Feasibility Assessment Cough and Chest Congestion Associated with RTIs

Tuesday, 15 October 2013

Dear Investigator Thank you for recently completing the Confidentiality Agreement (CDA) to participate in the feasibility assessment for a Multicenter phase III study in Brazil. The documents attached include the Feasibility Questionnaire and the draft Study Protocol Synopsis. The planned study recruitment is during the flu season in 2014, with an estimated recruitment period about 2 months. The duration of patient participation in the study will be about 5 days. Study Title: Single Blind, Randomized, Parallel Group, Multicenter Study For The Evaluation Of Efficacy Of Mucinex 1200 mg Daily Versus Mucosolvan 24Hrs 75 mg Daily For 5 Days In The Relief Of Productive Cough And Chest Congestion Associated With Respiratory Tract Infections (RTIs) The study will compare the effectiveness, safety and tolerability between Mucinex and Mucosolvan during a 5 day treatment period. The aim of this assessment is to receive feedback on the available patient population, your recruitment estimates, available site staff and interest and availability for participating in this study. Any comments to the proposed study design as well as its inclusion / and exclusion criteria are appreciated. We would be grateful if you could please review the information below and complete this questionnaire attached. Please return pages 5 to 9 of your completed questionnaire by .......(within two weeks of the above date) to the fax number / email address listed below. If you are interested in participating in this study, however, you cannot meet the deadline, please let me know. If you have any questions or would like additional information please feel free to contact us at any time.

Best regards

Dilza Camanho Medical Monitor RPS do Brasil Servios de Pesquisa Phone: +55 11 3527 4757 Mobile: +55 11 9204 3536 Fax: +55 11 3527 4747 Email: dcamanho@rpsweb.com

Reckitt Benckiser FQ V0.5 07OCT2013

Page 1 of 9

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

Draft Study Outline

Visit 1 (day 1)
Informed Consent application/signature collected Clinical history that emphasizes respiratory system Physical Examination (mainly auscultation of the lungs) Urine pregnancy test (if applicable) Cough and chest congestion rated by Visual Analog Scale (VAS) application Drug dispensed

Visit 2 (day 5 (+1))

Clinical history (new medications or complaints of AEs) Occurrence of adverse events Cough and chest congestion rated by Visual Analog Scale (VAS) application Investigators global assessment and rating of the treatment Withdrawal and accountability of drugs

PRIMARY OBJECTIVE
Reduction from baseline compared to final study visit in patients Visual Analog Scale (VAS) rating of cough severity. The result will be categorized (as Excellent, Very Good, Good, Regular or Bad).

SECONDARY OBJECTIVES
Comparison of the safety and tolerability of Mucinex (extended release) tablets and Mucosolvan 24Hrs capsules. Safety evaluation will be based on any Adverse Event (AE) reported during the Study. The incidence of AEs occurring during treatment. The AEs will be classified according to severity and seriousness. Tolerability evaluation will only consider AEs that were determined to be related to the study drug. Secondary Efficacy Endpoint: Reduction from baseline compared to final study visit of the Investigators VAS rating of abnormal sounds during auscultation of the lungs. The results will be categorized (as Excellent, Very Good, Good, Regular or Bad) Investigator global evaluation of the treatment effects according to a 5-point scale (Excellent, Very good, Good, Regular or Bad). Post Study Evaluation: To evaluate the level of satisfaction of the patients with the usage of the Mucinex tablets

SUBJECTS AND DURATION A total of 400 eligible male and female patients aged 12 to 75 years of age with productive cough and chest congestion associated with RTIs. Each patient will participate in the study for approximately 5 days and the recruitment period will be approximately 2 months (August and September). DRUGS ADMINISTRATION / DOSAGE Medication is to be taken after breakfast and after dinner. - Mucinex (extended release guaifenesin) 600 mg bi-layer tablet, at hour zero (after breakfast) and a second tablet at hour 12 (after dinner) with water beginning on Day 1 (total daily dose = 1200 mg guaifenesin). - Mucosolvan 24Hrs (extended release ambroxol) 75 mg capsule at hour zero (after breakfast) and one placebo capsule matching Mucosolvan 24Hrs capsule at hour 12 (after dinner) with water, beginning on Day 1 (total daily dose = 75 mg ambroxol).

