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Evaluation of COVID-19 Convalescent Plasma City of Hope #20204

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City of Hope National Medical Center 1500 E. Duarte Road

Duarte, CA 91010

Evaluation of Coronavirus Disease 19 (COVID-19) Convalescent Plasma

Version Date: June 26, 2020 Protocol Version: 01

City of Hope #: 20204 Sponsor/ Lead Site: City of Hope

Funding Support: Grant Funds and Internal Funds Participating Sites and Roles: City of Hope, Duarte (Data coordination and storage,

laboratory testing, and data analysis)

TGen (laboratory and data summaries)

CIRM Alpha Stem Cell Clinics: UC Irvine, UCSF, UCSD, UC Davis (specimen collection)

Dignity Health Medical Group, Ventura County (specimen collection)

Principal Investigator John A. Zaia, MD City of Hope National Medical Center for Gene Therapy T: (626)-218-1817 Email: [email protected]


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PROTOCOL TEAM

COH Co-Investigators

Biostatistician/ Co-Investigator

Paul Frankel, PhD City of Hope National Medical Center Dept. of Comp Quant Med T: (626)-218-5265 Email: [email protected]

Co-Investigator

Angelo A. Cardoso, MD, PhD City of Hope National Medical Center Center for Gene Therapy T: (626)-218-3858 Email: [email protected]

Co-Investigator

Kevin Morris, PhD City of Hope National Medical Center for Gene Therapy T: (626)-218-2839 Email: [email protected]

Protocol Development Scientist

Virginia Le Verche, PhD City of Hope National Medical Center Center for Gene Therapy T: (626)-218-8086 Email: [email protected]

Co-Investigator

Jana Dickter, MD City of Hope National Medical Center Div Infectious Disease T: (626)-218-8202

Email: [email protected]

Co-Investigator

Sanjeet Dadwal, MD City of Hope National Medical Center Div Infectious Disease T: (626)-218-8202 Email: [email protected]

Co-Investigator

Flavia Chiuppesi, PhD City of Hope National Medical Center Center for Gene Therapy T: (626)-218-3983


Co-Investigator

Shan Yuan, MD City of Hope National Medical Center Transfusion Medicine T: (626)-214-6006


Co-Investigator

Lefan Zhuang, MD City of Hope National Medical Center Transfusion Medicine T: (626)-258- 3570


TGen Co-Investigators:

Co-Investigator

John Altin Pathogen Genomics and Integrated Cancer Genomics Divisions T: (928)-226-6373 Email: [email protected]

Dignity Health Medical Group (Ventura County) Participating Physicians:

George Yu, MD St. John’s Hospital Camarillo 2309 Antonio Avenue Camarillo, CA 93010 Email: [email protected]

Micah Dickey, DO St. John’s Hospital Camarillo 2309 Antonio Avenue Camarillo, CA 93010 Email: [email protected]

Sofia Nelson, MD St. John’s Regional Medical Center 1600 N Rose Avenue Oxnard, CA 93030 Email: [email protected]

Jubran S. Dakwar, MD St. John’s Regional Medical Center 1600 N Rose Avenue Oxnard, CA 93030 Email: [email protected]

Josh Wolfsohn, DO St. John’s Regional Medical Center 1600 N Rose Avenue Oxnard, CA 93030 Email: [email protected]

Raj Bhatia, MD St. John’s Regional Medical Center 1600 N Rose Avenue Oxnard, CA 93030 Email: [email protected]

Ramsey Ulrich, MD 2601 East Main Street Suite 100 Ventura, CA 93003 Email: [email protected]

mailto:[email protected]


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EXPERIMENTAL DESIGN SCHEMA

Prospective biospecimen and data collection for analysis of the therapeutic effect of COVID-19 convalescent plasma (CCP) in severely ill COVID-19 patients.

Up to 500 prospective plasma donors will be screened, and up to 250 COVID-19 patients treated with CCP will be followed.

1: Treating physicians must be enrolled in a local IRB protocol involving CCP infusion for the treatment of adults with COVID-19, or in the Expanded Access protocol under IND19832 held by Mayo Clinic, or obtain a single patient emergency IND (eIND).

2: Volunteers will have the option to give ~50 mL of blood for research purposes only, and not undergo plasmapheresis.


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TABLE OF CONTENTS

SECTION ....................................................................................................................................................PAGE

Protocol Team ................................................................................................................................................ 2

Experimental Design Schema ......................................................................................................................... 3

Table of Contents ........................................................................................................................................... 4

List of Tables and Figures ................................................................................................................................ 5

Abbreviations .................................................................................................................................................. 6

Abbreviation Meaning ............................................................................................................................. 6

1.0 Objectives and Endpoints ................................................................................................................. 7 1.1 Primary Objectives ...................................................................................................................... 7 1.2 Exploratory Objectives ................................................................................................................ 7

2.0 Background....................................................................................................................................... 7 2.1 Overview and Rationale .............................................................................................................. 7 2.2 Overview of Study Design ........................................................................................................... 9

3.0 Participant Number, Cohort Characteristics, Eligibility and Involvement ...................................... 10 3.1 Sample Size and Cohort Characteristics ................................................................................... 10 3.2 Eligibility .................................................................................................................................... 11 3.3 Duration of Participation and What is Expected from Participants .......................................... 12

4.0 Study Calendar ............................................................................................................................... 13

5.0 Nasopharyngeal Swab Collection ................................................................................................... 13 5.1 Sample Collection ..................................................................................................................... 13 5.2 Labeling ..................................................................................................................................... 14 5.3 Initial Sample Processing, Storage and Distribution ................................................................. 14 5.4 Infectious Disease Handling, Processing, and Testing Procedures ........................................... 14

6.0 Blood Product Specimen Collection ............................................................................................... 14 6.1 Sample Collection ..................................................................................................................... 14 6.2 Labeling ..................................................................................................................................... 17 6.3 Initial Sample Processing, Storage and Distribution ................................................................. 17 6.4 Infectious Disease Handling, Processing, and Testing Procedures ........................................... 17

7.0 Clinical Data Collection ................................................................................................................... 18

8.0 Laboratory and Information Analysis ............................................................................................. 18 8.1 TGen SARS CoV-2 RT-PCR Assay ............................................................................................... 18 8.2 TGen SARS-CoV-2 Immunoassay .............................................................................................. 18 8.3 TGen CoV PepSeq Assay ........................................................................................................... 19 8.4 SARS-CoV-2 S-Lenti-based neutralizing antibody titer ............................................................. 19

