PROTOCOL NUMBER

PROTOCOL TITLE

Sponsored by:

Version number Version date

Product: Date: Protocol/Amendment No: PROTOCOL TITLE

Protocol number: Drug:

Protocol version: Protocol date: Sponsor:

Monitoring Team’s representative:

Coordinating investigator, address and phone number:

Principal investigator(s), address, phone number(s):

Clinical laboratory(ies):

Product: Date: Protocol/Amendment No: PROTOCOL SIGNATURE SHEET AND ACKNOWLEDGEMENT

I have read this Protocol and agree that it contains all necessary details for carrying out the study described. I understand that it must be reviewed by the Regulatory Agency and Independent Ethics Committee and approved or given favorable opinion before implementation.

The signature of the Principal Investigator and Sponsor or it’s representative below constitute their approval of this protocol and proved the necessary assurances that this study will be conducted according to the Declaration of Helsinki, ICH GCP guidelines and applicable regulatory requirements.

______Investigator’s printed name and signature Date

______Sponsor or sponsor’s representative Date

Product: Date: Protocol/Amendment No: TABLE OF CONTENTS

1. SUMMARY...... 6 2. INTRODUCTION AND RATIONALE...... 7 2.1 Background and epidemiology of targeted disease...... 7 2.2 Name and description of investigational medicinal product(s)...... 7 2.2.1 Summary of findings from nonclinical studies...... 7 2.2.2 Summary of findings from clinical studies...... 7 2.2.3 Summary of known and potential risks and benefits...... 7 2.2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s)...... 7 2.3 Study rationale...... 7 3. OBJECTIVES...... 8 3.1 Primary objective...... 8 3.2 Secondary objective...... 8 3.3 Exploratory objectives...... 8 4. STUDY DESIGN...... 9 4.1 Study description...... 9 4.1.1 Study duration per subject...... 9 4.1.2 Planned number of subjects and sites...... 9 4.2 Study endpoints...... 9 4.3 Study design and schematic diagram...... 9 4.4 Schedule of study assessments...... 9 4.5 Rationale for study design and selection of dose...... 9 5. STUDY POPULATION...... 10 5.1 Subject inclusion criteria...... 10 5.2 Subject exclusion criteria...... 10 5.3 Withdrawal criteria...... 10 5.4 Concomitant medication(s)/treatment(s)...... 10 5.4.1 Permitted concomitant treatments...... 10 5.4.2 Prohibited concomitant treatments...... 10 6. INVESTIGATIONAL MEDICINAL PRODUCT...... 11 6.1 Dosages, dosage modifications, dosage form and method of administration...... 11 6.2 Packaging...... 11 6.3 Labelling...... 11 6.4 Handling and storing requirements...... 11 6.5 Drug accountability...... 11 7. STUDY PROCEDURES AND METHODS...... 12 7.1 Efficacy study variables...... 12 7.1.1 Primary variable...... 12 7.1.2 Secondary variable...... 12 7.1.3 Exploratory Variable...... 12

Product: Date: Protocol/Amendment No: 7.2 Safety study variables...... 12 7.3 Randomisation, blinding and treatment allocation...... 12 7.3.1 Emergency breaking the assigned treatment code...... 12 7.4 Study procedures...... 12 7.4.1 Visits and examinations...... 12 7.4.2 Treatment compliance...... 12 7.5 Withdrawal of individual subjects...... 12 7.6 Replacement of individual subjects after withdrawal...... 12 7.7 Follow-up of subjects withdrawn from treatment...... 12 7.8 Premature termination of the study...... 12 8. SAFETY REPORTING...... 13 8.1 (Serious) Adverse event evaluation and reporting...... 13 8.1.1 Adverse event severity...... 13 8.1.2 Relationship to the study drug or the study procedures...... 13 8.1.3 Serious adverse event...... 14 8.1.4 Suspected Unexpected Serious Adverse Reactions...... 14 8.1.5 Reporting pregnancy...... 14 8.1.6 Follow-up of adverse events...... 14 8.1.7 Annual safety report...... 15 9. STATISTICAL ANALYSIS...... 16 10. ETHICAL CONSIDERATIONS...... 17 10.1 Subject Information and Informed Consent Form...... 17 10.2 Confidentiality...... 17 11. ADMINISTRATIVE ASPECTS AND PUBLICATION...... 17 11.1 Direct access to source data/documents...... 17 11.2 Amendments...... 18 11.3 Annual progress report...... 18 11.4 End of study report...... 18 12. REFERENCES...... 19

