NCR 001 Sponsored Therapeutics Discussion

Study participants will receive a 1 week follow up phone call to assess for additional, studyrelated side effects. 8. STUDY SCHEDULE OF EVENTS 8.1 Bolus Administration Informed Consent Eligibility Criteria Height Weight Vital Signs & PO21 x x x x x Medical History Concomitant Medications Urine Pregnancy Exam Serum Chemistry2 Complete blood count with platelets3 Urinalysis Complement Activation Assay4 Coagulation Panel5 Inflammatory Cytokine Assay6 Complete Physical Exam Abbreviated Physical Exam 12-Lead EKG 7 Echocardiogram8,9 Adverse Events10 x x Pre Dose x Injection and Interval Discharge 100μ #1 100μ #2 200μ #1 200μ #2 200μ #3 300μ #1 300μ #2 1 hr post final dose x x x x x x x x us e x on ly Screening x x x x 27 0 Description x x Fo rC R C x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 1. Vital signs and pulse oximetry and are obtained at baseline and between 2-6 minutes after completion of echocardiograms for each dose administration of NCR-001 or Defy and 1 hour after finishing the last dose. 2. Serum chemistry will include sodium, potassium, chloride, bicarbonate, urea, creatinine, calcium, magnesium, phosphate, glucose, total bilirubin, alkaline phosphatase, AST, ALT, LDH, albumin and total protein 3. Complete blood count will include hemoglobin, hematocrit, red cell count, MCV, MCH, MCHC, white cell count with differential count (neutrophils, basophils, eosinophils, lymphocytes and monocytes) and platelet count. 4. SC5b-9 complement activation assay 5. Coagulation panel includes INR, PTT and fibrinogen 6. Inflammatory cytokine assay (GM-CSF, IFNgamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p70), IL-13, MCP-1, TNF-alpha) 7. A 12-lead EKG with calculation of the QTc interval (Fridericia correction) will be performed 10 minutes prior to NCR-001 or Defy dose administration and between 2-6 minutes after completion of echocardiograms for each bolus dose of NCR-001 or Defy NCR-001-1 Clinical Trial Protocol V4 Dated 18 February 2018 CONFIDENTIAL 18 NCR 001 Sponsored Therapeutics Discussion

NCR: Sponsored Therapeutics Protocol: NCR-001-1 A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Date of Visit: _____ / ______ / ______ DD MON YYYY Site #: _______ Subject #: ____________ Subject Initials: _________ Screening Visit PROCEDURES AND EXAMS The following assessments must be completed: • Obtain Informed Consent and Document the process • [Add all procedures here, in bullet format] REMINDER: Only trained personnel who are listed on the Delegation of Responsibilities Log are approved to perform these examinations. Informed Consent Was the informed consent obtained prior to any study related procedures? No Yes Date patient or legally authorized representative signed informed consent: _____ / _______ / ________ DD MON YYYY same as date listed on the header Was a copy of the signed and dated informed provided to the patient? No Yes Was the patient given a chance to ask questions related to the study and were all questions answered to his/her satisfaction? No Yes Please describe method of consenting for this patient: __________________________________________________________________________________________ __________________________________________________________________________________________ __________________________________________________________________________________________ __________________________________________________________________________________________ __________________________________________________________________________________________ __________________________________________________________________________________________ _______________________________________________________ Signature of person conducting Consent Process INCLUSION CRITERIA: a patient must meet the following criteria at screening to be eligible for study: 1 2 Adult subjects 19 years of age or older, male or female Female subjects must no longer have child-bearing potential (>1-year post menopause or surgically sterilized), or must have a negative urine pregnancy test, and be using and continue to use for 30 days after the study a medically effective method of contraception 3 4 Protocol: NCR-001-1 V1.0 Page 1 of 5 Yes NO Yes NO Yes Yes NO NO NCR: Sponsored Therapeutics Protocol: NCR-001-1 A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Date of Visit: _____ / ______ / ______ DD MON YYYY Site #: _______ Subject #: ____________ Subject Initials: _________ Screening Visit EXCLUSION CRITERIA: A patient who meets any of the following criteria at either the screening visit or randomization will be excluded from the study: No No No No No No No No No No No No 1 2 3 4 5 6 7 8 9 10 11 12 ____________________________________________________ Principal Investigator’s Signature Demographic Data Vital Signs Protocol: NCR-001-1 V1.0 Page 2 of 5 _______________ Date YES YES YES YES YES YES YES YES YES YES YES YES NCR: Sponsored Therapeutics Protocol: NCR-001-1 A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Date of Visit: _____ / ______ / ______ DD MON YYYY Site #: _______ Subject #: ____________ Subject Initials: _________ Screening Visit 12-Lead Electrocardiogram: Clinical Laboratory Tests: Medical and Surgical History: MEDICATION HISTORY Current Medication Intake: No Yes (If yes, fill in below) NCR 001 Sponsored Therapeutics Discussion

