to 0.25% of 
the gross domestic product. The annual social, occupational, and healthcare costs 
attributable to COPD were estimated at 2.4 billion euros, with an expenditure of 
1,652-2,344 euros per patient and year. These costs have continued to rise as a result 
of the aging population, the increasing prevalence of this disease, and the price of 
new drugs and the latest therapeutic modalities. 
3.2. 
Background of the Disease and Current Treatment Modalities 
Albeit with significant seasonal variations, flare-ups or exacerbations of COPD 
represent 2% of all medical emergencies attended. Up to 40% of subjects presenting 
to a hospital Emergency Department due to an exacerbation of this illness have to be 
hospitalized. The consequences of severe COPD exacerbations are linked to high 
morbidity and mortality.9 Frequent use of antibiotics for its treatment has been 
associated with increased antibiotic resistance.10, 11 Exacerbations account for most 
of the healthcare costs associated with COPD.12 
Current treatment modalities for COPD include a preventive approach in the early 
phase of the illness, including socio-environmental measures (primary prevention by 
promoting smoking cessation and physical exercise) and “opportunistic” screening 
interventions (secondary prevention by reducing underdiagnosis by means of the 

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early detection of the disease). In the phase in which the process has already begun, 
pharmacological treatment measures are implemented (antibiotic therapy, 
bronchodilators, and corticotherapy) and antigen-specific vaccines are administered 
(pneumococcal capsule polysaccharide vaccine and flu vaccine). The advanced or 
sequelae phase of COPD is characterized by a severe limitation of physical activity, 
generally accompanied by disability and depression, and response to treatment is 
only partial or incomplete. 
Exacerbations are associated with a significant worsening in the patients’ quality of 
life, and the degree of disability caused by this condition depends on the number of 
exacerbations experienced.13 Albeit with seasonal variations, exacerbations of COPD 
are a frequent cause of consultations in both primary care and hospital services, and 
represent 2% of all medical emergencies attended. Exacerbations of infectious nature 
account for 1.5% of all emergencies attended in the hospital and for 13.7% of all 
infections. Up to 40% of subjects treated for this cause in the Emergency Department 
require hospitalization. Approximately 4% of the general European population 
consults their general practitioner at least once a year due to experiencing a 
respiratory exacerbation, and 20% of these consultations correspond to subjects with 
COPD. In Spain, empirical antibiotic treatment is prescribed in over 90% of cases of 
respiratory exacerbation of COPD, although sputum microbiology is only studied in 
5% of subjects. Penicillins, cephalosporins, and macrolides are the most widely used 
antibiotics for the treatment of exacerbations of chronic bronchitis and COPD in 
Spain, followed by quinolones.14  
Infection causes 75% of COPD exacerbations. Bacteria are responsible for half of 
these exacerbations of infectious etiology, which are mainly caused by 
Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and 
Chlamydia pneumoniae. However, in patients suffering from severe COPD presenting 

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with an exacerbation requiring mechanical ventilation, this infection might be caused 
by Pseudomonas aeruginosa. The rest of infectious exacerbations are caused by 
viruses, occasionally associated with bacteria, or exceptionally by other 
microorganisms.14  
In addition to directly affecting social and health resources consumption, any 
intervention that can reduce the incidence of COPD exacerbations can have a great 
impact on the morbidity and quality of life of the affected subjects. Because bacterial 
infections of the respiratory tract are a well-known risk factor for the onset of COPD 
exacerbations, prevention and appropriate treatment of these infections may 
represent an attractive modality for avoiding the development of exacerbations.  
The approach of identifying preventive therapeutic alternatives to avoid the 
development of COPD exacerbations is highly justified by the fact that controlling 
COPD exacerbations entails great costs for the subjects affected by this condition, 
society as a whole, and the NHS. However, there is currently little evidence of the 
existence of treatment modalities that can prevent the onset of COPD exacerbations 
associated with recurrent respiratory tract infections (RRTIs). 
Immunotherapy treatment with new bacterial immunogens has emerged in the last 
decade as a therapeutic alternative capable of stimulating innate and specific 
adaptive immunity of subjects with several diseases. Sublingual immunization has 
recently been proposed as an alternative modality of mucosal vaccination that offers 
greater advantages for immunization against antigens and allergens in the treatment 
of allergies and respiratory infections.15-22 However, this alternative has previously 
only been addressed in very few clinical trials (see below), which is why this trial is 
aimed at examining the effect of immunotherapy with bacterial immunomodulators 
on the prevention of the onset of COPD exacerbations in adults. 

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We will now proceed to describe the scientific rationale for this treatment modality, 
as well as the results of a limited number of open-label, uncontrolled and/or 
double-blind, randomized trials including a small number of subjects and whose 
findings suggest that this type of immunotherapy might reduce the risk of onset of 
RRTIs, and, in turn, lead to a decrease in the incidence of COPD exacerbations.  
 
 
 

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3.3. 
Name and Description of the Investigational Product 
Bactek® is the generic name of this bacterial vaccine manufactured over 10 years ago 
by Inmunotek, S.L. (Spain). It contains whole, inactivated bacteria and is prepared 
individually for each patient. The latest generation of this product is fundamentally 
characterized by three new features: 1) its adjuvant-like glycerol solution, 2) its 
content featuring a high concentration of the bacteria that are most frequently 
present in the respiratory tract of subjects with recurrent respiratory tract infections, 
and 3) its administration in spray format via the sublingual mucosa. 
According to this Clinical Trial protocol, each patient will be administered the Bactek® 
vaccine 
containing 
the 
following 
concentration 
of 
inactivated 
bacteria 
(109 bacteria/ml): Staphylococcus aureus (15%), Staphylococcus epidermidis (15%), 
Streptococcus pneumoniae (60%), Klebsiella pneumoniae (4%), Branhamella 
catarrhalis (3%), and Haemophilus influenzae (3%).The excipients that it contains are: 
glycerol (50%), pineapple essence q.s. (1 ml), sodium chloride (9 mg/ml), and water 
for injection q.s. (1 ml). This is the most frequently used bacterial composition in 
subjects with recurrent respiratory tract infections.  
The placebo is an identical solution to the investigational medicinal product, but 
without the active ingredient, which are the bacteria in this case. The placebo only 
contains 50% glycerol, pineapple essence q.s. 1 ml, sodium chloride 9 mg/ml, and 
water for injection q.s. 1 ml. 
 
 
 

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3.4. 
Summary of Findings of Potential Clinical Significance Obtained in Non-Clinical 
Trials and of Findings Relevant to the Current Trial Obtained in Clinical Trials 
3.4.1. 
Non-Clinical Studies 
Mucosa-associated lymphoid tissue (MALT) is a major contributor to the body's 
innate and adaptive immune system.19, 23, 24 Recent studies on animal research 
models suggest that the immunotherapy modality that uses the mucosal route 
(i.e., oral, sublingual, rectal, vaginal, and intranasal mucosal vaccines) for the 
administration of the antigen is a potentially safe and efficient approach for the 
induction of immune responses with potential for preventing infectious diseases 
caused by bacterial and viral pathogens that enter the body through the mucosal 
surfaces.4, 18, 19 
The immunological responses induced in the mucosa constitute an early and 
important defense line against several pathogens: bacteria, viruses, and parasites. 
Sublingual vaccination specifically induces antigen-specific immune responses of 
both types: mediated by activated B cells, involving the production of secretory IgA 
(surface IgA), IgM, and IgG antibodies; and CD4+ and CD8+ T-cell mediated responses, 
involving the production of Th2 (IL-4 and IL-10) and Th1 interleukins (TGF-β, IL-12, and 
IFN-γ), not only at the local mucosal level, but in the systemic compartments and the 
mucosa of distant locations from the administration site.23, 25, 26 The existence of a 
high number of antigen-presenting cells (APCs) such as dendritic cells (DCs) in the 
sublingual mucosa facilitates the uptake, processing, and subsequent presentation of 
the antigen to the CD4+ and CD8+ T cells in the drainage lymph nodes located near 
the administration site. Antigen-presenting cells (DCs and macrophages) present in 
the lymph nodes, intestine, and lungs control the activation, expansion, and survival 
of cells regulating different phenotypes and functions such as CD4+ effector helper 
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IL-10, CD4+ or CD8+ TGF-β-producing T cells (Th3-like), and CD4+CD25+ regulatory 
T cells (Treg) that inhibit CD4+ T-cell proliferation.27-33 
Both in enteric and respiratory models, as well as in relation to mucosal 
immunization, in addition to the induction of one of the main humoral defense 
mechanisms present in the mucosal surface (i.e., IgAs), the generation of responses 
mediated by  IFN-γ-producing CD4+ T cells (Th1) and cytotoxic responses mediated by 
CD8+ T lymphocytes (i.e., cytotoxic lymphocytes [CTLs]) that are key for protective 
immunity and the clearance of bacterial and viral pathogens have also been 
described.34-40  
The innate immune system is made up of several effectors, which primarily include 
macrophages, dendritic cells, and natural killer (NK) cells. Natural killer T (NKT) cells 
(CD3+CD16+/CD56+) are an important subset of lymphocytes featuring 
characteristics of both T and NK cells. These cells are part of both the innate and 
adaptative immune systems (antigen-specific B and T cells and their clonal memory 
responses) and act as a bridge between both types of immunity (innate and 
adaptative). These NKT cells form a subset of cells that has been assigned a protective 
role in infections, cancer, and sarcoidosis, although it has recently been attributed an 
important role in the immunopathogenesis of chronic pulmonary diseases, such as 
asthma, COPD, and hypersensitivity pneumonitis.41-45 
NKT cells have the ability to both promote and suppress immune responses through 
the activation of different subtypes with various functions. Activated CD4+ NKT cells 
produce both Th1 (IFN-γ and TNFα) and Th2 (IL-4, IL-10, and IL-13) cytokines, whereas 
CD4-CD8- (double negative) and CD4-CD8+ NKT cells produce Th1 cytokines and may 
exhibit antigen-specific cytotoxic and NK-like activity.43, 46, 47  

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It has been postulated that the innate immune system mediates acute responses 
against infectious agents, whereas an atypical adaptive response can cause a chronic 
inflammatory response. Thus, it has been suggested that infections by bacteria 
and/or viruses, such as the respiratory syncytial virus (RSV), might trigger a persistent 
acute innate immune response and eventually result in an atypical adaptive immune 
response causing a chronic inflammatory disorder, such as in the case of asthma and 
COPD.48-50   
Chronic obstructive pulmonary disease, which is characterized by respiratory 
bronchiolitis, chronic bronchitis, and emphysema, is largely mediated by a Th1 
immune response triggered primarily by CD4-CD8+ NKT cells (increased 
concentration of CD3+CD56+ CD1d-dependent NKT-like cells and decreased 
proportion of CD4+ NKT-like cells) selectively recruited in the lung and which, after 
interacting and activating macrophages, produce IL-13 and IL-17, consequently 
causing the chronic pro-inflammatory response observed in the COPD lungs.  
In the local airway mucosa, the CD1d-expressing antigen-presenting dendritic cells 
can capture low amounts of the viral antigen and stimulate the activation of NKT cells. 
An experimental model of chronic pulmonary disease simulating COPD in humans 
showed that, after a viral respiratory infection, NKT cells (CD1d-dependent) migrate 
toward the lungs and activate chronically, resulting in an increased selective 
production of IL-13 mRNA that causes the recruitment and chronic activation of 
pulmonary macrophages (expressing CD1d), which, in turn, contribute to the 
predominant production of IL-13 mRNA in the lungs (in addition to the production of 
this cytokine by CD3+CD4+ T cells), which acts as the main mediator of the chronic 
inflammatory response. In the model, the presence of IL-13 is a requirement for the 
induction of the mucosa cell metaplasia and airway hyperreactivity that cause chronic 
inflammatory pulmonary disease after a viral infection. A similar phenomenon has 

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been observed in lung samples from COPD lung transplant recipients. Hence, this is 
the first description of an immune axis comprised by NKT cells, macrophages, and IL-
13. Regulation of the NK cell function is a requirement for the optimal development 
of innate and adaptive immune antibacterial and antiviral responses.41, 49, 51-53  
A crucial aim in vaccine development is the induction of an immunological memory 
originating a reservoir of effector cells with the ability to increase their number, as 
well as react quickly and effectively for prolonged periods of time, with specific 
immune responses generated when the presence of the specific pathogen is 
detected. The induction of this type of memory response is conditioned by the nature 
of the antigen, the adjuvant, and the route of administration. Thus, sublingual 
immunization would boast the advantage of modulating the generation of memory 
CD4+ helper T cells (Th1) against specific inhaled pathogens by regulating the innate 
and adaptive antimicrobial defenses through the induction of humoral and cellular 
effector responses and maintaining a more effective, durable immune surveillance 
after the vaccination compared with other immunization routes.15-22, 54-68  
 
 

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3.4.2. 
Clinical Studies 
The importance of considering the possibility of inducing memory immune responses 
at the mucosal level is explained by the fact that most human infections start or affect 
mucosal surfaces (e.g. gastrointestinal infections induced by Escherichia coli, 
Clostridium difficile, Shigella, rotavirus, etc.; respiratory infections induced by 
Streptococcus pneumoniae, Haemophilus influenzae, the influenza virus, the 
respiratory syncytial virus, etc.; or genital infections induced by the human 
immunodeficiency virus (HIV), the herpes simplex virus, Neisseria gonorrhoeae, 
Chlamydia trachomatis, etc.). In COPD, approximately half of exacerbations are 
associated with lower respiratory tract infections, mostly caused by common 
pathogenic bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, 
which accelerate the deterioration of pulmonary function in COPD. A functional 
defect in the innate immune response mediated by macrophages has been described 
in these subjects with COPD, who exhibit a decreased phagocytic ability to eliminate 
the cited pathogens and an altered cytokine production leading to bacterial 
colonization, chronic activation, and an increased frequency of exacerbations and 
deterioration of pulmonary function. As residents of the pulmonary mononuclear 
phagocytes, alveolar macrophages play a key role in the defense against inhaled 
pathogens.69-73 
Immunomodulatory agents of diverse origin , including bacteria, can play an 
important role in the immunomodulation of the functional mechanisms of innate 
immunity mediated by NK cells, macrophages, and toll-like receptor (TLR2) molecules 
present on the surface of the alveolar macrophage whose expression and activation 
is involved in the recognition and phagocytosis of bacteria. Specific immunological 
functional defects against inhaled pathogenic bacteria are involved in the reduction 

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of bacterial clearance, thus leading to chronic infections that trigger 
exacerbations.71, 74 
Bacterial immunomodulators can play a significant role in preventing infections that 
trigger such exacerbations.75-78 Certain studies have demonstrated the efficacy of this 
type of product in the prevention of COPD exacerbations,60, 79-81 some of them 
including a relatively significant sample size of subjects.82 
A double-blind, placebo-controlled, randomized clinical trial (PARI-IS study) 
examined the effect of an immunomodulatory bacterial agent on the prevention of 
respiratory exacerbations in subjects with COPD. The results of this study showed 
that the immunomodulatory agent generated a clinical benefit in subjects with COPD 
by 
reducing 
the 
number 
of 
severe 
respiratory 
episodes 
requiring 
hospitalization.60, 75, 76, 78, 82-87 
A recent systematic review analyzed the results obtained in 13 randomized, 
placebo-controlled clinical trials83 including a total of 1971 subjects. The authors of 
the review acknowledged that two trials82, 88 (including 731 subjects) followed the 
appropriate methodology and reported actions for the exacerbations, but that the 
rest of them were of low methodological quality and failed to conclusively 
demonstrate an effect on the prevention of exacerbations. 
 