Reckitt Benckiser FQ V0.5 07OCT2013

Page 2 of 9

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

INCLUSION CRITERIA
To be eligible for study entry, all patients must satisfy all of the following criteria at screening. 1 Females of childbearing potential must be using one of the following acceptable birth control methods: a) IUD in place for at least 3 months prior to study; b) Barrier method (condom or diaphragm) with spermicide for at least 7 days prior to screening through 30 days beyond study completion (contraceptives will be provided to patients if needed); c) Stable hormonal contraceptive for at least 3 months prior to study through 30 days beyond completion of study; d) Abstinence (not be sexually active during the study. Patient must sign an assent that if they become active, they will use the barrier method of contraception). The sponsor will make arrangements for contraceptives to be provided. Females of non-childbearing potential should be surgically sterile (bilateral tubal ligation with surgery at least 6 months prior to study, hysterectomy or bilateral oophorectomy at least 3 months prior to study) or postmenopausal >2 years. A pregnancy test must be performed if last menses < 2 years prior to dosing. Men must not father a child during this study or for a period of 1 month after treatment. Good general health as determined by the Principal Investigators (PI) review of medical history and physical examination. Suffering moderate/severe, chesty, productive cough resulting from RTIs. Patient should show severity of the cough AND presence of abnormal respiratory sounds (only rhonchi and wheezing are permissible as assessed by auscultation of the lungs) at visit 1 as moderate/severe according to both VAS measures (VAS score 5 cm). Normally use, and are willing to use, non-prescription cough products to treat their cough. Agree to only use the products provided by the Investigator, during the course of the study. Have a cough that has not lasted longer than 48 hours. In the opinion of the Investigator are motivated and capable of participating in the study and have sufficiently good comprehension to accurately complete the VAS scores. Have read, understood, signed and received a copy of the Informed Consent Form (ICF) prior to initiation of study procedures.

3 4 5 6

7 8 9 10

EXCLUSION CRITERIA
Patients who meet any of the following criteria will be excluded from participating in the study: 1 2 Have any condition that, in the opinion of the Investigator, is cause for exclusion from the study. Are suffering from acute cough with complications (other than RTI ) within 30 days prior to entering the study e.g. chronic sinusitis, otitis media, chronic bronchitis, pneumonia, active allergic rhinitis or severe sore throat associated with excessive phlegm (mucus ) or the presence of crackles or pleural rubs upon auscultation at screening - only rhonchi and wheezing are permissible). Experienced febrile illness > 101F within 7 days prior to Day 1. Have chronic, recurring respiratory signs and symptoms due to conditions such as chronic allergic rhinitis, chronic sinusitis or chronic bronchitis (including acute exacerbations), asthma or wheezing. Have the following uncontrolled conditions: heart disease, thyroid disease, abnormal blood pressure, diabetes, liver or kidney disease, an enlarged prostate gland causing difficulty in urinating or history of anaphylaxis (without associated agent). Consume more than 21 alcoholic beverages per week or 3 alcoholic beverages per day (on average). Have a history of drug abuse within the last 12 months Have been exposed to any investigational drug within 1 month prior to the start of the study or if the patient plans to participate in any other investigational drug study while in this study. Are females less than 3 months post-partum, are currently breast feeding or have a positive urine pregnancy test (for women of child-bearing potential). Have a known hypersensitivity to guaifenesin, ambroxol or any ingredients in the test products. Have had major surgery and/or hospitalization in the last 3 months.
Page 3 of 9

3 4 5

6 7 8 9 10 11

Reckitt Benckiser FQ V0.5 07OCT2013

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

12 13

Have used a substance known to induce the cytochrome P450 enzyme system within the last 30 days. Have taken any of the following prior to enrollment into the study: - cough/RTI treatments (including ayurvedic/homeopathic and home remedies) within 3 days of the planned start day of the study e.g. cough and RTI relief products, decongestants (including menthol lozenges within 8 hours) - Antihistamines within 72 hours - Topical (intra-nasal or inhaled) steroids within 2 weeks - Systemic (oral and/or iv) corticosteroids within 30 days - Injectable (intramuscular) corticosteroids within 90 days. Use of an anti-cholinergic agent (e.g. ipratropium bromide) within 48 hours of enrollment. De-sensitization therapy (immunotherapy) in changing doses within 30 days prior to enrollment. Patients on maintenance immunotherapy are acceptable Use of a leukotriene antagonist within 7 days prior to enrollment. Received treatment with sleeping pills, sedatives, tranquilizers, muscle relaxants, opioids or antidepressants in the 7 days prior to the Day 1 visit, with the exception of chronic medications which had been received at a stable dose for at least the past 1 month Are suffering from a gastric ulcer, peptic ulcer or gastritis.

14 15 16 17

18

Disallowed Medication
The following is a list of concomitant medication restrictions: Have used a substance known to induce the cytochrome P450 enzyme system within the last 30 days. Have taken any of the following prior to enrollment into the study: o cough/RTI treatments (including ayurvedic/homeopathic and home remedies) within 3 days of the planned start date of the study e.g. cough and RTI relief products, decongestants (including menthol lozenges within 8 hours) o Antihistamines within 72 hours o Topical (intra-nasal or inhaled) steroids within 2 weeks o Systemic (oral and/or iv) corticosteroids within 30 days o Injectable (intramuscular) corticosteroids within 90 days Use of an anti-cholinergic agent (e.g. ipratropium bromide) within 48 hours of enrollment De-sensitization therapy (immunotherapy) in changing doses within 30 days prior to enrollment. Patients on maintenance immunotherapy are acceptable. Use of a leukotriene antagonist within 7 days prior to enrollment. Received treatment with sleeping pills, sedatives, tranquilizers, muscle relaxants, opioids or antidepressants in the 7 days prior to the Day 1 visit, with the exception of chronic medications which had been received at a stable dose for at least the past 1 month.

Reckitt Benckiser FQ V0.5 07OCT2013

Page 4 of 9

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

INVESTIGATOR DETAILS FIRST NAME: INSTITUTION: ADDRESS: ADDRESS: STATE / REGION: COUNTRY: SITE SETTING: General Hospital University Hospital TELEPHONE: FAX: ZIP / POSTAL CODE: EMAIL: Specialist Centre Other_________________ LAST NAME:

MEDICAL SPECIALIZATION:

___________________________________

Contact Information concerning clinical trials if different from above: CONTACT NAME: TELEPHONE: YES YES YES NO NO NO

CONTACT EMAIL: FAX: Do you have experience with Industry Sponsored Clinical Trials according to GCP? Do you have experience in clinical studies in RTI (Respiratory Tract Infections)? Do you have experience in studies in other indications?

If YES please state indications____________________________________________________________________

INVESTIGATOR INTEREST If you wish to participate, please specify below: YES, interested as per current study design Comments: YES, interested with modifications (please comment below)

If you do not wish to participate, please specify the reasons below: Lack of suitable patients Competing study at site Disagree with study design No time and/or staff

Other (please comment)________________________________________________________________________

Reckitt Benckiser FQ V0.5 07OCT2013

Page 5 of 9

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

SIGNATURE SECTION Research Pharmaceutical Services, Inc. (RPS) is strongly committed to protecting the privacy of those who entrust us with their personal information. Our employees, and all those who do business with us, trust and expect that we will protect their personal information in accordance with the promises we make. In furtherance of our commitment, RPS has certified to the Safe Harbor Agreement between the United States and the European Union, with respect to personal data processed as part of our Human Resource activities, Clinical Research Activities, Marketing activities, and our customer Information Management activities. Visit our website www.rpsweb.com for further information. By agreeing to the statement below and submitting your information for the purpose of creating a new Investigator profile or updating and existing Investigator profile, you or your authorized representative certifies that the information contained herein is, to the best of your knowledge, true and accurate information. You hereby authorize Research Pharmaceutical Services, Inc., and its affiliates. Visit our website www.rpsweb.com (hereafter, RPS) to obtain data and other information about you from Institutional Review Boards and other third parties who possess information of a similar type to that disclosed herein. My information can be stored electronically by RPS for the purpose of participation in clinical studies and/or feasibility assessments and on awarded projects my personal information can be transferred to the sponsor of the study for the purpose of Site identification during the Pre-Study Visits. Disclosure of such information by RPS to sponsors in no way guarantees my participation in any clinical trial. I understand I can review, edit and delete my record at any time. If applicable, I also understand that my data can be transferred outside of the European Union. In accordance with the international agreement, RPS complies with the provisions of the Safe Harbor exemption when exporting personal information from the European Union to the United States for the purpose of conducting clinical research activities. I understand that Data Protection levels may differ in some countries outside of the European Union and RPS may transfer my data to these countries. However, I understand that RPS will only use and share my personal information in a way that is consistent with the purposes for which the information was collected or subsequently authorized by me.