Protocol: NCR-001-1 V1.0 Page 3 of 5 NCR: Sponsored Therapeutics Protocol: NCR-001-1 A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Date of Visit: _____ / ______ / ______ DD MON YYYY Site #: _______ Subject #: ____________ Subject Initials: _________ Screening Visit _ _/_ _ _/_ _ _ _/_ _ _/_ _ _______________________________________________________ Signature of person collecting medical/surgical history _______________________________________________________ Principal Investigator’s Signature • _______________ Date I have created headers for each element, but the formatting is entirely up to you. • DO research other templates, there’s a ton online • DO think how best to collect this information, sequence, who needs to collect the data, do they need to sign and date the data collected? Protocol: NCR-001-1 V1.0 Page 4 of 5 NCR: Sponsored Therapeutics Protocol: NCR-001-1 A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Date of Visit: _____ / ______ / ______ DD MON YYYY Site #: _______ Subject #: ____________ Subject Initials: _________ Screening Visit Physical Examination (PE) Head, Neck, and Thyroid Normal Abnormal Clinically Significant? Ears, Nose and Throat Normal Abnormal Clinically Significant? Chest Normal Abnormal Clinically Significant? Lungs Normal Abnormal Clinically Significant? Cardiovascular Normal Abnormal Clinically Significant? Lymph Nodes Normal Abnormal Clinically Significant? Abdomen Normal Abnormal Clinically Significant? Skin Normal Abnormal Clinically Significant? Neurologic Normal Abnormal Clinically Significant? Musculoskeletal Normal Abnormal Clinically Significant? Comments: Is Patient eligible? Yes Date of Randomization and Treatment Visit? ____________________________________ No Reason(s) __________________________________________________________________ _______________________________________________________ Principal Investigator’s Signature Protocol: NCR-001-1 V1.0 Page 5 of 5 _______________ Date CLINICAL TRIAL PROTOCOL NCR-001-1 Version and date: Version 4, 18 February 2018 Sponsor: Sponsored Therapeutics 1635 East 18th Street City, ST 12345 us e on Protocol Number: ly Formal Title: NCR-001: A Dose Comparison of NCR-001 to Defy in Healthy Volunteers Specialist Doctor, MD Pennant University Medical Center 1234 Address Avenue City, ST 12345 rC University of Medical Center 12345 Medical Center City, ST 67890 Fo Imaging Core Lab: R C 27 0 Study Principal Investigator: 1 NCR-001-1 Clinical Trial Protocol V4 Dated 18 February 2018 CONFIDENTIAL Investigator Protocol Agreement PROTOCOL NO: NCR-001-1 PROTOCOL TITLE: NCR-001: A Dose Comparison of NCR-001 to Defy in Healthy Volunteers By signing, I confirm that I/my staff have read and understand this protocol and agree to comply with the conduct and terms of this study. I/we have agreed to abide by the following responsibilities: ly C  27 0     on  e   To conduct the study in compliance with this protocol, any future amendments, any conditions of the governing reviewing EC/IRB or regulatory agency. To supervise all testing involving human subjects. To abide by Good Clinical Practices (GCP), and all applicable regional or national regulations. Ensure that the requirements for obtaining informed consent from each study participant or their legal representative are met. To report any Serious Adverse Events in a timely manner as required by the protocol. To report any Serious Adverse Events to the IRB in a timely manner. To report Non-serious Adverse Events as required by the protocol. To maintain confidentiality and assure security of confidential documents that include but are not limited to: NCR 001 Sponsored Therapeutics Discussion

the protocol, case report forms, Investigator’s Brochure, final study documents, manuscript drafts, unpublished data, correspondence, etc. To cooperate fully with any regulatory agency audit. us  rC R Principal Investigator (name): _________________________________________ Fo Principal Investigator (signature): ______________________________________ 2 NCR-001-1 Clinical Trial Protocol V4 Dated 18 February 2018 CONFIDENTIAL SUSAR on Fo rC R C 27 USCA e IRB IV LVO MB MI NYHA OFP SAE us HEENT Adverse Event American Society of Echocardiography Chronic Obstructive Pulmonary Disease Electronic Case Report Form Electrocardiogram Food and Drug Administration Good Clinical Practices Head, eyes, ears, nose, and throat examination Institutional Review Board Intravenous Left Ventricular Opacification Minispheres Mechanical Index New York Heart Association Octafluoropropane Serious Adverse Event Suspected Unexpected Serious Adverse Reactions Ultrasound Contrast Agents 0 AE ASE COPD eCRF EKG FDA GCP ly TABLE OF ABBREVIATIONS 3 NCR-001-1 Clinical Trial Protocol V4 Dated 18 February 2018 CONFIDENTIAL Table of Contents CLINICAL TRIAL PROTOCOL ………………………………………………………………………………….. 