9.0 Statistical Considerations ............................................................................................................... 20 9.1 Study Populations and Accrual Rate ......................................................................................... 20 9.2 Time to Complete COH Accrual and Study Duration ................................................................ 20 9.3 Statistical Analysis Plan ............................................................................................................. 20

10.0 Ethical and Regulatory Considerations ........................................................................................... 22 10.1 Ethical Standard ........................................................................................................................ 22 10.2 Regulatory Compliance ............................................................................................................. 22 10.3 Recruitment of Participants ...................................................................................................... 22 10.4 Informed Consent Procedures .................................................................................................. 23 10.5 Registration ............................................................................................................................... 23 10.6 Participant Withdrawal ............................................................................................................. 23


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10.7 Special and Vulnerable Populations ......................................................................................... 24 10.8 Participant Confidentiality ........................................................................................................ 24 10.9 Potential Risks and Benefits to Participation ............................................................................ 25 10.10 Alternatives to Participation ..................................................................................................... 26 10.11 Conflict of Interest .................................................................................................................... 26 10.12 Future Use of Unused (Leftover) Samples Collected for This Study ......................................... 26 10.13 Financial Obligations, Compensation, and Reimbursement of Participants ............................ 26 10.14 Publication/ Data Sharing ......................................................................................................... 27

11.0 Data and Safety Monitoring and UP Reporting .............................................................................. 27

12.0 Appendices ..................................................................................................................................... 29 12.1 Appendix A: Registration Questionnaire for Treating Physicians ............................................. 29 12.2 Appendix B: Screening Questionnaire for COVID-19 Convalescent Donor for Plasma/Blood Donation 31 12.3 Appendix C: Specimen Shipping Guidelines to TGen ................................................................ 33 12.4 Appendix D: Specimen Shipping Guidelines to City of Hope .................................................... 35 12.5 Appendix E: COVID-19 Severity Grading Score (Pre-Specified Model) ..................................... 36

13.0 References ...................................................................................................................................... 37

LIST OF TABLES AND FIGURES

Figure 1 Prospective biospecimen and data collection for analysis of the therapeutic effect of COVID-19 convalescent plasma (CCP) in severely ill COVID-19 patients..................................................................... 10

Table 1 Study Calendar ............................................................................................................................... 13

Table 2 Blood Collection Details ................................................................................................................. 15

Table 3 COVID-19 Severity Grading Score .................................................................................................. 36


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ABBREVIATIONS

ABBREVIATION MEANING

AE Adverse Event

ASCC CIRM Alpha Stem Cell Clinic

CCP COVID-19 Convalescent Plasma

CIRM The California Institute for Regenerative Medicine

COH City of Hope

COVID-19 Coronavirus Disease 2019

CTCAE Common Terminology Criteria for Adverse Events

CTEP Cancer Therapy Evaluation Program DOB Date of birth eIND Single-patient emergency IND FDA Food and Drug Administration HIPAA Health Insurance Portability and Accountability Act

HHS Health and Human Services

HLH Haemophagocytic lymphohistiocytosis ICF Informed Consent Form

ID Identification

IRB Institutional Review Board NCI National Cancer Institute PI Principal Investigator

RPN Research patient number

SAE Serious Adverse Event/Serious Adverse Experience

SARS-CoV-2 Severe acute respiratory syndrome Coronavirus 2

SOC Standard of Care

TBD To Be Determined

TGen Translational Genomics Research Institute

US United States

WHO World Health Organization


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1.0 OBJECTIVES AND ENDPOINTS

The study is an exploratory observational study designed to provide critical eligibility testing for prospective COVID-19 convalescent plasma (CCP) donors, analyze CCP antibody profile, and document the clinical outcome in CCP recipients enrolled in the national expanded access program (EAP, IND#19832, NCT04338360), in single-patient emergency IND (eIND), or in a local IRB protocol involving CCP infusion for the treatment of adults with COVID-19. The specimens and data collected will inform on whether and how SARS-CoV-2 immunoglobulin properties in CCP correlate with clinical efficacy in CCP recipients, and generate hypothesis regarding the management of COVID-19. In addition, the protocol provides an avenue for collection of blood from COVID-19 convalescent volunteers interested in donating blood specimens for research purposes.

1.1 Primary Objectives

o Establish a testing service for screening prospective donors of COVID-19 convalescent plasma (CCP)

o Characterize the titer and neutralizing properties of SARS-CoV-2 antibodies in CCP

o Correlate the SARS-CoV-2 antibody characteristics in CCP with the outcome in COVID-19 patients treated with CCP

1.2 Exploratory Objectives

o Facilitate the recruitment of CCP donors in medically underserved areas

o Develop high-throughput methods for detection/characterization of SARS-CoV-2 neutralizing and non-neutralizing antibodies

o Develop a bank of convalescent plasma that would be available for future studies relating to the content of CCP

o Study the impact of antibody levels, donor characteristics and patient characteristics on outcome in COVID-19 patients treated with CCP

o Procure blood samples from COVID-19 convalescent volunteers for future COVID-19-related studies

2.0 BACKGROUND

2.1 Overview and Rationale

There is an urgent need for a validated treatment for COVID-19

In December 2019, a pneumonia associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The epidemic, named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), spread rapidly worldwide within 3 months, and was characterized as a pandemic by WHO on March 11, 2020. California is one of the most affected states in the United States, with over 206,697 COVID-19 confirmed cases and 5,868 COVID-19-related deaths as of June 26, 2020 (1). There is no proven effective treatment for COVID-19, but several strategies including vaccine candidates, antiviral agents, and passive immunotherapy are being evaluated in clinical studies.


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Convalescent plasma is available for the treatment of COVID-19

Transfusion of COVID-19 convalescent plasma (CCP), collected from patients who have recovered from the disease and developed anti-SARS-CoV-2 antibodies, is being tested in COVID-19 patients. Convalescent plasma has been used to fight other respiratory virus infections, including SARS coronavirus (SARS-CoV-1) ─ the nearest epidemic virus strain related to SARS-CoV-2 ─ avian influenza A (H5N1) virus, and influenza A (H1N1) pdm09 virus (2-6). There were mixed results, with lack of benefit seen in a study of severe influenza infection controlled using both high and low antibody-containing plasma (7). While the safety of plasma is generally accepted, the question of whether CCP is effective in treating COVID-19 patients remains unproven because of the lack of convincing evidence from controlled trials, the fact that each unit can vary in antibody level (i.e., uncertainty of an optimal preparation of convalescent plasma), and an unknown safety profile when used in severely ill patients (8). Noteworthy, antibody-dependent enhancement of infection (ADE) occurs when antibodies facilitate viral entry into host cells and enhance viral infection in these cells and is a concern with SARS-CoV-2. In ADE, infection of immune cells via Fc receptors is thought to induce sustained inflammation and/or cytokine storm. It has been described in virus infections such as Dengue, Zika (9) and in SARS (10), and the cytokine storm precipitated by ADE can be reproduced using a SARS-CoV-1 pseudovirus (11). Severe cases of COVID-19 illness have been linked to cytokine storm-like syndromes (11-13), and, in the lung, activation of innate immune cells, cascades of inflammatory activity, and tissue damage not unlike that seen in SARS-CoV-1 (10).

Nevertheless, based on the early case reports on the use of CCP in China (14-16), and the absence of available alternative treatments, the Food and Drug Administration (FDA) has allowed treatment of patients with CCP under three pathways: clinical trials, single patient emergency IND (eIND) and an Expanded Access Program (EAP, IND#19832, NCT04338360) (17). This program is led by the Mayo Clinic and facilitates access to CCP across the nation, and provides a protocol for its infusion in critically ill COVID-19 patients. The program was developed with funding from the Biomedical Advanced Research and Development Authority (BARDA) (18). Centers wishing to treat patients under this expanded access protocol must register online with the Mayo Clinic and qualify the patient as specified by the FDA guidance (17). However, this program does not provide CCP, and physicians must request plasma from their facility's regular supplier. The FDA requires quantitative SARS-CoV-2 antibody testing to determine the eligibility of prospective CCP donors (19).

What problems are faced in a convalescent plasma program?

We will address the three main issues encountered when treating a COVID-19 patient with CCP:

1) Identifying donors who have convalesced from COVID-19, especially in medically underserved areas. For this, our Outreach Coordinator will reach out to communities in California, including medically underserved communities, to identify potential CCP donors.

2) Qualifying the volunteer for eligibility as plasma donor. This is particularly important as a recent report suggests that some convalescent individuals have undetectable levels of antibodies (20). We will support their antibody testing and RT-PCR testing screen for eligibility, if required by the blood collection site, as many physicians and blood centers are not equipped to perform these tests.

3) Treating the patient and determining whether the plasma was effective. We will perform antibody characterization assays on CCP to understand the level of neutralizing antibody necessary for antiviral effect, the non-immunoglobulin elements in CCP that could affect the pathology of the COVID-19 syndrome. Future correlative studies may also include potential of ADE, genomic analysis and T cell


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responses. We will correlate these blood samples and CCP characteristics with outcome and antibody properties in COVID-19 patients treated with CCP.

Overall, this study will require prospective collection of NP swabs, blood samples and clinical data. It will contribute important information towards a better understanding of safety and outcome in management of the COVID-19 patients using CCP. The scientific approach outlined in this project will enable future studies aimed at investigating the role of CCP as a therapeutic agent. In this regard, it is possible that information learned will guide the physician in determining which patient is likely to benefit for such therapy and which is not. Also, it is possible that the character of the antibody (neutralizing vs non-neutralizing; or peptid-specific antibody) and other donor/recipient material characteristics will be predictive of outcome.

2.2 Overview of Study Design

The COVID-19 Coordination Program is composed of the CIRM Alpha Stem Cell Clinic (ASCC) network and two testing laboratories: the Laboratory for Cellular Medicine at COH, under the direction of Dr. A Cardoso, and Dr. Altin’s laboratory at the Translational Genomics Research Institute in Flagstaff (TGen North). It will interact with other medical centers that have hospitalized COVID-19 patients and are enrolled in local IRBs, the national expanded access program (EAP) (18) or eINDs. The Program provides information on IRB, EAP and eIND registration, prescreen and testing of potential CCP donors, collection of plasma sample from CCP units infused in COVID-19 patients, and collection of data on the outcome of the treatment and blood samples from CCP recipients. All the data generated during this project will be collected on a secured web-based portal managed by OnRamp Bioinformatics, Inc (see Section 10.8.1).

As shown on Figure 1, key MD Coordinators will be identified at the ASCC network centers and other sites that have access to COVID-19 convalescent individuals, and will be directed to our website to register. These MD Coordinators will invite a prospective donor(s) to visit our website if they are interested in becoming CCP donors for COVID-19 treatment. Self-referred donors will also contact our website. When convalescent volunteers register, they will be consented for screening, enter their identity and contact information, the specifics of their COVID-19 diagnosis, and complete a short questionnaire (see Appendix B). Individuals interested in donating blood for research purposes will also be consented and pre-screened online (see Appendix B). They will be filtered out if they are not found to be eligible by the COH Director of Transfusion Medicine Services. The eligibility will be reported to the local MD Coordinators who will then schedule the volunteers to donate blood and/or NP swab (only if required by the blood collection sites). Specimens will be shipped to TGen for completion of the eligibility testing and antibody potency assays (see Section 8 for details).

If the CLIA assay for quantitative SARS-CoV-2 serological titers shows a CCP donor has enough SARS-CoV-2 antibodies, the MD Coordinator will arrange for plasma collection at a local FDA-registered blood establishment, which will contribute to the development of a bank of plasma. Each blood collection center will be independent of this study and will follow standard of care AABB regulations for collection by plasmapheresis donation.

The treating physician will be responsible for registering to a local IRB, the EAP or eIND, and ordering CCP units. After registration on our portal and consent of the COVID-19 patient (see Appendix A), the treating physician will send to TGen a retain sample of CPP he/she is infusing in his/her COVID-19 patient. This retain sample will be analyzed at TGen and COH using antibody potency assays (see Section 8 for details). Treating physicians will be briefed on our webpage on consenting of the COVID-19 patient to share medical information and donate blood specimens (on the day of the CCP unit infusion [Day 0], 12-24h post each CCP unit infusion, and 7 days (± 3 days) post last CCP unit infusion, and on completion


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of the case report form (CRF) at the same time points and at discharge from the hospital and 28 days post last CCP infusion (Appendix E).

The severity of the COVID-19 in CCP recipients will be graded and compared to the type/level of antibody (see Section 9.3) in the CCP infused. Note that the COVID-19 Coordinating Program only assists the treating physician and does not alter the method of infusion or reporting of data to that trial, which will follow a local IRB, the EAP protocol developed by the Mayo clinic or an eIND protocol.

Note: There is an IRB reliance agreement in place for CIRM Alpha Stem Clinic Network sites. For other sites, there will be an agreement between the MD’s IRB indicating that COH is to be the IRB of record only for this study.

Figure 1 Prospective biospecimen and data collection for analysis of the therapeutic effect of COVID-19 convalescent plasma (CCP) in severely ill COVID-19 patients.

Up to 500 prospective plasma donors will be screened, and up to 250 COVID-19 patients treated with CCP will be followed.

1: Treating physicians must be enrolled on a local IRB protocol involving CCP infusion for the treatment of adults with COVID-19, or in the Expanded Access protocol under IND19832 held by Mayo Clinic, or obtain a single patient emergency IND (eIND).

2: Volunteers will have the option to give ~50 mL of blood for research purposes only, and not undergo plasmapheresis.

3.0 PARTICIPANT NUMBER, COHORT CHARACTERISTICS, ELIGIBILITY AND INVOLVEMENT

3.1 Sample Size and Cohort Characteristics

The total sample size for this study is not known and will be based on the demand for this testing service and the rate of spread of infection in the community. We estimate that we will test approximately up to 500 convalescent individuals, and evaluate up to 250 COVID-19 patients treated with CCP. For those


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who choose not to be CCP plasma donors, we will collect at least 50 blood specimens directly from these subjects for research purposes.

3.2 Eligibility

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

3.2.1 Prospective COVID-19 convalescent plasma donors

COVID-19 convalescent plasma volunteers must meet all regulatory requirements for conventional plasma and FDA’s additional considerations for COVID-19 convalescent plasma (https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds)

In addition, prospective CCP donors must:

- Age: ≥ 18 years - Be willing to complete a questionnaire - Be willing to donate blood samples - Permit medical record review - Have documented informed consent

Note: If volunteers can’t provide evidence of COVID-19, but are otherwise eligible, then we will test them for SARS-CoV-2 antibodies to confirm eligibility.

It is possible that other therapeutic protocols using CCP will request assistance from us in donor screening; if this occurs, those protocol eligibility requirements will be required by this COH study to access donor specimens and patient data.

3.2.2 COVID-19 convalescent blood donors who choose not to donate CCP

COVID-19 convalescent individuals willing to donate blood samples for research purposes must meet the following eligibility criteria:

- Evidence of COVID-19 documented by a laboratory test either by: a diagnostic test (e.g., a NP swab) at the time of illness OR a positive serological test for SARS-CoV-2 antibodies after recovery, if prior diagnostic testing was not performed at the time COVID-19 was suspected.

- Age: ≥ 18 years - Be willing to complete a questionnaire - Be willing to donate blood samples - Permit medical record review - Have documented informed consent

Note: If volunteers can’t provide evidence of COVID-19, but are otherwise eligible, then we will test them for SARS-CoV-2 antibodies to confirm eligibility.

3.2.3 COVID-19 convalescent plasma recipients

Any adult enrolled in a clinical trial involving the infusion of CCP for the treatment of COVID-19.

In addition, CCP recipients must:

https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-indshttps://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds


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- Be willing to provide blood samples - Permit medical record review - Have documented informed consent

3.3 Duration of Participation and What is Expected from Participants

3.3.1 For prospective COVID-19 convalescent plasma donors

CCP donors will be in the study from the time of informed consent until plasmapheresis is scheduled. They will agree to the following:

- Research use of up to 20 mL of blood collected at the time of screening.

- Permission to contact outside health care institutions involved in the donor’s care during his/her COVID-19 illness to obtain their medical record and related information to COH to allow documentation of COVID-19 infection.

Note: Some blood collection centers may require a negative result for COVID-19 (by RT-PCR on NP swab) if volunteers are between 14 and 27 days of convalescence. We will then perform this test if the convalescent volunteers don’t have record of a negative test for COVID-19.

3.3.2 For COVID-19 convalescent blood donors who choose not to donate CCP

COVID-19 convalescent donors will be in the study from the time of informed consent until blood collection is complete. They will agree to the following:

- Research use of up to 50 mL of blood collected one time only.

- Permission to contact outside health care institutions involved in the donor’s care during his/her COVID-19 illness to obtain their medical record and related information to COH to allow documentation of COVID-19 infection.

3.3.3 For COVID-19 convalescent plasma recipients

CCP recipients will be in the study from the time of consent to Day 28 post-last infusion of CCP unit, or at the time of hospital discharge, whichever comes last. CCP recipients will agree to the following:

- Research use of clinical data obtained retrospectively/prospectively from the medical records documenting health status during the COVID-19 illness.

- Permission to contact other outside health care institutions involved in the recipient’s care during his/her COVID-19 illness to obtain their medical record and related information to allow further documentation of the COVID-19 infection, time course and outcomes.

- Research use of up to 10.5 mL of blood collected at each the following timepoints: on the day of CCP unit infusion (baseline, Day 0), 12-24h after each CCP unit infusion, and 7 days (± 3 days) post last CCP unit infusion.

Note: As the CCP unit belongs to the treating hospital, COVID-19 patients do not need to consent for the collection of a retention sample from the plasma unit he/she receives.