 

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The immunomodulators used in all of these trials were bacterial lysates administered 
in capsules via oral swallowing. This oral route with distant mucosal stimulation, that 
is, at the level of the intestine, does not cause a systemic effect that is as effective as 
stimulation via the sublingual or nasal mucosal route.15, 19 
A number of studies suggest that the clinical benefit may be greater when 
immunomodulation is achieved by direct stimulation of elements of the immune 
system present in the sublingual mucosa.89, 90  
Overall, all studies69, 72, 73, 91 suggest that immunomodulation via mucosal 
immunization with bacterial antigens can be considered a safe and effective 
immunotherapeutic delivery alternative for a robust and long-lasting stimulation of 
the innate immune system with simultaneous enhancement of local and systemic 
specific adaptative immunity. The enhancement of these immune responses has 
shown an association with the ability to induce resistance to infection and to 
physiologically modulate the chronic inflammatory response.  
Therefore, these data strongly support the fact that immunization via the sublingual 
route can be an optimal option in terms of efficiency for the prevention of infections 
by inhaled respiratory bacteria. Moreover, it has not been demonstrated that the 
pharmacological agents currently available for the treatment of COPD 
(glucocorticoids, bronchodilators, azithromycin, and others) can exert a modulating 
effect on specific innate and adaptive responses of clinical relevance in the aberrant 
chronic inflammatory response associated with the progress of COPD. 
Chronic obstructive pulmonary disease is characterized by the presence of acute 
exacerbations (COPD-AEs), which, along with its clinical symptoms and the subjects’ 
spirometry results, define the risk of progression of the disease.92 However, there are 

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no specific “biomarkers” that allow for characterizing the subgroup of patients 
suffering from more frequent exacerbations. 
A number of studies have examined the inflammatory characteristics of sputum 
induced by hypertonic saline solution inhalation in patients with COPD, including its 
content in cells and inflammation-mediating molecules. However, there are currently 
very few biomarkers available for use in clinical settings for the assessment of 
COPD-AEs. In this study we are mainly interested in assessing the profile of the 
inflammatory cells present in the induced sputum of COPD patients. In this regard, 
there are a number of studies93-95 that suggest that a target cell in COPD is the airway 
and lung neutrophil, which is functionally affected and one of the possible and 
important contributors to tissue inflammation, bacterial colonization, exacerbations, 
and progressive pulmonary function deterioration.96-99 
In this disease, airway neutrophils are characterized by defective phagocytosis of 
pathogenic bacteria, a defective oxidative metabolism for the destruction of bacteria 
by an oxidative-dependent mechanism (oxidative burst), and an increased release of 
pro-inflammatory mediators such as cytokines and chemokines (IL-8, IL-6, and 
TNF-alpha) 
and 
proteolytic 
mediators 
(neutrophil 
elastase 
[NE], 
matrix 
metalloproteinase 9 [MMP-9], and myeloperoxidase [MPO]).100, 101  
All of this leads to the patients’ lungs being in a pro-inflammatory state (vicious cycle), 
associated with a dysfunction of the mucociliary system of the respiratory and cellular 
epithelium, a decrease in the alveolar phagocytic capacity, bacterial colonization, and 
damage to the lung tissue, which results in the development of an abnormal 
pro-inflammatory microenvironment in the lower respiratory tract that severely 
affects the clearance or elimination of bacterial pathogens.69, 72, 73, 102, 103 Bacterial 
colonization of the lower airways induces chronic inflammation that contributes to 
their progressive obstruction by poorly-defined mechanisms.104-106 

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Our hypothesis is that BACTEK can immunomodulate phagocytic cell dysfunction and 
tissue inflammation in the lungs. 
In this study, we aim to determine whether the neutrophil in the induced sputum can 
be used as a biomarker of altered innate immunity associated with the ability to 
eliminate the pathogenic bacteria that result in the pro-inflammatory state that 
causes the functional deterioration that characterizes patients with COPD-AEs. 
3.4.2. Clinical Studies 
A series of uncontrolled clinical studies on recurrent respiratory tract infections in 
adults and children have shown that the oral administration of polyvalent bacterial 
lysates improves clinical response by reducing the number, duration, and severity of 
infectious episodes.78, 80, 82, 83, 107-110 A small number of uncontrolled clinical studies 
performed with COPD subjects who received polyvalent bacterial preparations 
(lysates) through the oral administration route suggest a beneficial effect in the 
prevention of disease exacerbations, with a decrease in the number, duration, and 
severity of infectious episodes and a reduction in antibiotic use and healthcare 
resource consumption reflected in lower rates of hospital admissions. In addition, 
these clinical trials have demonstrated a positive impact on impaired immune 
functions, such as alveolar macrophage activity and interferon gamma production.  
The usefulness of this therapeutic modality using bacterial lysates as 
immunomodulators in clinical practice has been a matter of debate due to the 
contradictory results observed in trials performed with the various types of bacterial 
preparations used in different clinical settings. 
Several meta-analyses have been carried out on the use of various immunostimulants 
in respiratory infections: 

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− Bergemann et al. 85 carried out the first meta-analysis examining the efficacy 
of a bacterial lysate versus a placebo in reducing the number of acute 
exacerbations in subjects with chronic bronchitis, as well as a 
cost-effectiveness analysis. 
− The meta-analysis performed by Del-Río-Navarro et al.111 demonstrated that 
immunomodulators reduce the incidence of acute respiratory infections in 
children by an average of 40%. These investigators analyzed a total of 34 
placebo-controlled trials with a total of 3877 participants. 
− Schaad carried out a systematic review of the use of a bacterial lysate as an 
immunostimulant in pediatric subjects with recurrent respiratory tract 
infections.112 Eight randomized, controlled studies were included in this 
meta-analysis, which showed that the population treated with this lysate 
developed significantly and consistently fewer cases of recurrent respiratory 
tract infections (26.2%) over a six-month period. The compiled data suggest 
that this effect is even greater in subjects at an increased risk of suffering from 
recurrent respiratory tract infections. 
− Steurer-Stey et al.83 carried out a systemic review analyzing the results of 
13 randomized, placebo-controlled, clinical trials with a total of 1971 subjects. 
The authors of this review acknowledge that only two trials (including 
731 subjects) followed the appropriate methodology and reported an effect 
on the exacerbations. 
 
 

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 Collet et al. performed a randomized, double-blind, placebo-controlled trial113 
to study the effect of an immunostimulant agent (consisting of a lyophilized 
lysate of eight of the most common pathogens isolated in respiratory tract 
infections and administered orally) to prevent acute airway exacerbations in 
subjects with COPD. In the same issue of the journal, Anthonisen published an 
editorial letter76 praising the quality of the trial and pointing out that 
treatment with this bacterial lysate might be able to modify the course of 
COPD. This author also pointed out that, by halving the number of days of 
hospitalization, the costs resulting from this disease were very low, and made 
reference to the treatment’s ease of administration. 
 Orcel et al.’s study88 evaluated the preventive effects of oral vaccination with 
a bacterial lysate in elderly subjects with acute bronchitis. The results of this 
study suggested that the bacterial lysate exhibited a protective effect against 
acute bronchitis in elderly subjects. 
− In a 2006 review of the Cochrane Collaboration,114 six clinical trials comparing 
the effects of an H. influenzae vaccine in subjects with recurrent acute 
exacerbations of chronic bronchitis were analyzed. These six trials included a 
total of 440 subjects. The reviewers concluded that vaccinating subjects with 
recurrent acute exacerbations of chronic bronchitis in the fall season could 
reduce the number and severity of exacerbations during the following winter 
months. 
− There are recent, very determining results about the effectiveness of 
immunological immunomodulators of bacterial origin administered via the 
sublingual mucosa in reducing respiratory infections in a population of 
susceptible subjects. A double-blind, placebo-controlled trial (PARI-IS study) 
evaluating the adjuvant effect of a bacterial immunogen in preventing 

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exacerbations in COPD subjects showed a reduction in the number of serious 
respiratory episodes requiring hospitalization.82 Immunostimulation via the 
sublingual mucosa has shown to produce very intense innate and adaptive 
specific immune responses both locally and at a distant systemic level in the 
mucosa of the respiratory tract and lungs.15, 19 There are also studies that 
show that whole inactivated bacteria result in a much more robust 
macrophage stimulation than that caused by bacterial lysates.115, 116 However, 
there is still uncertainty about the type of innate and adaptive immune 
responses induced by these bacterial preparations that can effectively impact 
the clinical response of subjects with recurrent chronic respiratory tract 
infections.77  
- Recent studies involving the use of bacterial vaccines have been conducted in 
subjects with recurrent respiratory infections 68, 78, 80, 108, 110, 117-123 and in 
subjects with COPD,60, 75, 83, {Bourbeau, 2003 #14, 84, 87, 113, 124, 125 with their results 
suggesting their efficacy in reducing infectious episodes in these subjects. 
- A pilot clinical trial with Bactek® has recently evaluated the effect of its daily 
administration via the sublingual route, for a total of six months, in the 
prevention of recurrent infections of the upper and lower respiratory tract 
(RRTIs) in a cohort of adult subjects.126 This trial was carried out with a group 
of subjects with RRTIs (N = 17) to assess whether sublingual immunization with 
a polyvalent bacterial vaccine might cause an immunomodulatory effect on the 
antigen-specific immune response and has a clinical impact. An immunological 
assessment was performed both before and at the end of the immunization. 
These immunological determinations included: proliferation of antigen-
specific CD3+CD4+ and CD3+CD8+ T cells against Bactek® antigens, serum 
immunoglobulin levels, specific antibodies against the pneumococcal 

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polysaccharide and the tetanus toxoid, and lymphocyte subpopulations of B, T, 
and NK cells. It has recently been published in the journal Clinical Experimental 
Immunology126, 127 under the title: “Sublingual therapeutic immunization with 
a polyvalent bacterial preparation in patients with recurrent respiratory 
infections: immunomodulatory effect on antigen-specific CD4+ T cells and 
clinical impact”. 
During the twelve-month period elapsed since the start of the therapeutic 
immunization, an impact on clinical control was observed in the form of a 
significant decrease in the incidence of upper and lower respiratory tract 
infections compared with the number of RRTIs that the same subjects had 
experienced within the twelve months preceding the start of this treatment. 
This cohort of subjects exhibited a decrease in the frequency of episodes of 
RRTIs while receiving treatment with Bactek and during the follow-up period 
compared with the year preceding the start of the immunization. These clinical 
data are consistent with observations from another placebo-controlled study 
evaluating the bacterial vaccine in children, which showed that its clinical 
response is more effective in selected subjects who experienced a greater 
number of RRTIs in the year preceding the start of this therapy.110 
 
 

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The clinical trial with Bactek® demonstrated the existence of an association 
between a positive clinical response and an antigen-specific immune response 
mediated by CD4+ helper T cells.127 A significant increase in the proliferative 
capacity of CD3+CD4+ T cells against Bactek® antigens was observed after 
6 months of treatment with respect to the baseline (P <0.0001), and a 
significant increase in CD3+ T cells was also observed (P <0.05). No significant 
differences were observed in the serum levels of immunoglobulins, specific 
antibodies, or peripheral-blood lymphocyte subpopulations of B, T, and NK 
cells between the baseline and month 6. A significant reduction in the rate of 
respiratory infections was observed in the treated subjects compared with the 
rate of these infections during the year preceding the start of the immunization 
therapy (P <0.0001). The results of this study demonstrate that the long-term 
administration of a polyvalent bacterial preparation via the sublingual route in 
subjects with RRTIs exerts a stimulating effect on the immune response of 
CD4+ T cells against bacterial antigens, which could be associated with 
significant clinical benefits. 
The significant increase in the proliferative capacity of CD3+CD4+ T cells could 
be one of the main immunomodulatory mechanisms at the systemic level 
induced by sublingual vaccination with the polyvalent bacterial preparation 
(Bactek®). However, the specific lymphoproliferative response is not the only 
immune mechanism that might have been modified in subjects by 
immunization with the bacterial antigens. It is possible that the innate immune 
response was stimulated locally, at the level of the different mucosal 
compartments 
of 
the 
upper 
and 
lower 
respiratory 
tracts, 
by 
immunomodulating the fundamental defect of the macrophage-mediated 
immune response against the respiratory bacterial pathogens, as well as that 
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pro-inflammatory cytokines in this microenvironment.73 Stimulation of the 
innate response may have also contributed to the induction of the potent and 
sustained antigen-specific cellular immune response observed in immunized 
subjects.48 However, the activation and interaction of the immunological 
effector mechanisms of the specific innate and adaptive systems need to be 
clarified, particularly in the context of their potentially important role in 
therapeutic immunomodulation and observed clinical improvement.110 
An increase in the proliferative capacity of specific CD3+ CD4+ and CD3+CD8+ 
T cells against influenza virus antigens was also observed in this trial after 
6 months of treatment with Bactek®.12 The fact that the subjects had received 
the flu vaccine or had been infected by the influenza virus at least within the 
2 years preceding the start of the treatment with Bactek® suggests that the 
bacterial immunization could have induced an immunostimulatory effect, 
which, in turn, resulted in the immunomodulation of the ongoing cellular 
immune response against the viral antigens.128-132 This could be related to the 
existence of a dependence on the collaborative activity of the CD4+ T cells in 
increasing the number of antigen-specific CD4+ and CD8+ T cells133 and to the 
observed generation and induction of specific CD4+ helper T-cell responses 
that have been linked to effective immune responses in long-term 
immunization therapies.78, 107, 110 
The results of this pilot clinical study suggest a beneficial effect on the clinical 
response of RRTIs to a polyvalent bacterial vaccine administered sublingually 
and associated with an activation of the lymphoproliferative, antigen-specific 
CD4+ T-cell response against the bacterial antigens.12 Overall these results are 
in line with those obtained in other studies that demonstrate an association 

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between immunization with polyvalent bacterial immunomodulators and the 
clinical improvement of respiratory diseases.83, 108, 113, 124, 134, 135  
 
3.5. 
Summary of the Known Benefits for Human Subjects 
This type of product has long been administered to humans as an individualized 
formula, with similar products also being administered to animals. 
Several improvements derived from the knowledge obtained in studies on 
immunological mechanisms and leading to a greater clinical benefit have currently 
been introduced: 
• This preparation is formulated with fully inactivated whole bacteria that 
induce a much more intense and robust macrophage stimulation response 
than bacterial lysates or receptor-specific ligands, owing to the fact that 
they produce a global stimulation of all receptors.115, 116 
• This preparation is administered via direct deposition on the oral mucosa, 
mainly the sublingual one. This route of administration imitates the natural 
presentation of this type of antigen, as it involves the first mucosa that all 
antigens encounter when they enter the body through the respiratory and 
digestive systems. An extremely important component of the immune 
system, Waldeyer’s tonsillar ring, is located in the orocervical 
region.15, 19, 24 
• This preparation is administered as a spray in order to achieve a better 
dispersion over a large surface of the sublingual mucosa, thus allowing an 
improved uptake of the bacteria by the cells of the immune system. 

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• Given that it is administered as a spray, the patient has a lower sensation 
of deposited volume than if it were administered in the form of drops. In 
addition to increasing the area of the contact surface, this ensures that the 
subject will maintain contact between the preparation and the mucosa for 
longer. 
• This preparation contains glycerol (50%), which provides greater stability, 
a bacteriostatic effect, and greater adhesion between the product and the 
mucosa. 
• This preparation contains a pineapple flavoring agent that, together with 
the sweet taste of glycerol, helps to increase adherence and improved use 
of the preparation. 
The main benefit offered by this therapeutic vaccination is the achievement of an 
adequate level of immunization against germs against which the subject's body is 
unable to defend itself effectively, which consequently causes recurrent infectious 
processes, usually focal or in areas limited to specific systems or organs, without 
achieving an adequate spontaneous immunization against them. 
The fundamental advantage of the vaccine derives from its nature. It constitutes a 
preventive method that makes use of the body’s natural and physiological 
mechanisms of anti-infectious defense, without introducing chemical elements that 
are foreign to the body, except for the immunogenic elements (bacterial antigens). It 
offers a second advantage over other immunization systems; that is, it precisely uses 
the germs responsible for the infections that are to be controlled. These germs are 
administered to the subject after their adequate processing and their inactivation. 
 
 

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The main advantages of this preparation can be summarized in the following points: 
▪ An immune response is obtained against the germs that are usually involved in the 
infectious processes that recurrently affect the subject. 
▪ It reduces the overall use of antibiotics due to achieving an improved control of 
the infectious processes (number of cases and severity). 
▪ It reduces the consumption of health resources, including medical actions 
(consultations, emergencies, hospitalizations, etc.), as well as ancillary 
examinations, which can sometimes be uncomfortable or risky, as well as 
repeated blood tests. 
▪ It improves the patient’s clinical condition. 
▪ It confers a social and occupational advantage by reducing absenteeism. 
▪ It is not associated with any added risks. 
▪ It does not preclude the use of other treatments. 
▪ Overall, it is a much cheaper therapy.  
 
 

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3.6. 
Description and Rationale of the Route of Administration, Dosage, and Treatment 
Periods 
3.6.1. 
Description and Rationale of the Route of Administration 
This preparation (inactivated bacteria) is administered sublingually (oral mucosa) and 
initiates its effect on the immune system associated with said mucosa.  
The mucosa that covers the respiratory, digestive, genitourinary, conjunctival, and 
auditory tracts, as well as the exocrine gland ducts, form a functional unit that, 
altogether, covers an area of approximately 300 m2.  
The mucosal immune system has the following basic functions136:  
▪ To protect against pathogenic agents (anti-infectious effect). 
▪ To act as a barrier against the penetration of infectious or immunogenic 
components present in the mucosa into the bloodstream and/or the body (barrier 
effect). 
▪ To have a low reactivity against harmless antigens present on the mucosal surface 
(oral or mucosal tolerance). 
▪ To maintain mucosal homeostasis (immunoregulatory function). 
The basic characteristics of mucosal immunity that differentiate it from systemic 
immunity include:136 
▪ A highly developed innate immunity. 
▪   
 
 

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▪ The 
existence 
of 
characteristic 
populations 
of 
lymphocytes 
and 
monocytes/macrophages in the mucosal compartments that differ from those of 
the peripheral blood in their phenotype and functional characteristics. 
▪ The colonization of the mucosa and the exocrine glands by cells originating in 
lymphoid follicles (migration and settlement of mucosal lymphocytes, forming the 
so-called common mucosal immune system). 
▪ Remote transport of polymeric immunoglobulins through the epithelium 
(secretory immunoglobulins). 
Both the innate and acquired immune systems act in this common mucosal immune 
system,19 where they feature inductive sites of innate immune response and effector 
sites of this response.137 The inductive sites are formed by MALT and local/regional 
lymph nodes (LNs), whereas the effector sites are made up of different histological 
compartments, including the lamina propria of several types of mucosa, the stroma 
of exocrine glands, and the superficial epithelium137 (Figure 2, from 137).  
 
 

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Figure 2. Representation of the mucosal immune system in humans 
Stimulation of the oral mucosa can have an effect on distant mucosa136 by activating 
the effector mechanisms of the innate and acquired immune systems. Figure 2 shows 
the expression of mucosal IgA in response to different routes of administration of the 
cholera toxin B subunit.19 It should be noted that immunostimulation of the nasal 
mucosa is very effective in inducing the immune response in other types of mucosa. 
Oral/sublingual mucosal stimulation is as effective as nasal stimulation.15 The efficacy 
and persistence of the immune response induced by sublingual immunization 
suggests that this route is a very promising alternative to immunization via other 
mucosal routes.18  
The oral cavity harbours different types of mucosal tissue (masticatory, coating, and 
lingual).138 It contains a high density of antigen-presenting cells, mainly Langerhans 
cells,89 that boast a stimulating activity superior to that of the same cells present in 
the epidermis.89 The presence of other antigen-presenting cells such as plasmacytoid 
dendritic cells is very low.138  

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Although the sublingual region exhibits the highest permeability,139 other regions of 
the oral mucosa, such as the vestibular or cheek regions, also show an adequate 
degree of diffusion.139, 140 
 
Figure 3. Production of IgA according to the type of mucosa stimulated (from 19) 
 
 

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There are several bacterial immunomodulators that contain inactivated bacteria, 
bacterial lysates, or cellular components of bacteria. Overall, they generate a 
non-specific stimulation of the innate and adaptive immune systems that affects both 
the cellular and humoral responses, thus offering a new avenue for establishing 
antimicrobial therapies, as they can stimulate the body's defense mechanisms and, 
as a result, prevent certain bacterial, viral, and fungal diseases.107, 141-143 
3.6.2. 
Dosage 
The treatment is presented in a bottle with an integrated spray dispenser that allows 
its contents to be distributed over a large surface. The standard dose is two puffs of 
the spray administered on the sublingual mucosa in the morning, on an empty 
stomach in order to avoid interferences with food. Each puff dispenses approximately 
100 µl of liquid (2 x 108 bacteria). 
In patients diagnosed with severe COPD and who are receiving inhaled maintenance 
corticosteroid therapy (1-0-1), the investigational medicinal product must be 
administered in two sublingual puffs in the morning, on an empty stomach (before 
rinsing out the mouth with water) and two hours before the administration of the 
morning dose of the inhaled corticosteroids. 
3.6.3. 
Treatment Period 
The treatment period will last 12 months per subject. The treatment must be taken 
daily (2 puffs). 
 
 

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3.7. 
Notification stating that this trial will be carried out in accordance with this 
protocol, the Good Clinical Practice Norms and the pertinent regulatory 
requirements. 
This clinical trial will be carried out in accordance with the specifications set forth in 
this protocol and within the ethical and legal framework established by the Spanish 
Agency for Medicines and Medical Devices. Therefore, the following regulations will 
be applicable: 
▪ Spanish Royal Decree 223/2004, of February 6th, regulating clinical trials with 
medicinal products and clarifications on the application of the clinical trial 
regulations as of 1st May 2004 (version no. 6, dated May 2008). 
▪ Spanish Law 29/2006, of July 26th, on the guarantees and rational use of medicinal 
products and medical devices.  
▪ Spanish Order SCO 256/2007, of February 5th, laying down the principles and 
detailed Good Clinical Practice guidelines and the requirements to authorize the 
manufacturing and importation of investigational drugs for human use (Official 
Spanish Gazzette [BOE, Boletín Oficial del Estado] no. 38, of February 13th) and its 
amendment through Order SCO/362/2008, of February 4th (BOE 41, 
February 16th). 
▪ Good Clinical Practice Standards (International Council of Harmonization [ICH] E6: 
Good Clinical Practice: Consolidated Guideline, CPMP/ICH/135/95). 
▪ Spanish Organic Law 15/1999 on the Protection of Personal Data. 
▪ Basic Spanish Law 41/2002, of November 14th, regulating patient autonomy. 
▪ The latest version of the Helsinki Declaration (59th WMA General Assembly, Seoul, 

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October 2008). 
▪ The Oviedo Convention, of 4 April 1997, on human rights and biomedicine, ratified 
in the BOE of October 1999. 
▪ The Eudralex European regulation on medicinal products, volume 10, on clinical 
trials: 
▪ Directive 2001/20/EC of the European Parliament and the Council, of 4 April 2001, 
on the approximation of the laws, regulations, and administrative provisions of 
the Member States relating to the implementation of good clinical practices in the 
conduct of clinical trials with medicinal products for human use, aims to harmonize 
the laws of the Member States of the European Union in this respect.   
▪ Directive 2001/83/EC, as modified by Directive 2003/63/EC.  
▪ Directive 2005/28/EC lays down the principles and detailed GCP guidelines 
regarding investigational medicinal products for human use, as well as the 
requirements for authorizing the manufacture or importation of such medicinal 
products (transposed by ORDER SCO 256/2007, of February 5th). 
▪ Spanish Royal Decree 1276/2011, of September 16th, governing the adaptation of 
regulations to the International Convention on the rights of people with disabilities 
that reforms Article 2.m of Spanish Royal Decree 223/2004 governing clinical trials, 
recognizes that people with disabilities who participate in clinical trials have the 
right to access information in appropriate formats, in accordance with the design 
criteria set out for all, and to have the necessary support in order for them to make 
their own decision, without prejudice to the provisions laid down for cases in 
which the person with a disability is legally incapacitated by a court ruling. 
 
 

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By signing the protocol, the investigator commits to follow the instructions and 
procedures described in this protocol and the principles of Good Clinical Practice. 
3.8. 
Description of the Study Population 
Adult subjects (aged 35 to 85 years) with a clinical diagnosis of moderate or severe 
COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
classification.92 
3.9. 
References to the Literature and Relevant Data for the Trial Providing Background 
Information About the Trial   
It has been suggested that bacteria-derived products can act as non-specific 
immunomodulators by significantly increasing the innate immune response through 
toll-like receptors, the recognition of molecular patterns of bacterial nature, the 
activation of macrophages and the stimulation of their bacterial phagocytic and 
immunomodulatory activity by producing cytokines, and the activation of other 
effectors that might have a more specific reflection on the immune 
response.107, 144, 145 
The bacterial vaccines that have been used thus far to treat recurrent respiratory tract 
infections contain various formulations of bacterial strains, including those that 
commonly infect the upper and lower respiratory tracts. These preparations can 
contain inactivated whole microorganisms, bacterial lysates, or several bacterial cell 
components.107  
There are at least five medicinal products marketed in certain countries of the 
European Union that use bacteria, bacterial lysates, or bacterial fragments as 
immunomodulators in respiratory infections: Ismigen®, Respivax®, Broncho-Vaxom®, 
Ribomunyl®, and Luivac®. 

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The findings of the literature search relating to these products are detailed in the 
Investigator’s Brochure. 
Bactek® is a state-of-the-art bacterial vaccine that differs from other commercially 
available preparations in fundamental aspects that have been defined as crucial for 
the effectiveness of therapeutic immunization, such as its formulation (it uses whole 
inactivated bacteria instead of bacterial lysates and it contains glycerol as a excipient, 
which allows an optimal maintenance of its integrity) and route of administration (it 
is administered via the sublingual mucosa as opposed to the other routes, such as the 
oral, intranasal, and parenteral routes). 
Several studies have recently been carried out on subjects with recurrent respiratory 
infections68, 78, 80, 108, 110, 117-123 and COPD,60, 75, 83, {Bourbeau,2003#14, 84, 87, 113, 124, 125 with 
their results demonstrating the efficacy of bacterial vaccines in reducing infectious 
episodes in these subjects. 
A pilot clinical trial has recently evaluated the effect of the daily administration of 
Bactek®, via the sublingual route and for a total of six months, in the prevention of 
recurrent infections of the upper and lower respiratory tract (RRTIs) in a cohort of 
adult subjects.126 This trial was carried out with a group of subjects with RRTIs to 
assess whether sublingual immunization with a polyvalent bacterial vaccine might 
cause an immunomodulatory effect on the antigen-specific immune response and its 
clinical impact. Seventeen subjects with RRTIs were recruited for this trial. They all 
received a daily administration of a polyvalent bacterial preparation (Bactek®) 
administered sublingually for a total of six months. An immunological assessment was 
performed both at the beginning and at the end of the immunization. These 
immunological determinations included: proliferation of antigen-specific CD3+CD4+ 
and CD3+CD8+ T cells against Bactek® antigens, serum immunoglobulin levels, specific 
antibodies against the pneumococcal polysaccharide and the tetanus toxoid, and 

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lymphocyte subpopulations of B, T, and NK cells. This study has been published in the 
journal Clinical Experimental Immunology127 under the title “Sublingual therapeutic 
immunization with a polyvalent bacterial preparation in subjects with recurrent 
respiratory infections: immunomodulatory effect on antigen-specific CD4+ T cells and 
clinical impact”. 
During the twelve-month period of this study since the start of the therapeutic 
immunization, an impact on clinical control was observed in the form of a significant 
decrease in the incidence of upper and lower respiratory tract infections compared 
with the number of RRTIs that the same subjects had experienced within the twelve 
months preceding the start of this treatment. This cohort of subjects exhibited a 
decrease in the frequency of episodes of RRTIs while receiving treatment with Bactek 
and during the follow-up period compared with the year preceding the start of the 
immunization. 
These clinical data are consistent with observations from another placebo-controlled 
study evaluating the bacterial vaccine in children, which showed that its clinical 
response was more effective in selected subjects who experienced a greater number 
of RRTIs in the year preceding the start of this therapy.110   
The clinical trial with Bactek® demonstrated the existence of an association between 
clinical response and an antigen-specific immune response mediated by CD4+ helper 
T cells.127 A significant increase in the proliferative capacity of CD3+CD4+ T cells 
against Bactek® antigens was observed at 6 months with respect to the baseline 
(P <0.0001), and a significant increase in CD3+ T cells was also observed (P <0.05). No 
significant differences were observed in the serum levels of immunoglobulins, specific 
antibodies, or lymphocyte subpopulations of B, T, and NK cells between the baseline 
and month 6. A significant reduction in the rate of respiratory infections was observed 
in the treated subjects compared with the rate of these infections during the year 

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preceding the start of the immunization therapy (P <0.0001). Hence, the results 
demonstrate that the long-term administration of a polyvalent bacterial preparation 
via the sublingual route in subjects with RRTIs exerts a stimulating effect on the 
immune response of CD4+ T cells against bacterial antigens, which could be associated 
with significant clinical benefits. 
The significant increase in the proliferative capacity of CD3+CD4+ T cells could be one 
of the main immunomodulatory mechanisms at the systemic level induced by 
sublingual vaccination with the polyvalent bacterial preparation (Bactek®). However, 
the specific lymphoproliferative response is not the only immune mechanism that 
might have been modified in subjects by immunization with the bacterial antigens. It 
is possible that the innate immune response was stimulated locally, at the level of the 
different mucosal compartments of the upper and lower respiratory tracts, by 
immunomodulating the fundamental defect of the macrophage-mediated immune 
response against the respiratory bacterial pathogens, as well as that of other T, B, and 
NK-T effectors, thus normalizing the production of pro-inflammatory cytokines in this 
microenvironment.48, 73 Stimulation of the innate response may have also contributed 
to the induction of the potent and sustained antigen-specific cellular immune 
response observed in immunized subjects.48 However, the activation and interaction 
of the immunological effector mechanisms of the specific innate and adaptive systems 
need to be clarified, particularly in the context of their potentially important role in 
therapeutic immunomodulation and observed clinical improvement.110 
An increase in the proliferative capacity of specific CD3+ CD4+ and CD3+CD8+ T cells 
against influenza virus antigens was also observed in this trial after 6 months of 
treatment with Bactek®.12 The fact that the subjects had received the flu vaccine or 
had been infected by the influenza virus at least within the 2 years preceding the start 
of the treatment with Bactek® suggests that the bacterial immunization could have 

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induced an immunostimulatory effect, which, in turn, resulted in the 
immunomodulation of the ongoing cellular immune response against the viral 
antigens.128-132 This could be related to the existence of a dependence on the 
collaborative activity of the CD4+ T cells in increasing the number of antigen-specific 
CD4+ and CD8+ T cells133 and to the observed generation and induction of specific 
CD4+ helper T-cell responses that have been linked to effective immune responses in 
long-term immunization therapies.77, 78, 107 The results of this pilot study suggest that 
the polyvalent bacterial preparation administered sublingually to subjects with RRTIs 
associated with an activation of the specific lymphoproliferative, antigen-specific 
CD4+ T-cell response has a beneficial effect on clinical response. 
Overall, these results are in line with those obtained in other studies that demonstrate 
an association between immunization with polyvalent bacterial preparations and 
clinical improvement of respiratory diseases.83, 108, 113, 124, 134, 135  
The protocol presented for this Clinical Trial is a prospective, randomized, double-
blind, placebo-controlled study involving the use of a bacterial preparation (Bactek®) 
administered sublingually in a vulnerable population with a chronic respiratory tract 
disease (subjects with moderate and severe COPD). In this Clinical Trial we aim to 
prospectively determine whether daily sublingual immunization with Bactek® in 
subjects affected by this disease can generate a clinical benefit by preventing 
infections associated with COPD flare-ups or exacerbations by comparing them with 
a group of subjects receiving a placebo.  
 
 

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We will perform a more thorough evaluation in a specific subgroup to determine 
whether the efficacy of this product in preventing infections is associated with the 
ability of the immunotherapy to induce a robust and sustained, local and systemic, 
innate and specific immune response at the level of the lungs by immunomodulating 
macrophages, specific CD4+ helper T cells, and the pro-inflammatory response.  
Considering the high prevalence and cumulative high cost of the clinical management 
of chronic respiratory infections, as well as the frequent failure of conventional 
therapies, this new form of immunomodulation with bacteria could represent a new 
strategic design that is effective in reducing the cost, frequency, severity, and duration 
of COPD exacerbations. 
 
 
 

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4. 
OBJECTIVE AND PURPOSE OF THE TRIAL 
4.1. 
Primary Objective of the Trial 
▪ The main objective of this trial is to evaluate the efficacy of a bacterial vaccine 
administered sublingually compared to placebo in subjects with moderate and 
severe COPD based on the number of COPD exacerbations.  
▪ Secondary Objectives 
The secondary objective of this trial is to evaluate the impact of the investigational 
medicinal product on the following parameters: 
▪ Severity of the COPD exacerbations. 
▪ Time elapsed between the start of the treatment and the first COPD 
exacerbation. 
▪ Use of drugs (antibiotics, corticosteroids, etc). 
▪ Number of medical consultations due to COPD exacerbations.  
▪ Number of visits to the Emergency Department resulting or not in 
hospitalization. 
▪ Number of hospitalizations due to COPD exacerbations.  
▪ Days of hospitalization due to COPD exacerbations.  
▪ Health-related quality of life, as determined by an adapted version of a specific 
quality of life questionnaire: the COPD Assessment Test (CAT). 
 
 

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▪ Healthcare expenditure resulting from resource consumption during episodes 
of COPD exacerbations occurring during the trial period. 
▪ Variations (change between the baseline level and months 0, 3, 6, and 12, as 
well as in comparison with the placebo) in the following immunological 
parameters in the patients participating in the substudy (N = 60) and/or those 
of the induced sputum study (N = 20) (between month 0 prior to the 
administration of the vaccine and month 12):  
• Specific humoral response (concentration of serum IgG against Bactek® 
bacterial antigens and concentration of IgA in the patients’ saliva and 
induced sputum) against Bactek® antigens. 
• Specific cellular response (specific CD4+ T-cell response in PBMCs) by means 
of a CFSE assay, after stimulation with the bacterial antigens that compose 
Bactek®. 
In a subgroup of patients (n = 20) selected from the group of patients participating 
in the immunological substudy (n = 60), a genetic study consisting in an evaluation 
performed at month (M) 0 (visit 1) and month 12 following the start of the 
vaccination will be performed on samples of induced sputum to study the following: 
• mRNA and miRNA expression profiles in PBMCs. 
• Proteomics using the iTRAQ technique. 
• Phenotypic markers of leukocyte populations. 
• Neutrophil function studies: phagocytosis (Phagotest) and bacteriophage capacity 
of the neutrophils (oxidative burst). 

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• The first subgroup of subjects (N = 60) will be recruited from the HGUGM and 
HCSC hospitals. The subgroup of subjects on which the induced sputum study will 
be performed (N = 20) (selected from the group of 60 subjects described above) 
will be recruited from the HGUGM hospital.  
▪ Safety outcomes 
 
Overall rate, severity, and relationship of any adverse event (AE) per 
administration and patient. 
 
Assessment of local tolerability (tissular reactions in the administration 
site).  
 
Changes in standard laboratory parameters (serum chemistry and 
hematology). 
 
 

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5. 
TRIAL DESIGN 
5.1. 
Description of the Primary and Secondary Outcome 
▪  Primary outcome:  
▪   The primary efficacy outcome is a decrease in the mean number of COPD 
exacerbations. A clinical diagnosis of an exacerbation according to the GOLD 
definition will be considered92; that is, an event occurring throughout the natural 
course of the disease, characterized by a change of acute onset, beyond the daily 
variability, in the patient's dyspnea, cough, and/or expectoration, which may 
require a change in the patient’s usual medication.92, 146 
▪ Secondary outcomes: 
▪   Decrease in the rate of COPD exacerbations per study group at 12 months (end of 
the trial treatment) and 6 months after the trial’s termination (follow-up).  
▪ Decrease in the severity of the COPD exacerbations. The severity of the 
exacerbations will be measured based on the consumption of healthcare 
resources (i.e., visits to the Emergency Department, hospitalizations, or 
consultations), as follows: 
➢ ICU hospitalization: 4 points. 
➢ Standard hospitalization: 3 points. 
➢ Emergency Department visit: 2 points. 
➢ Consultation involving a change in the patient’s usual treatment: 
1 point. 
 
 

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▪ Time elapsed between the start of the treatment and the first COPD exacerbation. 
▪ Use of drugs (antibiotics, corticosteroids, etc). Drug consumption will be scored as 
follows: 
➢ Use of antibiotics: 1 point. 
➢ Use of inhaled corticosteroids: 2 points. 
➢ Use of systemic corticosteroids: 3 points. 
➢ Use of oxygen therapy: 4 points. 
➢ Use of mechanical ventilation: 5 points. 
 
▪ Number of hospitalizations due to COPD exacerbations.  
▪ Days of hospitalization due to COPD exacerbations.  
▪ Number of visits to the Emergency Room.  
▪ Number of unscheduled medical consultations due to COPD exacerbations.  
▪ Health-related quality of life, as determined by an adapted version of the 
specific CAT test. 
▪ Healthcare expenditure resulting from resource consumption during episodes 
of COPD exacerbations occurring during the trial period. 
▪ Variations (change between the baseline level and months 0, 3, 6, and 12, as 
well as in comparison with the placebo) in the following immunological 
parameters in the patients participating in the immunological substudy (N = 60) 
and/or those of the subgroup of the induced sputum study (N = 20) (between 
month 0 prior to the administration of the vaccine and month 12). 

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In the case of patients participating in the IMMUNOLOGICAL SUBSTUDY 
(n = 60), changes in the below parameters will also be assessed during the 
randomization visit (visit 1) and the visits corresponding to months 3, 6, and 12:  
- 
The specific humoral response (concentration of serum IgG against 
Bactek® bacterial antigens and concentration of IgA against Bactek® 
antigens in the patients’ saliva) assessed using the ELISA technique. 
- 
The in vitro proliferative response of specific T cells (CD3+/CD4+ and 
CD3+/CD8+) after stimulation with the bacterial antigens that  
Bactek®comprises , assessed by means of CFSE staining and flow 
cytometry. 
In a subgroup of patients (n = 20) selected from the group of patients participating 
in the immunological substudy (n = 60), the following parameters will also be 
evaluated in samples of induced sputum at month 0 (visit 1) and month 12: 
- 
IgA response to Bactek antigens assessed using ELISA technique. 
- 
Proteomic studies using the iTRAQ technique. 
- 
Genetic micro-RNA profile.  
- 
Phenotypic markers of leukocyte populations. 
- 
Neutrophil 
function 
studies: 
phagocytosis 
(Phagotest) 
and 
bacteriophage capacity of neutrophils (oxidative burst). 
 