1 Investigator Protocol Agreement……………………………………………………………………………………. 2 TABLE OF ABBREVIATIONS …………………………………………………………………………………….. 3 1. BACKGROUND ……………………………………………………………………………………………………….. 7 e on ly 1.1 Contrast Enhanced Echocardiography ……………………………………………………………………….. 7 1.2 Rationale for use in Endocardial Border Delineation …………………………………………………… 7 1.3 NCR-001: Acoustically active minispheres ………………………………………………………………….. 7 1.3.1 Preclinical efficacy studies in echocardiography ……………………………………………………………… 7 1.3.2 Non-clinical pharmacology and toxicology …………………………………………………………………….. 8 1.4 Pharmacokinetics and Pharmacodynamics of NCR-001 in Human Subjects ……………………….. 8 1.4.1 Mechanism of Action …………………………………………………………………………………………………… 8 1.4.2 Pharmacokinetics ………………………………………………………………………………………………………… 9 1.4.3 Distribution…………………………………………………………………………………………………………………. 9 1.4.4 Metabolism …………………………………………………………………………………………………………………. 9 1.4.5 Elimination…………………………………………………………………………………………………………………. 9 1.4.6 Special Populations ……………………………………………………………………………………………………… 9 us 2. OBJECTIVES …………………………………………………………………………………………………………… 9 2.1 Primary Objectives…………………………………………………………………………………………………………. 10 2.2 Secondary Objectives ……………………………………………………………………………………………………… 10 0 3. SUBJECT SELECTION ………………………………………………………………………………………….. 10 C 27 3.1 Inclusion Criteria……………………………………………………………………………………………………………. 10 3.2 Exclusion Criteria…………………………………………………………………………………………………………… 10 3.3 Withdrawal Criteria……………………………………………………………………………………………………….. 11 3.4 Replacement of Subjects …………………………………………………………………………………………………. 11 R 4. REGISTRATION PROCEDURES…………………………………………………………………………… 12 rC 4.1 Registration Process ……………………………………………………………………………………………………….. 12 5. TREATMENT PLAN………………………………………………………………………………………………. 12 Fo 5.1 Study Treatments …………………………………………………………………………………………………………… 12 5.1.1 Bolus ……………………………………………………………………………………………………………………….. 12 5.1.2 IV Infusion ……………………………………………………………………………………………………………….. 12 5.2 Safety Guidelines for Study Treatments…………………………………………………………………………… 13 5.2.1 Bolus ……………………………………………………………………………………………………………………….. 13 5.2.2 IV infusion………………………………………………………………………………………………………………… 13 5.3 Duration of Therapy ……………………………………………………………………………………………………….. 13 5.3.1 Bolus ……………………………………………………………………………………………………………………….. 13 5.3.2 IV Infusion ……………………………………………………………………………………………………………….. 13 5.4 Duration of Follow-up …………………………………………………………………………………………………….. 13 6. DOSING DELAYS/DOSE MODIFICATIONS …………………………………………………………. 13 7. STUDY ASSESSMENTS …………………………………………………………………………………………. 14 7.1 Screening and Informed Consent …………………………………………………………………………………….. 14 7.2 Specific Procedures…………………………………………………………………………………………………………. 14 7.2.1 Height and Weight …………………………………………………………………………………………………….. 14 7.2.2 Vital Signs ………………………………………………………………………………………………………………… 14 7.2.3 Medical History …………………………………………………………………………………………………………. 14 4 NCR-001-1 Clinical Trial Protocol V4 Dated 18 February 2018 CONFIDENTIAL 7.2.4 Concomitant Mediations …………………………………………………………………………………………….. 14 7.2.5 Clinical Laboratory Assessments …………………………………………………………………………………. 14 7.2.6 Physical Examination …………………………………………………………………………………………………. 15 7.2.7 12-lead Electrocardiogram (EKG) ……………………………………………………………………………….. 15 7.2.8 Echocardiograms ……………………………………………………………………………………………………….. 16 7.3 Assessments Performed by Study Visit…………………………………………………………………………….. 16 7.3.1 Screening ………………………………………………………………………………………………………………….. 16 7.3.2 Dosing ……………………………………………………………………………………………………………………… 17 7.3.3 Discharge………………………………………………………………………………………………………………….. 17 7.4 Long Term Follow-up …………………………………………………………………………………………………….. 17 8. STUDY SCHEDULE OF EVENTS ………………………………………………………………………….. 18 9. DOSE LIMITING TOXICITIES, ADVERSE EVENTS, AND REPORTING REQUIREMENTS………………………………………………………………………………………………………. 22 us e on ly 9.1 Dose Limiting Toxicity (DLT) …………………………………………………………………………………………. 22 9.2 Definition of Adverse Events …………………………………………………………………………………………… 23 9.3 Reporting Procedures for Adverse Events ……………………………………………………………………….. 23 9.3.1 Follow-up of an AE ……………………………………………………………………………………………………. 23 9.4 Serious Adverse Events …………………………………………………………………………………………………… 24 9.4.1 Reporting procedures for SAEs……………………………………………………………………………………. 24 9.5 Routine Adverse Event Reporting …………………………………………………………………………………… 24 9.6 Stopping Rules ……………………………………………………………………………………………………………….. 24 9.7 Integrative Safety Analysis ……………………………………………………………………………………………… 25 0 10. PHARMACEUTICAL INFORMATION ………………………………………………………………… 25 R C 27 10.1 NCR-001 ………………………………………………………………………………………………………………………. 25 10.1.1 Storage and Preparation of the Investigational Product ……………… …