Product: Date: Protocol/Amendment No: 1. SUMMARY

Rationale:

Objective:

Study design:

Study population:

Intervention:

Main study variables/endpoints:

Product: Date: Protocol/Amendment No: 2. INTRODUCTION AND RATIONALE 2.1 Background and epidemiology of targeted disease (a)Description of the population to be studied (b)References to literature and data that are relevant to the trial, and that provide background for the trial.

2.2 Name and description of investigational medicinal product(s) Name and description of the investigational product(s).

2.2.1 Summary of findings from nonclinical studies

2.2.2 Summary of findings from clinical studies

2.2.3 Summary of known and potential risks and benefits

2.2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).

2.3 Study rationale

Product: Date: Protocol/Amendment No: 3. OBJECTIVES A detailed description of the objectives and the purpose of the trial.

3.1 Primary objective

3.2 Secondary objective

3.3 Exploratory objectives

Product: Date: Protocol/Amendment No: 4. STUDY DESIGN 4.1 Study description

4.1.1 Study duration per subject The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.

4.1.2 Planned number of subjects and sites

4.2 Study endpoints A specific statement of the primary endpoints and the secondary endpoints,if any, to be measured during the trial.

4.3 Study design and schematic diagram A description of the type/design of trial to be conducted (e.g., double-blind, placebo- controlled, parallel design) and a schematic diagram of trial design, procedures, and stages.

4.4 Schedule of study assessments

4.5 Rationale for study design and selection of dose

Product: Date: Protocol/Amendment No: 5. STUDY POPULATION

5.1 Subject inclusion criteria

5.2 Subject exclusion criteria

5.3 Withdrawal criteria (i.e., terminating investigational product treatment/trial treatment) and procedures specifying: (a) When and how to withdraw subjects from the trial/ investigational product treatment. (b) The type and timing of the data to be collected for withdrawn subjects. (c) Whether and how subjects are to be replaced. (d) The follow-up for subjects withdrawn from investigational produkt treatment/trial treatment.

5.4 Concomitant medication(s)/treatment(s) Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.

5.4.1 Permitted concomitant treatments

5.4.2 Prohibited concomitant treatments

Product: Date: Protocol/Amendment No: 6. INVESTIGATIONAL MEDICINAL PRODUCT

6.1 Dosages, dosage modifications, dosage form and method of administration

6.2 Packaging

6.3 Labelling

6.4 Handling and storing requirements

6.5 Drug accountability Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.

Product: Date: Protocol/Amendment No: 7. STUDY PROCEDURES AND METHODS

7.1 Efficacy study variables

7.1.1 Primary variable

7.1.2 Secondary variable

7.1.3 Exploratory Variable

7.2 Safety study variables

7.3 Randomisation, blinding and treatment allocation

7.3.1 Emergency breaking the assigned treatment code In emergency situations the treating physician, often an investigator, may need to break the treatment code immediately, or as quickly as possible if he/she finds it is in the best interest of the trial subject. Consequently, in order to do so, the investigator must have unrestricted and immediate access to break the treatment code. Breaking the treatment code is usually conducted via code envelopes or electronic systems such as telephone or web based systems such as IVRS and IWRS. If the blinding is prematurely broken, it is the responsibility of the investigator to promptly document and explain any unblinding to the sponsor. Study treatment must be discontinued after emergency unblinding.

7.4 Study procedures

7.4.1 Visits and examinations

7.4.2 Treatment compliance

7.5 Withdrawal of individual subjects

7.6 Replacement of individual subjects after withdrawal

7.7 Follow-up of subjects withdrawn from treatment

7.8 Premature termination of the study

8. SAFETY REPORTING

Product: Date: Protocol/Amendment No: 8.1 (Serious) Adverse event evaluation and reporting

An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. Pre- or post-treatment complications that occur as a result of protocol mandated procedures (e.g., blood draw) during or after screening will be considered an AE. Clinically significant changes in physical examination findings and abnormal objective test findings (e.g., clinical laboratory, vital signs) should also be recorded as AEs.