 

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▪ Safety outcomes 
 
Overall rate, severity, and relationship of any adverse event per 
administration and patient. 
 
Assessment of local tolerability (tissular reactions in the administration 
site).  
 
Changes in standard laboratory parameters (serum chemistry and 
hematology). 
5.2. Description of the Trial Type/Design 
Prospective, multicenter, randomized, double-blind, parallel, placebo-controlled 
clinical trial. 
Phase II/III.  
Group I - The active group will receive the bacterial vaccine sublingually for 12 
months. 
Group II - The group that will receive placebo sublingually for 12 months. 
 
 

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5.2.1. 
Overview of the Trial Design, Procedures, and stages 
Table 1 
VISIT No. 
Baseline 
1 
2 
3 
4 
5 
6 
Time (months since the start of the vaccination) 
 
0 
3 
6 
12 
15 
18 
Period window 
 
 
±10 
days 
±10 
days 
±10 
days 
±10 
days 
±10 
days 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographic data (including area of residence) 
X 
 
 
 
 
 
 
Vital signs (BP and HR) 
X 
 
 
 
 
 
 
Tobacco consumption (no. of cigarettes/day x no. 
of years/20) 
X 
X 
X 
X 
X 
X 
X 
Medical history/complete examination 
X 
X 
X 
X 
X 
X 
X 
Exhaled CO 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
X 
X 
 
X 
Serum chemistry 
X 
 
 
X 
X 
 
X 
Viral serology testing (HBV, HCV, and HIV) 
X 
 
 
 
X 
 
X 
Complete immunological evaluation 
X 
 
 
X 
X 
 
X 
Immunological substudy (N = 60) 
 
X 
X 
X 
X 
 
X 
Immunological substudy with induced sputum 
(N = 20) 
 
X 
 
 
X 
 
 
Spirometry 
X 
 
 
 
X 
X 
X 
Recording of concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
 
Recording of healthcare resource consumption 
X 
X 
X 
X 
X 
X 
X 
Randomization no. 
 
X 
 
 
 
 
 
No. of days of antibiotic treatment required 
 
X 
X 
X 
X 
X 
X 
Subject’s visual analog scale score 
X 
X 
 
 
X 
X 
X 
Investigator’s visual analog scale score 
X 
X 
 
 
X 
X 
X 
Quality of life questionnaire   
X 
X 
X 
X 
X 
X 
X 
Provision of the patient diary 
 
X 
X 
X 
X 
 
 
Collection of the patient diary 
 
 
X 
X 
X 
 
 
Delivery of the sublingual vaccine 
 
X 
X 
X 
 
 
 
Collection of the sublingual vaccine 
 
 
X 
X 
X 
 
 
Recording of the no. of days of hospitalization 
 
X 
X 
X 
X 
X 
X 
Recording of adverse events 
 
X 
X 
X 
X 
X 
X 
Recording of unscheduled visits 
 
X 
X 
X 
X 
X 
X 
Recording of trial dropout/termination cause 
 
X 
X 
X 
X 
 
 
Comments 
X 
X 
X 
X 
X 
X 
X 
CRF review 
X 
X 
X 
X 
X 
X 
X 

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Abbreviations: BP = blood pressure. HR = heart rate. CO = carbon monoxide. HBV = hepatitis 
B virus. HCV = hepatitis C virus. CRF = case report form. 
Duration of the Trial 
The trial is scheduled to comprise a 12-month treatment period and a 6-month 
post-immunization follow-up period (18 months total per subject). The trial shall end 
with the trial’s database lock. 
All subjects will start treatment with Bactek vs. placebo in a stable clinical 
condition.  
• 
The subjects shall attend study visits every 3 months and whenever they develop 
symptoms of respiratory infection. 
• 
They must strictly record the number of days of oral or systemic antibiotic 
treatment required until the remission of their ailment (COPD exacerbation). 
• 
The number of days of hospitalization required due to the severity of the clinical 
condition (COPD exacerbation both during and after the immunization [6 
months]) will be strictly recorded until the patient’s clinical symptoms resolve 
and they are discharged home in a stable clinical condition.  
• 
The pre- and post-immunization quality of life will be recorded using the specific 
CAT survey. 
▪ Baseline Visit (prior to the start of the treatment) 
The baseline visit can take place 1-4 weeks before the start of the treatment 
(visit 1), and the following tests will be performed that day (Table 1): 
▪ Informed consent. 

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▪ Inclusion and exclusion criteria. 
▪ Demographic data (including residence data). 
▪ Vital signs (body temperature [BT] and HR). 
▪ Tobacco consumption (no. of cigarettes/day x no. of years/20). 
▪ Medical history/complete examination (description of the abnormality). 
▪ Measured exhaled CO. 
▪ Collection of blood samples to perform the following tests: 
 Hematology 
 Serum chemistry 
 Viral serology testing 
 Immunological assessment  
A blood sample of each patient will be collected during the baseline visit for the 
following:  
- 
Determination of serum levels of IgG, IgA, and IgM. In patients with 
IgG levels <500 mg/dl or IgA levels <6 mg/dl, a determination of the IgG subclasses 
will be performed (nephelometry, Beckmann Coulter, USA) to rule out an 
immunodeficiency. 
- 
Serum concentration of the anti-pneumococcal and anti-tetanus 
toxoid antibodies. An in vivo response study will also be performed in patients with 
low levels of antibodies in order to rule out an immunodeficiency in antibody 

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production. 
▪ Spirometry. 
▪ Recording of concomitant medication. 
▪ Pregnancy test (for women of childbearing age). 
▪ Recording of the consumption of healthcare resources. 
▪ Subject’s visual analog scale score. 
▪ Investigator’s visual analog scale score. 
▪ Quality-of-life questionnaire. 
▪ Comments. 
▪ CRF review. 
▪  “IMMUNOLOGICAL SUBSTUDY”: variations in the below immunological 
parameters will be evaluated in a subgroup of patients (n = 60) during visit 1 
(month 0, prior to the administration of the vaccine) and at months 3, 6, and 
12:  
- 
The specific humoral response (concentration of serum IgG against 
Bactek® bacterial antigens and concentration of IgA against Bactek® 
antigens in the patients’ saliva) assessed using the ELISA technique. 
- 
The in vitro proliferative response of specific T cells (CD3+/CD4+ and 
CD3+/CD8+) after stimulation with the bacterial antigens that 
compose Bactek®, assessed by means of CFSE staining and flow 
cytometry. 

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- 
Phenotypic flow cytometry study of the following PBMCs: CD19+ B, 
CD3+ T, CD4+ T, and CD8+ T lymphocytes; CD56+ NK cells; monocytes 
(CD11b/CD18); and NKT (CD1d and CD161) cells. 
The below parameters will also be evaluated in samples of induced sputum at 
month 0 (visit 1) and month 12 in a subgroup of patients (n = 20) selected from 
the group of patients participating in the immunological substudy (n = 60): 
- 
IgA response to Bactek antigens assessed using ELISA technique. 
- 
Capacity for the intracellular destruction of the previously opsonized 
viable bacteria contained in Bactek®, assessed based on the number 
of colony-forming units after incubation and lysis.  
- 
Concentration of cytokines (TNF, IFN- γ, IL-1α, IL-1ß, IL-2, IL-4, IL-5, 
IL-6, IL-8, IL-10, IL-12, IL-13, MCP-1, MIP-1α, IL-17, and IL-22) in the 
cell-free fluid, assessed using a multiplex system. 
- 
Proteomics using the iTRAQ technique. 
- 
Phenotypic markers of leukocyte populations. 
- 
Neutrophil 
function 
studies: 
phagocytosis 
(Phagotest) 
and 
bacteriophage capacity of neutrophils (oxidative burst). 
▪ Visits During the Trial 
 
First visit (month 0) 
▪ Randomization no. (only during visit 1). 
▪ Tobacco consumption (no. of cigarettes/day x no. of years/20). 
▪ Medical history/complete examination (description of the abnormality). 
▪ Measured exhaled CO. 

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▪ Blood collection for the immunological substudy. 
▪ Induced sputum collection in the case of patients included in the immunological 
substudy subgroup (N = 20). 
▪ Registration of concomitant medication. 
▪ Registration of health resource consumption. 
▪ Recording of the number of days of antibiotic treatment required. 
▪ Subject’s visual analog scale score. 
▪ Investigator’s visual analog scale score. 
▪ Quality-of-life questionnaire. 
▪ Provision of the patient diary. 
▪ Delivery of the sublingual vaccine (visit 1). 
▪ Recording of the no. of days of hospitalization. 
▪ Registration of adverse events. 
▪ Registration of unscheduled visits. 
▪ Recording of trial dropout/termination cause. 
▪ Comments. 
▪ CRF review. 
The schedule of visits and evaluations to be performed during the treatment 
period are detailed in Table 1. 

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▪  Unscheduled visits: 
Trial subjects may attend an unscheduled visit whenever they experience a 
worsening of the disease under study. 
The tests/determinations performed during these visits will be recorded in the 
case report form. 
▪ End of trial visit (see Table 1). 
5.3. 
Description of the Measures Taken to Minimize/Avoid Bias 
5.3.1. 
Randomization 
Randomization will be done in blocks of 6, using a list of random numbers 
(randomization list) generated by the Head of the Clinical Epidemiology and Clinical 
Research Methodology Unit of Health Research Institute Hospital Universitario 
Clínico San Carlos (using Random Software). 
The treatment assignment should always be carried out starting with the lowest 
number and progressing in a correlative way in increasing order. 
5.3.2. 
Blinding 
This is a prospective, multicenter, randomized, double-blind clinical trial comparing a 
treatment group with a placebo group. The ratio between the group receiving active 
treatment (group I) and the group receiving placebo (group II) is 1:1. 
 
 

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5.4. 
Description of the Trial Treatment 
5.4.1. 
Description of the Trial Treatment 
The trial medication consists of an investigational medicinal product and a placebo. 
All patients included in the active group (Bactek®) of this trial will receive the same 
composition of Bactek® (described below). 
▪ Investigational medicinal product: 
Polyvalent bacterial vaccine Bactek® contains different inactivated species 
(109 bacteria/ml) of bacteria that are frequently present in the respiratory 
tract: 
▪ Staphylococcus aureus  
15%  
▪ Staphylococcus epidermidis  
15%  
▪ Streptococcus pneumoniae  
60% (containing a mixture of serotypes 
6B, 19F, 23F, 1, 3, 5, 9V, 14, and 20 in the same proportion) 
▪ Klebsiella pneumoniae 
4%  
▪ Branhamella catarrhalis  
3%  
▪ Haemophilus influenza  
3% 
It contains the following excipients: glycerol (50%), pineapple essence (q.s 1 ml), 
sodium chloride 9 mg/ml, and water for injection (q.s. 1 ml). 
 
 

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▪ Placebo  
Identical solution to that of the investigational medicinal product, but without 
the active ingredient (bacteria). It contains glycerol (50%), pineapple essence 
(q.s. 1 ml), sodium chloride (9 mg/ml), and water for injection (q.s. 1 ml). 
5.4.2. 
Description of the Doses and Dosage Regimen of the Investigational Medicinal 
Product 
The Investigational Medicinal Product must be administered exclusively via the 
sublingual route. The doses shall be administered below the tongue or on the cheeks 
(oral mucosa). The vaccine must be retained at this location, without swallowing it, 
for a total of 2 minutes, and then swallowed. The doses should preferably be 
administered on an empty stomach to avoid interferences with food. 
The first dose shall be administered in the Hospital or Clinic in order to instruct the 
subject on the correct administration of the medication. The rest of the doses will be 
taken by the subject themself at home. 
The established dosage regimen consists of the administration of two daily pulses in 
the sublingual region for a total of 12 months. 
In patients diagnosed with severe COPD and who are receiving inhaled maintenance 
corticosteroid therapy (1-0-1), the investigational medicinal product must be 
administered in two sublingual puffs in the morning, on an empty stomach (before 
rinsing out the mouth with water) and two hours before the administration of the 
morning dose of the inhaled corticosteroids. 
 
 

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5.4.3. 
Description of the Pharmaceutical Form, Packaging, and Labeling of the 
Investigational Medicinal Product 
The Technical Director of Inmunotek, S.L. guarantees the manufacture and adequate 
quality of the Investigational Medicinal Product in accordance with Annex 13 of the 
Good Manufacturing Practices guidelines.  
The Investigational Medicinal Product will be supplied by Inmunotek, S.L. through the 
Hospital Pharmacy Department. The latter shall acknowledge receipt of the 
treatments in writing and be responsible for their correct storage and dispensing. 
Although the Investigational Medicinal Product remains stable at room temperature 
(25 °C), all supplies of this study medication should be stored in a refrigerated 
enclosure (between 2 °C and 8 °C). Access to the medication will be limited to the 
Principal Investigator, authorized members of their department, and the Pharmacy 
and/or nursing department. 
Inmunotek S.L. will store the protocols concerning the manufacture and control of 
the batches of the products manufactured for the clinical trial in the master file, 
retaining samples of each batch up to twelve months after the expiry date. 
The labeling of the samples for the clinical trial shall comply with the provisions of 
Annex 13 of the Good Manufacturing Practice guidelines for medicinal products in 
the European Union. 
▪ The labels on the secondary packaging (box) will include the following information: 
a. Sponsor’s name, address, and telephone number. 
 