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4.0 STUDY CALENDAR

Table 1 Study Calendar

Section

Study Activity

Co

nse

nt

Scre

en

ing

On

th

e d

ay

of

CC

P in

fusi

on

12

-24

h

po

st e

ach

CC

P in

fusi

on

7 d

ays

(± 3

day

s) p

ost

last

CC

P in

fusi

on

28

day

s p

ost

last

CC

P

infu

sio

n

End

of

stu

dy

g

Window

Prospective CCP donor

10.4 Online informed consent X

7.0 Online pre-screening questionnaire/Data collection

X

3.2. Eligibility/ Registration X

6.0 Blood and NP swab collectionb Xa

Convalescent blood donor who choose

not to donate CCP

10.4 Online informed consent X

7.0 Online pre-screening questionnaire/Data collection

X

3.2. Eligibility/ Registration X

6.0 Blood collectionc X

COVID-19 recipient

10.4 Informed Consent X

6.0 Blood collectiond Xe X X

7.0 Data collection X X X X X

10.3 Reliance agreementf X

Other specimen

6.0 Plasma sample collection from CCP unit used to treat COVID-19 patient

X

a. Screening procedures for the prospective CCP donors may result in their disqualification as CCP donors. b. Blood samples (~20 mL total) will be collected into green/gray top tubes (1 x 8 mL) and red/gray top (1 x 8.5 mL) and will

be assayed for SARS-CoV-2 immunoassay, PepSeq and S-Lenti neutralization assays. NP swab will be performed only if required by blood center for donors between 14 and 27 days of convalescence.

c. Blood samples (~50 mL, 8-8.5 mL per tube) will be collected in 4 green/gray top 8 mL tubes and 1 red/gray top 8.5 mL tube.

d. At each timepoint: blood samples will be collected in green/gray tube (1 x 8 mL) and in PAXgene® blood RNA tube (1 x 2.5 mL).

e. The baseline sample on the day of infusion should be collected before CCP infusion. f. Institutions enrolling patients to be treated with CCP must have an IRB reliance agreement with COH before beginning

any research activities including screening patients for eligibility.

g. End of study for CCP recipient will be at discharge from the hospital or 28 days post last CCP infusion, whichever comes last.

5.0 NASOPHARYNGEAL SWAB COLLECTION

5.1 Sample Collection

NP swabs will be collected from prospective CCP donors, only if required by the blood collection center performing the plasmapheresis, and if the convalescent volunteers don’t have record of a negative test


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for COVID-19. Samples will be collected either from MD-referred or self-referred prospective plasma donors after online consent and review of the online questionnaire by a physician. The NP swabs will be collected at MD sites, ASCC sites or at home by a trained medical professional using personal protective equipment (PPE) per CDC/LACDPH guidelines.

Specimen Type

Volume of Collection per Timepoint

Additional Sample Collection Instructions Receiving and processing laboratory

NP Swab 2 swabs NP swabs will sample the nasopharynx through each nostril

TGen Clinical Pathology

Flagstaff AZ

5.2 Labeling

COH will provide NP swab collection kits to MD sites, ASCC sites and mobile phlebotomy companies. The NP swab specimens will be labeled with the COH protocol number, donor ID number, donor’s initials, donor DOB and time/date of NP swab.

5.3 Initial Sample Processing, Storage and Distribution

Specimens will be stored at 2-8°C and shipped overnight on ice packs, or stored frozen and shipped to TGen on dry ice if specimen shipment will occur more than 72 hours after specimen collection (see Appendix C). Samples will be processed for the presence of SARS-CoV-2 by RT-PCR within 48h from sample receipt.

5.4 Infectious Disease Handling, Processing, and Testing Procedures

TGen is a CLIA-approved laboratory and uses a FDA EUA approved assay for detection of SARS-CoV-2 for screening of the candidate donors. All CLIA-requirements are in place for safe handling of specimens. See Section 8 for more details on the testing procedures.

6.0 BLOOD PRODUCT SPECIMEN COLLECTION

6.1 Sample Collection

Research blood specimens will be collected by venipuncture at MD sites, ASCC sites or at home by a trained medical professional using personal protective equipment (PPE) per CDC/LACDPH guidelines.

1- From prospective CCP donors: Research blood samples (total volume ~20 mL) will be collected at the Alpha Stem Cell Clinic sites or MD sites after online consent and review of the online questionnaire by a physician.

2- From convalescent blood donors who choose not to donate CCP: Research blood samples (total one-time volume ~50 mL) will be collected at the Alpha Stem Cell Clinic sites or MD sites after online consent and review of the online questionnaire by a physician.

3- From CCP recipients: Optional research blood samples (~10 mL) will be collected at each of the following timepoints at MD sites after consent: before CCP unit infusion (baseline), 12-24h after each CCP unit infusion, and 7 days (± 3 days) post last CCP unit infusion.


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4- From the CCP unit used to treat COVID-19 patient: A retention sample of plasma (≥500 uL) will be collected via ‘pigtail’ retention sample from the unit infused in CCP recipient at infusion sites at the end of infusion or, if retention sample is not available, then ~1 mL of CCP plasma will be collected from the infusion bag at the start of infusion. If a patient receives multiple plasma units from the same CCP donor, only one CCP sample will be collected.

Table 2 Blood Collection Details

Notification to TGEN Laboratory

of Pending Collection

Tube Type Labeling and Collection Details Post-collection

Instructions

From prospective CCP donors 1. Upon receipt, promptly enter blood specimen in inventory system at TGen

2. Aspirate plasma from green/gray top tube and serum from red/gray top tube and transfer into a clean test tube.

Notes: Tubes should not be recentrifuged once the barrier is formed. If recentrifugation is required for improved serum or plasma quality, then aspirate serum/plasma first into a properly labeled clean test tube

3. Enter specimens in testing queue and perform assay in next available run.

4. Record result

5. Complete sign-off of result and report on portal.

6. Send cryopreserved plasma aliquot for testing to the Lab for Cellular Medicine at COH. Label tube with the COH protocol number, subject ID

Notify in advance Send calendar

invite via e-mail to Erin Kelley

([email protected]) or designee

Red/gray top SST tube

1. Label tube with the COH protocol number, donor ID number, donor’s initials, DOB, and time/date of blood draw.

2. This is a single timepoint of collection. 3. Collect 1 x 8.5 mL in red/gray top SST tube. 4. Invert the tube 5 times immediately after collection. 5. Clot for 30 minutes in a vertical position in a tube

rack at room temperature. 6. Centrifuge the tube within 2 hours of collection to

separate serum from cells, or refrigerate at 2-8ºC until centrifugation.

7. Spin the tube at room temperature at a speed of 1000 to 1300 RCF for 10 minutes in a swinging bucket centrifuge and 15 minutes in a fixed-angle centrifuge.

8. Ship at 2-8ºC on ice packs by overnight carrier.

Green/gray top

PST tube


2. This is a single timepoint of collection. 3. Collect 1 x 8 mL in green/gray top PST tube. 4. Invert the tube 8 to 10 times immediately after

collection. 5. Centrifuge the tube within 2 hours of collection to

separate plasma from cells, or refrigerate at 2-8ºC until centrifugation.



From convalescent blood donors who choose not donate CCP

Notify in advance

Send calendar invite via e-mail to

Erin Kelley ([email protected])

or designee

Red/gray top SST tube


2. This is a single timepoint of collection. 3. Collect 1 x 8.5 mL in red/gray top SST tube. 4. Invert the tube 5 times immediately after collection. 5. Clot for 30 minutes in a vertical position in a tube

rack at room temperature. 6. Centrifuge the tube within 2 hours of collection to


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Instructions

separate serum from cells, or refrigerate at 2-8ºC until centrifugation.



number, and time of collection

Green/gray top

PST tube


2. This is a single timepoint of collection. 3. Collect 4 x 8 mL in green/gray top PST tube. 4. Invert the tubes 8 to 10 times immediately after

collection. 5. Centrifuge the tubes within 2 hours of collection to

separate plasma from cells, or refrigerate at 2-8ºC until centrifugation.

6. Spin the tubes at room temperature at a speed of 1000 to 1300 RCF for 10 minutes in a swinging bucket centrifuge and 15 minutes in a fixed-angle centrifuge.


From COVID-19 patients treated with CCP

Notify in advance

Send calendar invite via e-mail to

Erin Kelley ([email protected])

or designee

Green/gray top

PST tube

1. Label tube with the COH protocol number, patient ID number, patient’s initials, DOB, and time/date of blood draw.

2. Collect 1 x 8 mL green/gray top PST tube AT EACH TIMEPOINT.

3. Timepoints of collection are stated in Section 4.0.

4. Invert the tube 8 to 10 times immediately after collection.

5. Centrifuge the tube within 2 hours of collection to separate plasma from cells, or refrigerate at 2-8ºC until centrifugation.



PAXgeneblood RNA tube

1. Label tube with the COH protocol #, patient ID number, patient’s initials, DOB, and time/date of blood draw.

2. Collect 1 x 2.5 mL in Paxgene tube AT EACH TIMEPOINT.

3. Timepoints of collection are stated in Section 4.0.

4. Invert tubes 8 times after collection. 5. Ship at 2-8ºC on ice packs by overnight carrier.


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Instructions

CCP retaining sample from CCP infused in COVID-19 patient

Notify in advance Send calendar

invite via e-mail to Erin Kelley

([email protected]) or designee

Clear

no additive tube

1. Label tube plasma unit ID, blood bank establishment, COH protocol number, CCP recipient’s ID number and initials, DOB, time/date of CCP infusion.

2. Retain sample will be collected via ‘pigtail’ at the end of infusion or, if not possible, then ~1 mL of CCP plasma will be collected from the infusion bag at the start of infusion.


6.2 Labeling

Blood samples will be labeled with the COH protocol number, donor’s or patient’s ID number and initials, DOB, and time/date of collection.

Plasma samples will be labeled with the plasma unit ID, blood bank establishment, COH protocol number, CCP recipient’s ID number and initials, DOB, and time/date of CCP infusion.

6.3 Initial Sample Processing, Storage and Distribution

Centrifuged blood samples in red/gray and green/gray top tubes, blood samples for RNA analysis and plasma in clear top tubes will be shipped at 2-8ºC on ice packs by overnight delivery to TGen.

At TGen, plasma (collected from green/gray top tubes) and serum (collected from the red/gray top tubes) will be transferred and aliquoted to test tubes labeled with the COH protocol #, subject ID number, and date of collection (see Appendix C).

Plasma from the clear tubes will be transferred and aliquoted to test tubes with the COH protocol #, plasma unit ID, CCP recipient ID number, and date of collection (see Appendix C).

No HIPAA –identifiers will be included once the specimens are processed at TGen.

For TGen use: Plasma samples will be placed either in a queue for immediate testing, or cryopreserved for later antibody tests. Specimen from donors who have an antibody titer ≥1:160 will be prioritized for PepSeq assay analysis at TGen and testing for neutralizing antibody at COH. Plasma samples with


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7.0 CLINICAL DATA COLLECTION

1. Data will be collected using electronic data collection forms. The case report form (CRF) was designed based on the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) COVID-19 rapid CRF and the Mayo EAP. Data will be collected through examination, interview and review of hospital notes.

2. Data will be requested by the Study PI as needed.

3. Refer to Section 10.8.2 regarding distribution of clinical data to non-COH collaborators.

4. Data from COVID-19 patients will be obtained from the electronic health record retrospectively and prospectively.

5. Outside health care institutions involved in the convalescent donor’s care during his/her COVID-19 illness may be contacted to obtain their medical record and related information to allow further documentation of the COVID-19 infection, time course and outcomes.

8.0 LABORATORY AND INFORMATION ANALYSIS

8.1 TGen SARS CoV-2 RT-PCR Assay

The TGen SARS-CoV-2 RT-PCR Assay is a real-time reverse-transcription polymerase chain reaction (RT-PCR) assay targeting conserved regions of the N and S genes in the SARS-CoV-2 genome. The assay is intended for the qualitative detection of nucleic acid from the SARS-CoV-2 in respiratory specimens, such as nasopharyngeal or oropharyngeal swabs and nasopharyngeal wash/aspirate or nasal aspirate specimens collected from individuals suspected of being exposed to COVID-19 or who meet the clinical and/or epidemiological criteria. The sensitivity and specificity of the TGen SARS CoV-2 RT-PCR Assay is equivalent to CDC’s revised assay. The TGen assay is an EUA validated test, was designed, and subsequently validated, not to cross react with any known human viruses. As part of the assay's analytical validation, 20/20 samples consisting of collection medium spiked with SARS-CoV-2 RNA at 3.13 genome copies per ml and and 20/20 spiked at 6.25 viral genome copies per ml tested positive by the assay. The TGen SARS-CoV-2 RT-PCR Assay has been designed to minimize the likelihood of false positive and false negative test results. TGen has incorporated a living Quality Management system that not only includes numerous quality controls, but constantly evaluates potential for errors, redesigns processes and training to prevent such errors and improves overall quality assurance. Laboratory technicians employed by TGen’s high complexity CLIA-certified laboratory meet CMS requirements. The laboratory uses automation, a laboratory information management system and barcoded sample tracking to minimize handling errors and sample swaps. Furthermore, each sample is interrogated by two different assays, targeting different SARS-CoV-2 genes, both of which must match in order to yield a reported result.