In the differentiation between medical history and AEs, the following points will be considered: • Conditions that started before signing of the informed consent, and for which no symptoms or treatment are present until signing of either informed consent, are recorded as medical history (e.g., seasonal allergy without acute complaints). • Conditions that started before signing of the informed consent, and for which symptoms or treatment are present after signing of either informed consent, at unchanged intensity, are recorded as medical history (e.g., allergic pollinosis). • Conditions that started or deteriorated after signing of the informed consent will be documented as AEs.

All AEs will be reported from the time a signed and dated ICF is obtained, until completion of the last study-related procedure. The Investigator is responsible for collecting all AEs (both serious and non-serious). All AEs occurring during the clinical investigation must be documented in the source documents and the (e)CRF. AEs will be discussed in the Clinical Study Report (CSR).

8.1.1 Adverse event severity

8.1.2 Relationship to the study drug or the study procedures

8.1.3 Serious adverse event

Product: Date: Protocol/Amendment No: Serious adverse event (SAE) is defined as any adverse experience that meets any of the following criteria:  Results in death.  Is life-threatening.  Requires inpatient hospitalization or prolongation of existing hospitalization.  Results in persistent or significant disability/incapacity. Disability means a substantial disruption of a person’s ability to conduct normal life’s functions.  Is a congenital anomaly/birth defect.  Is another medically important serious event as judged by the Investigator, and is defined as requiring intervention to prevent one of the outcomes listed in the definition above

The Investigator or clinical site personnel should notify the Sponsor or the designated CRO of all SAEs, regardless of relationship to the investigational drug, within 24 hours of clinical site personnel becoming aware of the event.

8.1.4 Suspected Unexpected Serious Adverse Reactions

Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information (as described in the Reference Safety Information, provided in the Investigator’s Brochure).

8.1.5 Reporting pregnancy

Prior to enrollment in the study, female subjects of childbearing potential must be advised of the importance of avoiding pregnancy during the trial and the potential risks associated with an unintentional pregnancy. During the study, female subjects are to be instructed to contact the Investigator immediately if they suspect they might be pregnant. The Sponsor must be contacted immediately and a decision will be made regarding continuation of the pregnant woman in the study based upon the circumstances surrounding the pregnancy. Pregnancy is not reportable as an AE, however, complications may be reportable and will be decided on a case by case basis. A pregnancy form will be utilized to capture all pregnancy-related information until birth of the child.

8.1.6 Follow-up of adverse events AEs will be handled according to common clinical practice. If necessary, in order to obtain additional information to ensure the safety of the subject, additional blood and urine samples may be taken at the Investigator’s discretion. Information relative to other means of investigational diagnostics used in relation to the AE will also be

Product: Date: Protocol/Amendment No: communicated. All AEs occurring at any time during the study (including the follow-up period) will be followed until satisfactory resolution (e.g., value back to baseline value) or stabilisation or until final database lock. In the case of ongoing AEs at the moment of database closure, the data obtained at the moment of database closure will be used in the statistical analysis. The follow-up of the AE will be documented in the source documents and will be described in the final CSR, only if considered relevant by the Investigator.

Any pregnancy must be followed by the investigator until delivery or to the end of pregnancy.

8.1.7 Annual safety report

Development Safety Update Report (DSUR) is intended to serve as an annual report to regulatory authorities. In order to promote a comprehensive analysis and presentation of the safety profile of the investigational drug, a sponsor should prepare a single DSUR with data pertinent to all dosage forms and strengths, all indications, and all patient populations under study with the investigational drug, wherever feasible. If this is not possible (e.g., when the data are not available to the sponsor), an explanation should be provided in the introduction section of the DSUR. If more than one sponsor is involved in drug development, particularly in a co-development or other contractual agreement, a single DSUR can be submitted.