 

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b. Pharmaceutical form, route of administration, and number of units.  
c. 
Batch number or code identifying the contents and packaging operation. 
d. Reference code allowing identification of the trial. 
e. Trial subject identification number/treatment number.  
f. 
Investigator’s name (if not included in points a or d). 
g. Instructions for use. 
h. “Exclusively for use in clinical trials”. 
i. 
Storage conditions. 
j. 
Expiry date in a month/year (MM/YYYY) format. 
k. “Keep out of the reach of children”. 
▪ The labels on the primary packaging (bottles) will include the following 
information: 
a. Sponsor’s name: Inmunotek. 
b. Pharmaceutical form, route of administration, and number of units.  
c. Batch number or code identifying the contents and packaging operation. 
d. Reference code allowing identification of the trial. 
 
 

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e. Trial subject identification number/treatment number.  
The investigational medicinal product will be packaged in six boxes, each containing 
2 or 3 bottles of the product, to be dispensed to each trial subject. All bottles contain 
the same concentration of the vaccine. During visit 1, the first box containing 3 bottles 
will be dispensed. During visit 2, boxes 2 and 3, both containing two bottles, will be 
dispensed and box 1 will be collected. During visit 3, boxes 4, 5, and 6, all containing 
2 bottles, will be dispensed and boxes 2 and 3 will be collected. During visit 4, boxes 
4, 5, and 6 will be collected. 
The volume of leftover medicinal product contained within the returned vials will be 
measured to allow for assessing the degree of compliance with the prescribed dosing 
of the trial medication. 
5.5. Expected Duration of the Trial. Description of the Sequence and Duration of the 
Trial Periods, Including Follow-up 
Duration of the recruitment period: approximately 5 years. The recruitment period 
will end on 31/Mar/2018. 
Total trial duration: 7 years (estimated duration). 
The trial will last a total of 18 months per subject.  
All subjects will be administered either the sublingual vaccine or a placebo for 
12 months (52 weeks). The clinical response will be recorded every 3 months up to a 
maximum of 12 months (52 weeks), as well as 3 and 6 months following treatment 
completion (6-month follow-up period without vaccination). 
5.6. Description of the Subject “Termination Criteria” and “Discontinuation Criteria” 
During the Entire Trial or Parts of It 

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The trial shall end with the trial’s database lock. 
Subjects may temporarily discontinue the treatment for 7 to 14 days in any of the 
following cases: 
• Severe or very severe COPD exacerbation. 
Acute exacerbations will be graded according to the following scale: 
1. Mild (home care with or without contact with the subject’s doctor). 
2. Moderate (requiring a visit to the Emergency Department). 
3. Severe (requiring hospitalization). 
4. Very severe (requiring intubation and mechanical ventilation). 
5.7. Investigational Medicinal Product Accounting Procedures 
Both the investigational medicinal product and the placebo will be sent to the 
Hospital's Pharmacy Service following Inmunotek’s receipt of the approval issued by 
both the CREC and the Spanish Agency of Medicines and Medical Devices. 
The trial medication must be dispensed or administered in compliance with the 
procedures described in this document. Only subjects included in the trial may 
receive the trial medication in accordance with all applicable regulatory 
requirements. 
The trial medication must be stored in a secure location until it is delivered to the trial 
subjects. 
The principal investigator, or their designated person, will be responsible for the 
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submitted by Inmunotek. This person will document the amount of medication 
received from Inmunotek, the amount dispensed to the trial subjects, and the 
amount returned by the trial subjects. 
At the end of the trial, both the monitor and the Principal Investigator will create an 
inventory of both the unused medication and the medication returned by the trial 
subjects. This medication will be returned for its destruction to Inmunotek, S.L., as 
sponsor of the trial. 
5.8. Maintenance of the Randomization Codes and Code Unlocking Procedures 
In double-blind trials such as this one, the Investigator has a Code Unlocking 
mechanism available in case of emergency. This Code Unlocking should only be 
performed in case of emergency, whenever the Investigator needs to be aware of the 
identity of the trial drug in order to provide appropriate medical treatment or, when 
necessary, to ensure the safety of the trial participants. Inmunotek, S.L. must be 
informed immediately if a Code Unlock is executed for any subject. The reason for 
this Code Unlock must be documented on the cover or on the appropriate page of 
the CRF, along with the date and acronym of the person who unlocked the code. 
5.9. Identification of any Datum to Be Recorded Directly in the CRFs and to Be 
Considered as an Original Datum 
The visual quality-of-life scales will be completed directly in the CRF both by the 
subjects and the investigator and will be considered as source documents. 
6. Screening and Withdrawal of Trial Subjects 
A total of 180 subjects will be screened from the Pulmonology Services of Hospital 
General Universitario Gregorio Marañón, Hospital Clínico San Carlos of Madrid, 
Hospital Infanta Leonor, Hospital Universitario de Torrejón de Ardoz, Hospital 

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Universitario 12 de Octubre, Hospital Universitario La Paz, and Hospital Universitario 
de Vic. 
These screened subjects will have been diagnosed with moderate or severe COPD. 
6.1. Subject Inclusion Criteria 
Recurrent respiratory infections are usually defined as those that occur at a 
frequency of at least three episodes in one year.79, 147 The Global Strategy for the 
Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary 
Disease92 defines a COPD exacerbation as an event occurring throughout the 
natural course of the disease, characterized by a change of acute onset, beyond 
the daily variability, in the patient’s dyspnea, cough, and/or expectoration, which 
may require a change in the patient’s usual medication.92, 146 
To unify the criteria, a COPD exacerbation will be considered to be recurrent when 
it occurs at a frequency of at least three episodes in one year.79, 92, 146, 147 
In this study we will include subjects who meet the following criteria: 
▪ Subjects who have provided their written informed consent. 
▪ Subjects of both sexes. 
▪ Subjects aged between 35 and 85 years. 
▪ Subjects who are capable of complying with the dosing regimen. 
 
 

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▪ Subjects with a diagnosis of moderate or severe COPD according to the GOLD 
criteria.148 
 Subjects with a predicted post-bronchodilator force expiratory volume in 
the first second (FEV1) <50% (50% - 30%), with or without chronic 
symptoms (e.g., coughing or sputum production).  
▪ Subjects who have experienced at least three moderate exacerbations (i.e., those 
requiring treatment with antibiotics, systemic corticosteroids, or both, as 
prescribed by their general practitioner or pulmonologist in the standard 
consultation and/or the Emergency Department of their Clinic) or two 
exacerbations with at least one requiring hospitalization due to a COPD 
exacerbation and the other one a moderate exacerbation occurred within the last 
year. 
▪ Subjects who have not changed their medication for the maintenance treatment 
of COPD within the past 6 months. 
▪ Subjects with an accumulated consumption of ten or more pack-years. The 
subjects may or may not be active smokers. 
▪ The subjects included in the trial must live in the Autonomous Community of 
Madrid throughout the study period (September to May).  
▪ Subjects included in the trial may have been vaccinated with pneumococcal 
polysaccharide vaccine at least 4 weeks before starting the administration of 
Bactek®. 
▪ Women of childbearing age must use an approved method of contraception (oral, 
vaginal, transdermal, intrauterine device [IUD], etc. or barrier methods) and 
obtain a negative result in the urine pregnancy test performed during the 
screening visit. 
6.2. Subject Exclusion Criteria 

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▪ Subjects outside the allowed age range. 
▪ Subjects who are unable to cooperate and/or have a severe psychiatric disorder. 
▪ Women who are pregnant, breastfeeding, expect to become pregnant during the 
study (including assisted reproduction), or who refuse to use contraceptives 
during the study (including barrier methods). Women who become pregnant 
during the clinical trial will have to discontinue their participation in it. 
▪ Subjects who have participated in a study or clinical trial with an investigational 
product within the 3 months preceding their inclusion in this study. 
▪ Subjects diagnosed with asthma based on the guidelines of the American Thoracic 
Society and the European Respiratory Society. If the investigators are unable to 
differentiate between COPD and asthma after applying the criteria listed in the 
following table, a bronchodilator test with inhaled salbutamol must be performed, 
excluding those subjects with FEV1 changes >400 ml. 
Medical History 
COPD 
ASTHMA 
Smoker or ex-smoker 
Almost all 
Possible 
Onset of symptoms <35 years 
Rare 
Common 
Chronic productive cough 
Common 
Uncommon 
Dyspnea 
Persistent and progressive 
Variable 
Waking up in the middle of the night 
with dyspnea and wheezing noises 
Uncommon 
Common 
Significant 
daytime 
or 
daily 
symptomatology changes 
Uncommon 
Common 
▪ Subjects with a diagnosis other than COPD that causes them to have an unstable 
condition or a life expectancy <3 years. 
 
 

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▪ Subjects who experienced a COPD exacerbation within 4 weeks prior to the start 
of the trial. 
▪ Subjects with moderate COPD who required treatment with inhaled 
corticosteroids in the last 4 weeks. 
▪ Subjects with moderate COPD who received systemic corticosteroids (orally, 
intramuscularly, or intravenously) in the last 4 weeks. 
▪ Subjects diagnosed with a Primary (European Society for Immunodeficiencies 
[ESID] guidelines) or Secondary Immunodeficiency within the 12 months 
preceding their inclusion in the clinical trial or the trial’s baseline visit. 
▪ Subjects diagnosed with a chronic lymphoproliferative disease.  
▪ Subjects diagnosed with a chronic infectious disease (tuberculosis [TB], HCV, HIV, 
or HBV). 
▪ Subjects with chronic heart disease, arrhythmias, or episodes of arrhythmia 
secondary to the use of bronchodilators. 
▪ Subjects diagnosed with COPD and chronic colonization by Pseudomonas 
aeruginosa. 
▪ Subjects with COPD and bronchiectasis diagnosed by CT imaging before the age 
of 40. 
▪ Subjects diagnosed with very severe COPD according to the GOLD classification. 
▪ Subjects requiring home oxygen therapy or non-invasive mechanical ventilation. 
▪ Subjects with a history of hypersensitivity to any of the vaccine’s components. 
▪ Subjects 
receiving 
immunosuppressive 
treatment 
with: 
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methotrexate, ciclosporin, cyclophosphamide, tacrolimus, antimalarial drugs, or 
gold salts. 
▪ Subjects who have been treated with monoclonal antibodies such as rituximab or 
TNF-alpha inhibitors in the last 6 months. 
▪ Subjects receiving chronic treatment with azithromycin or inhaled antibiotics 
(tobramycin or colistin). 
6.3. Subject Withdrawal Criteria and Procedures 
6.3.1. 
When and How to Withdraw Subjects from the Trial/Investigational Product 
Any subject who has signed the informed consent and been assigned a randomization 
number will be considered a participant in the trial. 
In the Informed Consent form, the subjects will be informed that they have the right 
to abandon the trial at any time without having to give any explanation and without 
any prejudice to them. This case will be considered as a voluntary dropout. In this 
event, the investigator must determine which of the following reasons is the main 
cause of such dropout: 
▪ Any adverse event for which the investigator would not have deemed it necessary 
for the patient to abandon the trial. 
▪ A concomitant disease. 
▪ Withdrawal of the consent. 
▪ Other causes. 

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Subjects who are withdrawn from the trial at the Investigator’s discretion will be 
considered withdrawals. A withdrawal from the trial may be caused by any of the 
following circumstances: 
▪ Treatment with a forbidden medication, as defined in this protocol. 
▪ Deviation from the protocol, violation of the inclusion/exclusion criteria, or 
deviation from the treatment plan specified in this protocol (e.g., incorrect 
administration of the study medication or failure to attend the trial assessments). 
▪ Pregnancy. 
▪ If the Investigator deems that the subject’s continued participation in the trial 
could be detrimental to their well-being. 
▪ Intolerable adverse events at the investigator’s and/or the subject’s discretion. 
▪ Poor compliance with the protocol or lack of treatment adherence. 
The cause of the subject's dropout or withdrawal from the trial and the date on which 
it took place will be recorded in the CRF and the subject’s medical record. In the event 
that the investigator recorded more than one cause for such dropout or withdrawal, 
they shall indicate which one was the main cause.  
All cases of trial dropout caused by an adverse event shall be immediately notified to 
Inmunotek S.L, as the trial sponsor. 
Any subject who drops out or is withdrawn from the trial before receiving the 
investigational medicinal product or the placebo will be considered a “screening 
failure”. 
6.3.2. 
Type of Data that will be Collected from the Withdrawn Subjects 

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All subjects who abandon the trial, regardless the cause, will be included in the 
statistical evaluation of the trial results, and the total number of withdrawals, the 
different causes of such withdrawals, and the moment they occurred in relation to 
the trial period must be recorded in detail. 
No data will be collected for the statistical analysis from subjects considered to be 
screening failures. 
6.3.3. 
Whether and How Subjects are to be Replaced 
For the purposes of assessing the efficacy of the treatments under study, subjects 
whose cause of withdrawal is not related to any aspect of this trial (disease, 
medication, etc.) and whose withdrawal occurs before the expected six-month 
assessment, must be replaced. 
6.3.4. 
Follow-up of Dropouts/Withdrawn Subjects 
No follow-up will be carried out in the event of voluntary dropouts. 
If the withdrawal is due to pregnancy, the subject will be followed to evaluate the 
outcome of the pregnancy (also including its early termination), and information 
about the mother's and child's condition will be sent to Inmunotek, S.L. The child will 
be followed for up to eight weeks after the delivery. 
All cases of trial dropout caused by an adverse event shall be immediately notified to 
Inmunotek S.L, as the trial sponsor, who will follow the event according to the current 
legal regulations. 
 