Agree

Principal Investigator/ Authorized Representative Signature

Disagree

Principal Investigator/ Authorized Representative Signature _________________________________

Please note: This form must be returned with signature of the Principal Investigator or his/her authorized representative. If you sign on behalf of the Principal Investigator, you are confirming that you are his/her authorized representative.

Reckitt Benckiser FQ V0.5 07OCT2013

Page 6 of 9

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

PATIENT POPULATION Please complete

1 How many patients between 12 and 75 years of age with productive cough and chest congestion associated with respiratory tract infections (RTIs), and in which you indicate an expectorant/mucolytic drug do you see per month at your site during the flu season? Please also provide your source of estimate: MEDICAL RECORDS PI ESTIMATE From the patients in question 1, approximately how many of these patients would meet all of the inclusion and none of the exclusion criteria? (see page 3 and 4 of this document) Taking into account responses to the questions 1 to 2 above, your review of the inclusion and exclusion criteria, referral patterns as well as the impact competing studies may have on recruitment (recruitment period planed during the flu season 2014) how many patients do you think you can enrol into the study per month?

patients per month

patients per month 3

patients per month

Based on your experience, what would enable you to enhance recruitment for the study (e.g. any protocol change)?

A. What would be the main reasons for a patient who meets the Inclusion / Exclusion criteria not to enrol on this study?

B. Can you estimate the following for your site? _______% Screen Failure Rate 6 ________% Drop Out Rate YES NO PROBLEM AT SITE
Page 7 of 9

Do you anticipate any problems with the inclusion/exclusion criteria or the study design? If yes please comment in the table below INCLUSION EXCLUSION CRITERIA # OR DESIGN

Reckitt Benckiser FQ V0.5 07OCT2013

PROBLEM EC APPROVAL

REASON

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

What would be the main motivation for patients to participate in this study?

A. With a short two month recruitment period it is important that sites can maximise their recruitment potential, can you work with other doctors/departments/schools/colleges/care homes etc? YES NO Please provide detail as to how you would find patients by referrals:

B. Would advertising help you recruit patients faster What type of advertising would work best for your site? Newspaper Radio Internet Direct Mail

YES

NO Email Other (please specify below)

__________________________________________________________________________________________ 9 In order to select the best months for recruitment, can you please estimate how many patients your site could enroll on a month by month basis? June July August September

10

Have your site conducted industry sponsored clinical studies over the last 5 years? YES NO If YES please provide the information below (provide information for the last 5 years)
Phase of Study Recruitment Period (months) Therapeutic Area / Indication Number of Patients Completed Inpatient / Outpatient Patient Population Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex Similar to this Study Less Complex More Complex
Page 8 of 9

Reckitt Benckiser FQ V0.5 07OCT2013

Number of Patients Enrolled

Feasibility Assessment Cough and Chest Congestion Associated with RTIs

11

In order to participate in the trial, it is important to know if you have sufficient staff to utilise in your department that can assist the patients, dispensing study drug (for this study, study drug should be dispensed by an individual that cannot be the investigator unblinded staff) and input data into the eCRF. How many of the following staff members do you have? Sub Investigators Study Nurses Study Co-ordinator / Data Manager Unblinded staff (pharmacist or nurse who will not be involved in patient assessment) Other staff in support of Clinical Trials

12

For contract finalisation for your site can you please clarify the following Contract required with Would the contract be Principal Investigator Hospital Pharmacy Other__________________

Hospital contract template

RPS contract template

Approximate time taken to finalise the contract at your site ________ weeks. 13 Have you planned to participate in any other trials that could compete for the same patients during the flu season of 2014? Yes No

Thank You Very Much For The Time Spent Completing This Questionnaire PLEASE RETURN PAGES 5 to 9 BY EMAIL OR FAX TO
PLEASE SEND THE COMPLETED QUESTIONNAIRE TO

Dilza Camanho Email: Fax: dcamanho@rpsweb.com +55 11 3527 4747

Reckitt Benckiser FQ V0.5 07OCT2013

Page 9 of 9