9. STATISTICAL ANALYSIS

(a)A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).

Product: Date: Protocol/Amendment No: (b)The number of subjects planned to be enrolled. In multicenter trials, the number of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.

(c) The level of significance to be used.

(d)Criteria for the termination of the trial.

(e)Procedure for accounting for missing, unused, and spurious data.

(f) Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in the protocol and/or in the final report, as appropriate).

(g)The selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed subjects, all eligible subjects, evaluate-able subjects).

10.ETHICAL CONSIDERATIONS Documented approval from appropriate IRBs/ECs will be obtained for all participating centers/countries prior to study start, according to ICH GCP guidelines, local laws, regulations and organizations. When necessary, an extension, amendment or renewal of the IRBs/ECs approval must be obtained and also forwarded to the Sponsor.

Product: Date: Protocol/Amendment No: 10.1 Subject Information and Informed Consent Form Subject information and ICF will be provided to Investigator sites. Prior to the beginning of the study, the Investigator must have the IRB/EC written approval/favorable opinion of the written ICF and any other written information to be provided to subjects. The written approval of the IRB/EC together with the approved subject information/ICF must be filed in the study files and a copy of the documents must also be provided to the Sponsor by the Investigator site.

Written ICF must be obtained before any study specific procedure takes place. If applicable, a legally authorized representative may provide informed consent on behalf of the subject. Participation in the study and date of ICF given by the subject should be documented appropriately in the subject’s files. A signed copy of the subject ICF will be provided to the subject or subject’s authorized representative.

10.2 Confidentiality

All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. Subject names will not be supplied to the Sponsor. Only the subject number will be recorded in the CRF/eCRF, and if the subject’s name appears on any other document (e.g., pathologist report), it must be obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a computer will be stored in accordance with local data protection laws. Subjects will be informed in writing that representatives of the Sponsor, IRB/EC or Regulatory Authorities may inspect their medical records to verify the information collected and that all personal information made available for an audit or inspection will be handled in strictest confidence and in accordance with local data protection laws. If the results of the study are published, the subject’s identity will remain confidential. The Investigator will maintain a list to enable subjects’ records to be identified.

11.ADMINISTRATIVE ASPECTS AND PUBLICATION

11.1 Direct access to source data/documents Representatives of Regulatory Authorities may conduct inspections of the Investigator study site. The Investigator agrees to provide to representatives of a Regulatory Authority access to records, facilities and personnel for the effective conduct of an inspection. The investigator agrees to allow monitoring, audits, IRB/ERC review and regulatory authority inspection of trial-related documents and procedures and provide for direct access to all trial-related source data and documents.

The investigator must maintain copies of all documentation and records relating to the conduct of the trial in compliance with all applicable legal and regulatory requirements. This documentation includes, but is not limited to, the protocol, worksheets/case report forms, adverse event reports, consent forms, investigator’s curricula vitae, laboratory reference ranges, laboratory certification. By signing this protocol, the investigator agrees that documentation shall be retained until at least 15 years after the termination of trial.

Product: Date: Protocol/Amendment No: 11.2 Amendments A ‘substantial amendment’ is defined as an amendment to the protocol or any other supporting documentation, that is likely to affect to a significant degree: - the safety or physical or mental integrity of the subjects of the trial; - the scientific value of the trial; - the conduct or management of the trial; or - the quality or safety of any intervention used in the trial. All substantial amendments will be notified to the Ethics Committee and to the competent authority. Non-substantial amendments will not be notified to the Ethics Committee and the competent authority, but will be recorded and filed by the sponsor.

11.3 Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the Ethics Committee and competent authority once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments.

11.4 End of study report The sponsor will notify the Ethics Committee and the competent authority of the end of the study within a period of 90 days. The end of the study is defined as the last patient’s last visit. In case the study is ended prematurely, the sponsor will notify the Ethics Committee and the competent authority within 15 days, including the reasons for the premature termination.

Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the Ethics Committee and competent authority.

Product: Date: Protocol/Amendment No: 12.REFERENCES

Product: Date: Protocol/Amendment No: Appendix 1

Product: Date: Protocol/Amendment No: