GCP SOP EPRIC 13Oct2017 ______

Confidential Not to be copied Version 5.0 GCP SOP EPRIC 13Oct2017 _________________________________________________________________________________ Effect of Probiotic on Rhinovirus Induced Colds NCT 02679807 13 October 2017 SOP # 200 Form B Version no. 02 Date: 08 December 2014 Page 1 of 40 DuPont – CRIM JB0004 Confidential Not to be copied GCP SOP Effect of Probiotic on Rhinovirus Induced Colds Protocol number: MK EPRIC Sponsor: Danisco Sweeteners Oy Sponsor Address: Active Nutrition Sokeritehtaantie 20 FI-02460 Kantvik, Finland Protocol version number: 5.0 Date of issue: <October 13, 2017> Page 2 of 40 Confidential Not to be copied GCP SOP DECLARATIONS OF SPONSOR AND INVESTIGATORS Declaration of sponsor This clinical study protocol was subject to critical review and has been approved by the sponsors. The information it contains is consistent with: • The current risk-benefit evaluation of the study product • The moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki and the principles of GCP as described in the ICH Harmonized Tripartite Guideline Topic E6: ‘’Guidelines for Good Clinical Practice’’, as well as in the applicable local guidelines. The investigator will be supplied with details of any significant or new findings, including adverse events, relating to treatment with the study product. Declaration of the investigators I confirm that I have read the above protocol. I understand it, and I will work in accordance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki and GCP guidelines. Page 3 of 40 Confidential Not to be copied GCP SOP RESPONSIBLE PERSONNEL Principal Investigator Ronald B. Turner, MD, Department of Pediatrics P.O. Box 800386 University of Virginia School of Medicine Charlottesville, Virginia 22908, [email protected] Telephone: +1-434-243-9864, Fax: +1-434-982-4246 Study Manager / Markus Lehtinen, PhD, R&D Immunoanalyses, Manager, Sokeritehtaantie 20 Sponsor 02460 Kantvik, Finland, [email protected], Telephone: +358 40 1397813, Fax: +358 10 431 5555 Project Manager Liisa Lehtoranta, PhD, Scientist Sokeritehtaantie 20 02460 Kantvik, Finland Telephone: +358 407 667 418 Fax: +358 10 431 5555 [email protected] Study Statistician Teppo Huttunen 4Pharma, Ltd Lemminkäisenkatu 1 FI-20520 TurkuFinland Telephone: +358 40 582 3793 [email protected] Database Manager Jari Turunen 4Pharma, Ltd Lemminkäisenkatu 1 FI-20520 Turku Finland Telephone: +358 44 029 7783 [email protected] Study Monitor Jackie Edwards, RN, MHA, CCRA, Office: 434 985-9890 Mobile: 434 249-2564 Fax: 434 990-5772 [email protected] Page 4 of 40 Confidential Not to be copied GCP SOP PROTOCOL SYNOPSIS Study title Effect of Probiotic on Rhinovirus Induced Colds Study phase II Study objectives To study the effect of probiotic supplementation on common cold illness episodes induced by rhinovirus. Study population Healthy adults, aged 18-60 Inclusion and exclusion INCLUSION CRITERIA AT ENROLLMENT: criteria • Subject must be 18-60 years of age • Subject must read and sign a copy of the approved Consent Form INCLUSION CRITERIA AT DAY -28 • Female subjects must be using an effective birth control method INCLUSION CRITERIA AT CHALLENGE: • Female subjects must be using an effective birth control method • Subject must have a serum neutralizing antibody titer of less than or equal to 1:4 to rhinovirus type 39 EXCLUSION CRITERIA AT ENROLLMENT: EXCLUSION CRITERIA AT DAY –28 • Antibiotic use within 3 months prior to study start • Female subjects with a positive urine pregnancy screen • History of use of probiotics in the preceding two weeks • Current cancer diagnosis or immunosuppressive therapy in the last 6 months Page 5 of 40 Confidential Not to be copied GCP SOP • Any clinically significant abnormalities of the upper respiratory tract • Any clinically significant acute or chronic respiratory illness • Any clinically significant bleeding tendency by history • Hypertension that requires treatment with antihypertensive medications • History of angina or other clinically significant cardiac disease • Any medical condition that in the opinion of the Principal Investigator is cause for exclusion from the study • History of regular use (more than 3 days in 7) of tobacco products within the preceding two weeks • History of drug or alcohol abuse in the 6 months preceding the study EXCLUSION CRITERIA AT CHALLENGE: • Any upper respiratory infection or allergic rhinitis in the two weeks prior to the challenge • Any medical condition that in the opinion of the Principal Investigator is cause for exclusion from the study • Positive pregnancy screen prior to challenge • Use of any anti-inflammatory (steroids or NSAIDs) or cough/cold or allergy preparation in the two weeks prior to the challenge Study design Randomized, double-blinded, placebo-controlled Study product Bifidobacterium animalis subsp. lactis Bl-04 as powder mixed into drink. Response variables and Primary efficacy endpoints • Incidence of clinically defined rhinovirus- • Primary efficacy associated cold episodes Page 6 of 40 Confidential Not to be copied GCP SOP • Secondary efficacy Secondary efficacy • Exploratory endpoints • Duration of illness episodes • Infection rate • Viral load • Proportion shedding the virus Exploratory endpoints • Blood transcriptomics • Fecal, nasal, and throat microbiota • Nasal cytokine response • Cold questionnaire comparison Safety AEs and SAEs will be followed throughout the trial Statistics Sample size A sample size of 95 completed subjects/arm would be expected to detect a reduction in rhinovirus- induced illness of 20% (from 60% to 40%) with 80% power with p = 0.05. α Methdology The primary endpoint, the incidence of rhinovirus- associated illness episodes between the treatment groups will be tested with a chi-square test and logistic regression model. T-test, Mann-Whitney U test, chi-square test and ANOVA will be used for secondary parameters. Descriptive statistics for safety and other variables will be reported. Page 7 of 40 Confidential Not to be copied GCP SOP ABBREVIATIONS ADR Adverse Drug Reaction AE Adverse Event Bl-04 Bifidobacterium animalis subsp. lactis Bl-04 eCRF Electronic Case Report Form CSR Clinical Study Report DMP Data Management Plan DVP Data Validation Plan EIA Enzyme Immunoassay ELISA Enzyme Linked Immunosorbent Assay GCP Good Clinical Practice HLA Human Leukocyte Antigen IB Investigator’s Brochure ICH International Conference on Harmonisation IEC Independent Ethical Committee IP Investigational Product IRB Institutional Review Board ITT Intented To Treat MedDRA Medical Dictionary for Regulatory Activities NSAID Nonsteroidal anti-inflammatory drugs PBMC Peripheral Blood Mononuclear Cells qPCR Quantitative Polymerase Chain Reaction RV Rhinovirus SAE Serious Adverse Event TMF Trial Master File Page 8 of 40 Confidential Not to be copied GCP SOP SCHEDULE OF EVENTS Screening Day Day Day Day Day Day Day Day Day Day Day Day -28 -21 -14 -7 0 1 2 3 4 5 6-14 21- 28 Consent x Review of x x inclusion/exclusion Serum neutralizing x* x x antibody Urine Pregnancy x x Screen for females Start of dietary run-in x period Compliance check/ x x x x resupply Probiotic/placebo x x x x x x x x x x x treatment Assessment of blinding x Nasal swab for x x x microbiomics Throat swab for x x x x x(14) microbiomics Throat swab for culture x x Fecal sample for x microbiomics Blood for transriptomics x x x Nasal lavage for viral x PCR Nasal lavage for IL- x x x x x x x x 8/multiplex Symptom assessment x x x x x x Rhinovirus challenge x Nasal lavage for x x x x x quantitative RV culture Symptom diary x Assessment of Adverse x x x x x x x x x x x Events Assessment of Concomitant x x x x x x x x x x Medications * Volunteers will be screened for neutralizing antibody under an existing screening protocol at the University of Virginia (IRB-HSR #9948). Volunteers who are found to have antibody titers ≤1:4 to the study virus will be invited to consent for participation in the EPRIC study. Only volunteers who were tested more than 12 weeks prior to the screening visit will have serology repeated at this visit. Page 9 of 40 Confidential Not to be copied GCP SOP TABLE OF CONTENTS Contents 1. INTRODUCTION ......................................................................................................................... 13 1.1 BACKGROUND .................................................................................................................................. 13 1.2 STUDY PRODUCT .............................................................................................................................. 14 1.3 SUMMARY OF KNOWN POTENTIAL RISKS AND BENEFITS TO HUMAN SUBJECTS ................................. 14 2 STUDY OBJECTIVES ................................................................................................................. 16 2.1 PURPOSE OF THE TRIAL .................................................................................................................... 16 2.2 OBJECTIVES ..................................................................................................................................... 16 2.2.1 Primary objective ............................................................................................................................ 16 2.2.2 Secondary objectives ......................................................................................................................

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