 

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7. TREATMENT OF SUBJECTS 
7.1. 
Treatment to be Administered, Including the Name of All Products and Doses 
7.1.1. 
Treatments and Doses to be Administered 
This trial will be performed with two parallel groups in a 1:1 ratio. Each group will 
receive one type of treatment. 
Group I will receive an active treatment consisting of a bacterial vaccine administered 
sublingually. 
Group II will receive a placebo as treatment. 
7.1.2. 
Treatment Administration Schedule 
The first dose of the treatment will be administered in the Hospital or the Clinic during 
visit one of the trial. The rest of the doses will be administered by the subject themself 
at home. The treatment will last 12 months per subject. 
The treatment will consist in a total of 13 bottles that will be dispensed to each trial 
subject: 
The investigational medicinal product will be provided in six boxes, each containing 
2 or 3 bottles of the product, to be dispensed to each trial subject. All bottles contain 
the same concentration of the vaccine. 
During visit 1, the first box containing 3 bottles will be dispensed. 
During visit 2, boxes 2 and 3, both containing two bottles, will be dispensed and box 
1 will be collected. 

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During visit 3, boxes 4, 5, and 6, all containing 2 bottles, will be dispensed and boxes 
2 and 3 will be collected. 
During visit 4, boxes 4, 5, and 6 will be collected. 
7.1.3. 
Route/Mode of Administration of the Treatments to be Administered 
The trial medication must be administered exclusively via the oral route 
(sublingually). The doses shall be administered below the tongue or on the cheeks. 
The vaccine must be held at this location, without swallowing it, for a total of 
2 minutes, and then swallowed. The doses should preferably be administered on an 
empty stomach. 
The first dose shall be administered in the Hospital or the Clinic in order to instruct 
the subject on the correct administration of the medication. The rest of the doses will 
be administered by the subject themself at home. 
7.1.4. 
Treatment Periods, Including the Follow-up Period  
The treatment and follow-up periods will jointly last 18 months (12 months of 
treatment and 6 months of post-vaccination follow-up without Bactek®). 
7.2. 
 Medication/Treatments Permitted (Including Rescue Medication) and Not 
Permitted Before and/or During the Trial 
Permitted medication: 
• 
All investigators agree to follow the COPD treatment guidelines as recommended by 
the GOLD143 and that all subjects will be treated in the same way.  
• Annual flu vaccine. 

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• Pneumococcal polysaccharide vaccine (>4 weeks before starting treatment with 
Bactek®). 
7.3. 
Procedures for Monitoring Subject Compliance 
The first sublingual dose will be administered in the Hospital, whereas the rest of the doses 
will be administered in the subjects’ home. 
In order to monitor treatment compliance, the subjects must: 
▪ Complete and submit the medication log sheets provided to them. 
▪ Attend the visits scheduled both for assessments and to dispense and collect the 
corresponding medication. 
▪ Return the medication that they received during the previous visit.  
To evaluate the degree of compliance with the prescribed dosing of the trial medication, 
the sponsor (Inmunotek, S.L.) will measure the volume of medication leftover in the vials 
that it will receive during each scheduled visit. 
 
 

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8. EFFICACY ASSESSMENT 
8.1. 
Specification of Efficacy Parameters 
▪ Primary outcome: the number of COPD exacerbations due to infectious episodes 
diagnosed by the clinician in charge. 
▪ Secondary outcomes: 
▪ Rate of COPD exacerbations per patient included in the study. 
▪ Decrease in the severity of the COPD exacerbations.  
▪ Time elapsed between the start of the treatment and the first COPD 
exacerbation.  
▪ Use of drugs (antibiotics, corticosteroids, etc). 
▪ Number of medical consultations due to COPD exacerbations.  
▪ Number of hospitalizations due to COPD exacerbations.  
▪ Days of hospitalization due to COPD exacerbations.  
▪ Number of visits to the Emergency Department resulting or not in 
hospitalization. 
▪ Health-related quality of life, as determined by an adapted version of the 
specific CAT test. 
▪ Ratio between the number of COPD exacerbations and the healthcare 
expenditure resulting from resource consumption during episodes of COPD 
exacerbations occurring during the trial period. 
 
 

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▪ Variations (change between the baseline level and months 0, 3, 6, and 12, as 
well as in comparison with the placebo) in the immunological parameters 
described in page 63. 
▪ Safety outcomes: 
 
Overall rate, severity, and relationship of any adverse event per 
administration and patient. 
 
Assessment of local tolerability (tissular reactions in the administration 
site).  
 
Changes in standard laboratory parameters (serum chemistry and 
hematology). 
8.2. 
Methods Used to Assess, Record, and Analyze the Efficacy Parameters 
From the beginning of the trial, the subjects shall attend five scheduled visits (baseline visit, 
three follow-up visits, and the end of trial visit) with the study physician and unscheduled 
visits whenever their clinical condition warrants it. 
During the baseline visit, the study doctor will conduct a detailed clinical interview during 
which the following will be recorded and performed: 
- Screening of patients meeting the inclusion criteria. 
- Signing of the informed consent form by the patient and the investigator. 
- Collection of demographic data and ensuring that the patient will reside in the 
Autonomous Community of Madrid throughout the study period (September to May). 
- Measurement and recording of vital signs (BP and HR). 
- Collection of tobacco consumption data using the following formula: no. of cigarettes/day 
x no. of years/20 (baseline visit and visits 1, 2, 3, and 4). 

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- Testing for exhaled CO  measure (all visits). 
- Detailed medical history and general examination of the patient will be conducted, 
recording the data in the CRF (baseline visit and visits 1, 2, 3, and 4). 
- Female subjects included in the study must provide a urine sample (first morning void) on 
which a pregnancy test will be performed based on a qualitative one-step chromatographic 
immunoassay (Acon) determining the presence of beta-human chorionic gonadotropin 
(beta-HCG). Subjects with a positive pregnancy test will not be included in the trial. 
- Collection of blood from each subject (baseline visit, month 6, month 12, and end of trial 
visit at month 18) and analysis of the following parameters: 
• Complete blood count (flow cytometry). 
• Blood biochemistry, including basal blood glucose levels and liver 
function tests (enzymatic methods). 
• Viral serology testing: HCV, HBV, and HIV (ELISA serology). 
• General immunological parameters. 
- All patients included in this trial will undergo a spirometry test during the baseline and 
end of trial visits (visits 4, at 12, 15, and 18 months from the start of the vaccination). 
Spirometry testing will be performed using the spirometer according to the protocol of the 
Respiratory Function Tests Unit of all hospitals participating in the trial. 
 
 

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- Any concomitant medication will be recorded in the CRF during all visits. 
- The healthcare resources consumption will be recorded during all visits using the CRF. 
- The number of days of antibiotic treatment required will be recorded during visits 1-4 
using the CRF. 
- A visual analog scale will be scored by the subjects during all visits and the result will be 
recorded in the CRF. 
- A visual analog scale will be scored by the investigator during all visits and the result will 
be recorded in the CRF. 
- The CAT Quality-of-Life Questionnaire will be completed during all visits. 
- The Patient Diary will be provided during visits 1-4.  
- The Patient Diary will be collected during visits 2-4. 
- The sublingual vaccine will be dispensed during visits 1-3. 
- The sublingual vaccine will be collected during visits 2-4. 
- The number of days of hospitalization due to a COPD exacerbation will be recorded during 
visits 1-4.  
- The CRF will be used for this purpose. 
- The adverse events occurred during the trial will be recorded during visits 1-4. The CRF 
will be used for this purpose. 
 
 

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- Any unscheduled visit required due to COPD exacerbations will be recorded during visits 
1-4.  
- The CRF and CRF of unscheduled visits will be used for this purpose. 
- The patients who dropped out from the trial during its course and the cause for the 
dropout will be recorded during visits 1-4. The CRF will be used for this purpose. 
- Any observation deemed appropriate about any aspect of the trial will be recorded in the 
CRF during all visits. 
- The trial monitor will review the CRF during all visits. 
9. SAFETY ASSESSMENT 
9.1. 
Specification of Safety Parameters 
All adverse events occurring during the course of the trial shall be recorded and assessed 
in order to evaluate the safety. They will be analyzed thoroughly, both during scheduled 
controls and whenever a subject notifies an abnormal incident. Exacerbations of COPD will 
not be considered Adverse Events because they constitute events that are to be expected 
within the course of the disease and their quantification is the primary objective of this 
trial. 
Adverse events spontaneously manifested by a subject throughout the entire trial should 
also be recorded, always avoiding questions that might guide the subject’s response. 
 
 

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Severity Assessment Definitions: 
Mild:  
Transient symptoms that do not affect the subject’s daily activities. 
Moderate: 
Evident symptoms that have a moderate impact on the subject’s daily 
activities. 
Severe:  
Symptoms that have a considerable impact on the subject’s daily 
activities.  
All adverse events, both severe and non-severe, will be recorded in the corresponding 
section of the case report form. 
 
Causal Relationship with the Investigational Medicinal Product 
Probable: 
There are sufficient reasons and documentation to assume the 
existence of a causal relationship. 
Possible:  
A causal relationship is conceivable and cannot be ruled out. 
Unlikely: 
The event is most likely related to an etiology other than the 
investigational medicinal product. 
9.2. 
Methods and Schedule Used to Assess, Record, and Analyze the Safety Parameters 
Definitions: 
• 
Adverse Event (AE): any untoward health occurrence in a Subject or a clinical 
trial subject treated with a medication and which does not necessarily have a 
causal relationship with the treatment. Exacerbations of COPD will not be 
considered Adverse Events because they constitute events that are to be 
expected within the course of the disease and their quantification is the primary 
objective of this trial. 
• 
Adverse Reaction (AR):  any unintended and harmful response to an 
investigational medicinal product, regardless of the dose administered. 

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• 
Serious Adverse Event (SAE): 
Any adverse event that, at any dose: 
- Leads to death. 
- Is life-threatening for the subject (term “life-threatening” included in the 
definition of SAE refers to the fact that the Subject is at a risk of dying as a result 
of the event but not that, had the event been more intense, it could have 
caused the Subject's death). 
- Results in the hospitalization or prolongation of an existing hospitalization. 
- Causes a permanent or significant disability or incapacity. 
- Results in a congenital anomaly or birth defect. 
- Involves the transmission of any infectious agent (through the medicinal 
product). 
The investigator shall rely on their own medical judgment to determine whether 
an Adverse Event is serious in other situations. Major medical events that, 
despite not posing an immediate risk of death or not resulting in death or 
hospitalization, may endanger the subject or require intervention to prevent one 
of the other outcomes listed in the above definition, should also be considered 
serious. 
• 
Suspected Unexpected Serious Adverse Reaction (SUSAR): an adverse reaction 
whose nature or seriousness is not consistent with the product information (e.g., 
the investigator's brochure in the case of an investigational medicinal product 
not authorized for marketing or a summary of product characteristics in the case 
of an authorized medicinal product). 
Adverse reactions can be classified into: 
 
 

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• 
Local reactions 
Those appearing in the administration site. They may manifest as a mild burning, 
swelling, or itchy sensation in the oropharyngeal region. Gastrointestinal 
discomfort may develop in some cases. The onset of local reactions does not 
imply that the dosing schedule should be discontinued or changed. Their 
presence should be carefully assessed. 
• 
Systemic reactions 
Those appearing in parts of the body other than the administration site. The 
severity of these adverse reactions shall be scored according to the following 
grading system149: 
Grade 1: Transient, mild systemic reaction or mild discomfort (<48 hours) not 
requiring medical intervention nor therapy. 
Grade 2: Moderate systemic reaction leading to a moderate limitation in the 
subject’s activity and requiring barely any medical intervention or 
therapy. 
Grade 3: Severe systemic reaction leading to a severe limitation in the subject’s 
activity and requiring some sort of medical therapy/care, and, 
potentially, hospitalization. 
Grade 4: Life-threatening reaction leading to an extreme limitation in the 
subject’s activity and requiring medical therapy and intervention and, 
probably, hospitalization or palliative care. 
 
 

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Adverse events, broken down by severity and intensity, will be summarized using the 
MedDRA dictionary, by treatment group, system organ class, and preferred term, 
indicating the number of subjects per treatment group, the number and frequency 
of subjects reporting the event, and the number of events. 
9.3. 
Procedures for Recording and Reporting Adverse Events and Intercurrent Diseases, 
and for Submitting their Reports 
All events meeting the definition of an adverse event should be collected and 
recorded between the start of the first trial-related activity (after the subject’s 
signature of the informed consent) and the end of the post-treatment follow-up 
period required by the protocol. Subjects will be questioned whether they noticed 
any adverse event during each visit to the site. All adverse events, whether observed 
by the investigator or reported by a subject, should be recorded in the corresponding 
section of the case report form and evaluated by the investigator. 
The minimum information to be specified shall be the description, severity, duration, 
temporal sequence, and method of detection of the adverse event. The treatment 
administered to manage the event must also be specified. 
The investigator shall immediately report all serious adverse events and/or suspected 
unexpected serious adverse events (SUSARs), regardless of their relation to the 
investigational medicinal product, by telephone (607 600 638) or fax (916 639 732), 
to the staff of Inmunotek’s Medical Department (always within the first 24 hours of 
their onset). The initial and follow-up reports shall identify the trial subjects by a 
unique identification code assigned to each one of them. 
 
 

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The regulations in force will be followed when issuing the safety information notification 
to the Health Authorities, the Research Ethics Committees, and the investigators. 
If a suspected unexpected serious adverse reaction occurs within the context of a 
double-blind clinical trial, the treatment code of the particular subject must be disclosed 
for reporting purposes. Whenever possible, blinding should be maintained for the 
investigator and the persons responsible for the analysis and interpretation of the results, 
as well as for drafting the study conclusions. 
9.4. 
Type and Duration of the Follow-up of Subjects After an Adverse Event 
9.4.1. 
Follow-Up of Non-Serious AEs 
All non-serious adverse events of severe intensity and possibly or probably related to the 
investigational product should be followed until the subject has recovered and all concerns 
have been resolved. 
Cases of chronic conditions: 
No follow-up is required until the “recovered” status is reached. Once the subject has 
completed the trial, these cases may be closed with a result category of “recovering” or 
“not recovered”.  
All other non-serious AEs must be followed until the outcome of the event is “recovering” 
(for chronic conditions) or “recovered”, or until the end of the post-treatment follow-up 
period set out in the protocol, whichever comes first, and until all concerns related to the 
AEs have been resolved. 
 