8.2 TGen SARS-CoV-2 Immunoassay

The purpose of this test is to qualify the donor based on antibody titer. According to the revised FDA guidance, eligible CCP donors should have defined SARS-CoV-2 neutralizing antibody titers (i.e., greater than 1:160 if available, or at least 1:80 otherwise) (17). We are pursuing two parallel approaches to implement a basic CLIA assay for quantitative SARS-CoV-2 serological titers: The InBios quantitative immunoassay, with IgG and IgM read out, will be our start-up assay for screening of donors. It will indicate whether prospective plasma donors meet the eligibility criteria of ≥1:80, but won’t provide the exact antibody titer. We are developing an in-house more qualitative assay as back-up using Luminex technology. It will be used for the analysis of the research samples (i.e from blood donors for research

https://media.tghn.org/medialibrary/2020/04/ISARIC_COVID-19_RAPID_CRF_24MAR20_EN.pdfhttps://media.tghn.org/medialibrary/2020/04/ISARIC_COVID-19_RAPID_CRF_24MAR20_EN.pdf


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use, from CCP units and from CCP recipients) and will be compared with the InBios assay for sensitivity/specificity, robustness of operation and with our correlative antibody assays (PepSeq and S-Lenti). Blood samples will be processed in a CLIA-certified laboratory at TGen’s Flagstaff campus. The InBios assay will utilize the kits that are supplied by the manufacturer. For the Luminex assay, we have beads coated with SARS-CoV-2 S protein and after incubation in diluted plasma samples and washing, these are incubated with a fluorophore-labeled anti-IgG or anti-IgM secondary antibody. The bead-antibody conjugates will be evaluated for fluorescence on a MagPix instrument (Luminex). For both screening assays, an antibody titers of ≥1:80 will be the qualifying titer for plasma donation. CCP that have an antibody titer ≥1:160 will be prioritized for functional analysis at TGen and COH. Plasma samples with 105-plex assay can be performed at a very small scale without loss of sensitivity (e.g. 0.5 µL of serum per assay). Because the peptides are synthesized enzymatically (using in vitro transcription/translation), rather than chemically, they have high sequence fidelity and can be long.

Using the PepSeq platform, we have constructed a pan-human-virome library of 244,000 30mer peptides and demonstrated the detection of reactivity to dozens of human viruses at the expected seroprevalences. A subset of the library covers all pre-pandemic members of the Coronaviridae family (including the 4 endemic human-infecting strains as well as SARS-CoV, MERS-CoV and SARS-CoV-2) and detects reactivity in ~95% of healthy subjects. We are currently designing supplemental libraries to cover the complete diversity of all available SARS-CoV-2 proteomes (>2,000, as of April 9, 2020) and this assay will be available in April 2020. We will use the PepSeq assay to define the immunogenic repertoire of SARS-CoV-2 in the CCPs, and to interrogate potential associations between the representation of viral immunogenic epitopes and therapeutic responses and clinical outcomes. These data will be very important for assessing the potential for ADE in the immune plasma.

8.4 SARS-CoV-2 S-Lenti-based neutralizing antibody titer

The purpose of this test is to determine which plasmas have neutralizing antibody vs non-neutralizing. The test is based on Spike-pseudotyped lentiviral vectors (S-Lenti) that were engineered so that their envelope expresses the SARS-CoV-2 Spike protein, which is critical for the entry of SARS-CoV-2 into permissive cells. S-Lenti encodes for the full-length SARS-CoV-2 Spike protein and contains silent


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mutations to increase protein expression in a mammalian system. We have confirmed effective expression of the S glycoprotein in transfected cells. S-Lenti vectors expressing either eGFP or luciferase will be used for this assay; inhibition of infection will be measured quantitatively using the fluorescence signal generated.

In the S-Lenti neutralization assay, serial dilutions of CCP are incubated for 60 min with S-Lenti vector at an optimal MOI, and then added to VERO E6 cells, which express the ACE2 receptor and are permissive to SARS-CoV-2 infection. We are also generating lung epithelial A549 cells expressing ACE2, which can be used as an alternative SARS-CoV-2 permissive cell line. Plasma from non-infected donors will be used as negative controls, as well as cell lines lacking ACE2 expression. As positive control, we will use samples from a bank of plasmas from recovered COVID-19 patients. Recombinant human ACE2-Fc protein (Acro Biosystems) that effectively blocks SARS-CoV-2 S protein binding to the cell will serve as a second negative control for alternative S-Lenti entry to target cells. As part of this study, the S-Lenti neutralization assay is being scaled-up into a 384-well format, and automated into an epMotion liquid handling system. This assay will be qualified by analyzing a panel of CCP in a neutralization assay with SARS-Cov-2 live virus, to be performed at TGen under BSL-3 conditions. Results will be correlated with those of the PepSeq assay to pinpoint optimal or suboptimal antigen sites for neutralization of virus.

9.0 STATISTICAL CONSIDERATIONS

9.1 Study Populations and Accrual Rate

The total sample size for this study is not known and will be based on the demand for this testing service and the rate of spread of infection in the community. We estimate that we will test approximately up to 500 convalescent individuals, and evaluate up to 250 COVID-19 patients treated with CCP. For those who choose not to be CCP plasma donors, we will collect at least 50 blood specimens directly from these subjects for research purposes. The projected accrual rate will be influenced by the epidemic, but it is anticipated that there will be a peak of enrollees early in the study and then a slower period of enrollment will taper off in 9-12 months.

9.2 Time to Complete COH Accrual and Study Duration

It is anticipated that donor and patient accrual will be completed in 9-12 months.

Study duration (time from activation to data analysis) is expected to be approximately 1 year.

9.3 Statistical Analysis Plan

CCP units infused in COVID-19 patients will be assayed for a) SARS-CoV-2 immunoassay b) CoV PepSeq assay and c) SARS-CoV-2 lenti-based neutralizing antibody titer.