 

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9.4.2. 
Follow-Up of Serious AEs 
All adverse events classified as serious (SAEs) must be followed until the outcome of the 
event is “recovered”, “recovered with sequelae”, or “death”, and until all concerns have 
been resolved. 
The investigator must send the SAE follow-up information to Inmunotek, S.L., as the trial 
sponsor, within 5 days of obtaining the follow-up information. 
10. 
STATISTICS 
10.1. 
Description of the Statistical Methods to be Used, Including the Schedule of any 
Planned Interim Analysis 
The study analysis will be performed after the database lock. The intention-to-treat (ITT) 
population will be composed of subjects who took at least one dose of the trial medication. 
The analysis will be performed on both the ITT and per-protocol populations. 
The randomization will be evaluated by comparing the baseline variables (month 0) in both 
study groups according to the Consolidated Standards of Reporting Trials (CONSORT) due 
to their clinical relevance. Qualitative variables will be reported together with their 
frequency distribution, and quantitative variables will be reported together with their 
mean and standard deviation, or, in case of asymmetry, with their median and interquartile 
range. If confounding is detected, the effects will be adjusted with the potentially 
confounding variables using the appropriate model adjustments. 
The following variables will be analyzed to determine whether they follow a normal 
distribution: number of exacerbations, duration of the episodes, need for antibiotic 
therapy, number of hospital admissions, duration of the hospital admissions, 
immunological outcomes described in the trial design (page 67), quality of life, and direct 
costs.   

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These variables will be described together with their mean and standard deviation, or, in 
case of asymmetry, with their median and interquartile range. Differences between the 
means will be analyzed using Student’s T test in the case of variables with a normal 
distribution and Mood’s median test in the case of variables without a normal distribution. 
The absolute effect (difference in estimators) and its precision will be estimated with a 95% 
confidence interval (CI) in all cases. 
The rate of exacerbations per patient and the severity of these exacerbations will be 
compared using the chi-square test or Fisher’s exact test. The relative risks will be 
estimated together with their 95% CI. The number needed to treat (NNT) or number of 
events prevented per treatment will be estimated. 
The rate of episodes occurred over time will be calculated, and the hazards ratio (HR) will 
be estimated together with its 95% CI following a Cox proportional-hazards model. The NNT 
(number of patients that need to be treated to avoid an event) will also be estimated. 
To compare the change in the immunological variables described in the trial design 
(page 67) at 0, 3, 6, 12, and 18 months, an analysis of covariance will be performed, 
estimating the mean difference over time in both study groups. 
The cost-benefit ratios in the study groups will be estimated together with their 95% CI, 
and compared using non-parametric tests. 
The safety variables will be compared using the chi-square test in the case of qualitative 
variables or Student’s T test in the case of quantitative variables whenever they meet 
parametric assumptions, or using non-parametric test in the opposite case. 
The statistical software that will be used is STATA 11. 
 
 

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10.2. 
Number of Anticipated Subjects and Rationale. Calculation Method Used for 
Determining the Sample Size and Data Used for Such Purpose 
The calculation of the sample size is based on the efficacy measured based on the 
decrease in the number of episodes of COPD exacerbations during the 12-month 
treatment period of the trial per subject. 
The ratio of subjects to be distributed among the active treatment and placebo 
groups will be 1:1. 
We estimate that subjects from group I (active treatment with the bacterial vaccine) 
will achieve a 60% decrease in their number of COPD exacerbations compared with a 
30% decrease among those of group II (placebo). With an alpha error of 0.05 and a 
beta error of 0.2, and assuming a dropout rate of 20-25%, the number of subjects to 
be recruited would be 90 per study group, with an overall total of 180 trial subjects. 
10.3. 
Significance Level to be Used 
The significance level for the efficacy assessment will be 0.05 for a type I error (α) and 
0.2 for a type II error (β). 
10.4. 
Trial Termination Criteria 
The trial shall be considered completed when the last recruited subject completes 
the last trial visit. 
10.5. 
Procedures to Justify Missing, Unusual, or False Data  
Prior to the inclusion of the first patient in the trial, the trial monitor will carry out an 
initiation visit to the site. During this visit, trial investigators will receive training on 
Good Clinical Practice standards, procedures specific to the trial protocol, and the 
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The first trial monitoring visit is planned to take place as soon as the first patient has 
been included in the trial. The monitor assigned by Inmunotek, S.L. will regularly visit 
the site during the course of the clinical trial. Each and every one of the trial CRFs are 
expected to be monitored in order to prevent data loss, identify unusual data, and 
detect the presence of false data. 
In the event of missing data, these will be corrected during the database lock with 
the last observation carried forward (LOCF) technique, which involves carrying over 
the last available data to maintain the ITT. 
10.6. 
Procedures for Reporting any Deviation from the Original Statistical Plan 
The regulations in force will be followed when reporting information on any deviation 
from the original statistical plan. 
The final report shall include a description of the deviations from the statistical plan 
that occurred during the course of the trial. 
10.7. 
Selection of Subjects to be Included in the Analysis 
Recruited subjects: subjects signing the informed consent, meeting the selection 
criteria, and assigned a treatment number. 
Safety analysis population: randomized subjects who have taken at least one dose. 
Per-protocol efficacy analysis population: randomized subjects completing the 
50-week efficacy assessment period and adequately complying with the protocol. 
These subjects will be assigned to the actual treatment group.  
Any significant deviation from the treatment schedule will result in an exclusion from 
the “per-protocol” dataset. More detailed information can be found in the Statistical 
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Intention-to-treat analysis population: all randomized subjects who have taken at 
least one dose and have been subjected to the week 25 assessment. These subjects 
will be assigned to the corresponding treatment group. 
The medical history and demographic data will be described in the intention-to-treat 
population per treatment group.  
11. 
DIRECT ACCESS TO THE SOURCE DATA/DOCUMENTS 
Source documents are defined as all original documents, data, and records (e.g., 
medical records, clinical and administrative charts, laboratory reports, subject diaries 
or assessment questionnaires, pharmacy dispensing records, data recorded by 
computerized tools, copies or transcriptions certified after being verified as exact 
copies, x-rays, subject files, and records stored at the pharmacy, laboratories, and the 
medico-technical departments involved in the clinical trial). 
Both the principal investigator and the associate investigators will allow the trial 
monitors to inspect the source documents and case report forms when requested 
throughout the course of the trial. 
The investigator must also enable access to the source data/documents in the 
following cases: 
• 
In the event that Inmunotek wishes to perform an audit of the Clinical Trial. 
 
 

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• 
In the event that the Competent Authorities wish to perform a Clinical Trial 
Inspection as part of the process of confirming the validity of the trial conduct 
and the integrity of the collected data. 
• 
In the event that the CRECs involved wish to check the Trial’s progress. 
During the process of obtaining the subject’s informed consent, the principal 
investigator or associate investigators will request the subject's consent in writing to 
have direct access to their data. The subject’s acceptance to participate in the trial 
also grants their permission to examine, analyze, verify, and reproduce any records 
and medical reports that may be relevant for the trial’s assessment. Any party (e.g., 
national and international Regulatory Authorities, trial monitors, and auditors) 
granted direct access to this information must take all reasonable precautions within 
the limits of the applicable legal requirements to maintain the confidentiality of the 
subjects’ identities and of the information patented by the sponsor. 
12. 
QUALITY CONTROL AND ASSURANCE 
Inmunotek, as the trial sponsor, is responsible for implementing and maintaining the 
trial's quality assurance and control systems through updated Standard Operating 
Procedures and the correct monitoring of the Clinical Trial. 
To ensure the trial’s quality, Inmunotek, through the trial monitor, will verify that: 
• 
The source documents and other trial records are accurate, complete, updated, 
and correctly filed.  
 
 

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• 
The data required by the protocol are accurately reported in the CRFs and are 
consistent with the source data. 
• 
That both the principal investigator and the associate investigators follow the 
approved protocol and amendments, if any. 
• 
That the written informed consent was obtained prior to each subject's 
participation in the trial. 
• 
That the investigator and trial staff are performing the specified trial functions 
as set out in the protocol and have not delegated these functions to 
unauthorized individuals. 
• 
That the investigator is only recruiting subjects who meet the selection criteria. 
• 
That all doses and/or any treatment changes are well documented for each of 
the trial subjects. 
• 
That the adverse events, concomitant treatments, and intercurrent illnesses 
are being reported in the CRFs in accordance with the provisions of the 
protocol. 
• 
That the visits, tests, and examinations that the subjects failed to complete are 
clearly reported as such in the CRFs. 
• 
That all withdrawals and dropouts of the subjects included in the trial are 
reported and justified in the CRFs. 
• 
That all adverse events have been reported appropriately within the time 
frames established by the GCP guidelines, the protocol, the CREC, the sponsor, 
and the applicable legal regulations. 
• 
That the investigator is retaining all essential documents.  
• 
That the investigator has been informed of any deviation from the protocol, the 
Standard Operating Procedures, the Good Clinical Practices guidelines, and the 

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applicable regulations, and that the necessary measures have been applied to 
prevent recurrences of the deviations detected. 
13. ETHICAL ASPECTS RELATED TO THE TRIAL 
All parties involved in this trial undertake to strictly observe the Good Clinical Practice 
guidelines and the ethical considerations set forth by the current Spanish Legislation 
governing clinical trials, as well as the corresponding recommendations derived from 
the European Legislation, as specified in point 3.7 of this protocol. 
To ensure the subjects’ rights, the Principal Investigator or the associate investigators 
will explain the trial’s objectives and requirements, the nature of the medicinal 
product under study, and its possible side effects, in a language understandable to 
the Subject, in the Subject information sheet. The information to be provided 
includes: a description of the trial objectives, the methodology to be used, the type 
of treatment, the benefits that the Subject may obtain from the treatment, the risks 
to which they may be exposed, and the right to withdraw from the trial if they wish 
to do so. 
All subjects must provide their written informed consent before being included in the 
trial. The informed consent forms shall be stored by the investigator in the trial file 
during the course of the trial and thereafter for the time stipulated by the legislation 
in force (at least 15 years). 
The research staff will ensure that the relevant consent form is completed according 
to the subject’s age. 
14. DATA PROCESSING AND FILING 
Inmunotek, S.L. will provide the CRFs that must be fully completed and legible. Any 
omission of data must be justified in all cases. The member of the research team 
responsible for making corrections in the cited forms must write their initials and the 
date on which the correction was made in the location of the amendment. 
 
 

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The investigator shall submit a list with the signature and handwritten initials of each 
of the collaborators authorized to make data entries or changes in the case report 
forms. If any modification is made throughout the course of the study, an updated 
list of authorized signatures must be provided. 
Subject data recorded in the CRFs during the course of the trial must be documented 
in an anonymous manner, exclusively identifying the subject by their assigned 
number. If the subject needs to be identified due to exceptional safety reasons or by 
indication of the Regulatory Authorities, the investigator will be obliged to maintain 
the confidentiality of such information. 
The investigator must retain the original documents for each trial subject comprising 
all demographic and medical information, including laboratory data, and keep a copy 
of the signed informed consent form. All information recorded in the CRFs must be 
traceable to the original documents stored in the subject's file. Data without an 
original written or electronic record will be defined before the start of the trial and 
directly recorded in the CRFs, where they will be documented as original data. 
The investigator must safeguard and maintain the essential documents defined by 
the ICH guidelines, the Good Clinical Practice guidelines, and the local regulations for 
at least 15 years following the trial’s termination or completion. The Subjects’ 
medical records and other original data will be retained for the maximum time 
permitted by the hospital. To this end, the sponsor shall provide the investigator with 
a file, which the investigator must update as often as necessary. 
The investigator's file must be accessible during monitoring visits, and in case of an 
audit and/or inspection. 
Inmunotek, S.L. is responsible for the updated master file of all documentation 
relating to the trial and must keep all this information during the entire shelf life of 
the medicinal product. Any change in the data ownership must be documented. In all 
cases, the documents must be made available to the competent authorities if so 
requested by them. Once the trial period has ended for each subject, the trial monitor 
will collect their case report form, which they will subsequently review, recording any 

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discrepancy, concern, or comment about it in a separate document. The monitor shall 
discuss this list of discrepancies with the investigator in order to correct the 
corresponding data in the case report form. Any corrections resulting from this 
discussion must be made by the authorized research staff. Neither the trial monitor 
nor any delegate of Inmunotek, S.L. is authorized to enter data or make corrections 
in the case report forms. 
Upon completion of this review, the data corresponding to all the subjects included 
in the trial will be computerized, using a double data entry system, for their 
subsequent statistical analysis. Once processed, the original forms will be filed 
together with all relevant trial documentation in the Medical Department of 
Inmunotek, S.L. This file will be clearly identified in case its review or audit is required. 
15. FINANCING AND INSURANCE 
Inmunotek, S.L. has taken out a Civil Liability insurance policy in accordance with the 
current legislation. 
16. PUBLICATION POLICY 
The results or conclusions derived from this trial shall preferably be disclosed in 
scientific publications referencing the corresponding Ethics Committee. The 
anonymity of the subjects participating in the trial shall be maintained at all times.  
 
 

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The partial or full publication or disclosure of the data or conclusions obtained from 
the clinical trial will be performed by mutual agreement between the investigator 
and Inmunotek, S.L. If the Trial Sponsor fails to do so within one year, the 
investigators will be free to publish the results obtained in the trial. 
17. ANNEXES 
N/A 
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preceding is a true and faithful English translation of 
a document submitted to me in Spanish: 
Don 
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