Patient/recipient characteristics will include: Documentation of pulmonary infiltrates, temperature, lymphopenia (y/n), ferritin, co-morbidities, vasopressor required, SaO2 on room air at time of treatment (or lowest value if on oxygen or ventilator support), respiratory rate, elevated troponin, LDH, CRP, creatinine, absolute lymphocyte count, age, hepatic enzyme above normal, highest cytokine levels (if available, IL-6, IL-10, INF-ɣ, or TNF-α), and d-dimer status if available. Co-morbidities will include pre-existing obesity (BMT >30), pulmonary disease, chronic kidney disease (and stage), diabetes, hypertension (and grade), cardiovascular disease (and type), HIV (with or without CD4


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The second clinical endpoint is the reporting of adverse reactions to CCP.

Additionally, patient outcome will be assessed on a 7-point ordinal scale, as recommended by the WHO R&D Blueprint Group (24):

1. Death 2. Hospitalized, on invasive mechanical ventilation or ECMO 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring low flow supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than per protocol RDV administration) 7. Not hospitalized

This simple ordinal scale allows comparison to ongoing COVID-19 treatment studies, e.g. remdesivir randomized studies in both moderate and severe patients, which can help put the outcomes in context with both the SOC and treatment arms to provide similar context defining the severe group of COVID-19 patients (25). This ordinal scale will be evaluated at days 0, 1 and 28 post-CCP infusion.

We will also test our data-driven model and the pre-specified model (Appendix E) on the validation data set.

Other endpoints of interest are:

1. Duration of hospitalization (days)

2. Time to clinical improvement (days): Clinical improvement is defined as disease improvement from Day 0 to 28 post-CCP infusion on a 7-point ordinal scale.

The Primary Analysis/Sample size justification: The descriptive analysis of day-28 mortality of recipients will naturally be compared to reported data from other studies, however, patient selection and changes in patient care over time limit our ability to interpret such differences. As a result, the main focus of our analysis will focus on demonstrating that the antibody content of donor plasma increases the odds of surviving past Day 28. We will also examine donor antibody levels and how this relates to the duration of hospitalization.

If donor plasma quality, as measured by SARS-CoV-2 antibody levels and neutralizing potency, has a statistically significant and positive impact on patient outcomes, this would be considered evidence of benefit of convalescent plasma, and further provide better guidance on donor selection and serum qualification.

When the sample size is 250 patients, the logistic regression test to rule out a zero coefficient of effect (p = 0.050 two-sided) will have 86% power to detect a coefficient of 0.405 (an odds ratio of 1.500); this assumes that one normally distributed covariate of neutralizing antibodies is being added to the model after adjustment for prior covariates, that its multiple correlation with covariates already in the model is negligible (donor is unrelated to patient characteristics) and, that the proportion of successes at the mean of neutralizing antibodies is 0.500 and the power is to detect a change to 0.60 at one standard deviation increase in the antibodies.

As part of this analysis, we will develop a nomogram for the probability of success (alive at Day 28), accounting for patient, donor material and donor antibody characteristics measurable covariates. This will follow a similar approach taken by Fardet (26), with approximately the same sample-size.


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Exploratory Analysis

Other antibody measures and other endpoints will also be explored to further refine our understanding of the influencers of outcome to convalescent plasma in this setting.

10.0 ETHICAL AND REGULATORY CONSIDERATIONS

10.1 Ethical Standard

This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of Research (US National Commission for the Protection of Human Participants of Biomedical and Behavioral Research, April 18, 1979) and the Declaration of Helsinki.

10.2 Regulatory Compliance

This study is to be conducted in compliance with the IRB approved protocol and according to the following considerations:

o US Code of Federal Regulations (CFR) governing clinical study conduct a. Title 45 Part 46 – Protection of Human Participants

o US Federal legislation, including but not limited to b. Health Insurance Portability and Accountability Act of 1996

o Applicable state and local laws. For research occurring in California, this includes but is not limited to State of California Health and Safety Code, Title 17

o Applicable CIRM policies and procedures o Applicable institutional research policies and procedures

10.3 Recruitment of Participants

The study will be posted online at www.ccpp19.org as a California-specific service, and on www.clinicaltrials.gov.

10.3.1 Recruitment of MD Coordinators:

The backbone of our infrastructure involves the CIRM Alpha Stem Cell Clinic (ASCC) Network through which our Outreach Coordinator will engage key pulmonologists, infectious disease (ID)/ intensive care unit (ICU) specialists. In addition we will engage with physicians via:

- The National Convalescent COVID-10 Plasma Expanded Access Program (EAP). The COVID-19 Coordination Program website will be posted on the EAP website linking us to more than 150 sites in California that have already registered to treat COVID-19 patients with CCP.

- Specific sites who are treating COVID-19 patients and need access to donor testing. For example, a single group in Ventura County, that includes a communication system the reaches 150 MDs in 8 Dignity Health hospitals and a Kaiser Permanente hospital, has expressed their need for plasma antibody testing. The Alpha Stem Cell Clinic Network we will extend this model to as many sites as possible throughout California.

- State and County Public Health departments that oversee the NP swab testing and have recently been recognized as key to locating potential plasma donors based on their records. We will seek-up this information and be available to provide the testing necessary to qualify these candidate donors.

http://www.ccpp19.org/http://www.clinicaltrials.gov/


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- Commitment from a large plasma collection group (Vitalant and LifeStream) to work with us in solving the ‘intake’ problem for plasma collection, namely the qualification of the candidate donor. This group has committed to work with us in increasing the efficiency of donor qualification.

10.3.2 Recruitment of Convalescent Donors:

MD-referred convalescent donors: Potential plasma/blood donors who recovered from COVID-19 will be approached by their own physician or MD Coordinator via email or phone (COH or non-COH physician) and screened by an online interaction (see Appendix B).

Self-referred convalescent donors: Convalescent volunteers aware of the use of CCP as a therapy for COVID-19 will directly contact their local blood banks or various websites such as www.conquercovidtogether.com, www.survivorcorps.com and on LifeStream website to donate plasma/blood and will be directed to our portal.

10.4 Informed Consent Procedures

All convalescent donor participants will undergo standard consent through an online portal managed by OnRamp Bioinformatics. Information on the security of the portal and data confidentiality is available in Section 10.8.1.

CCP recipients will undergo written informed consent procedure as dictated by the COH Human Research Protections Office prior to performing any screening procedures that are not part of standard-of-care. Informed consent will be obtained online for the plasma/blood convalescent donors, and by the treating physician for the treated COVID-19 patients. With the support of research personnel or designee, he/she will explain the nature, duration, purpose of the study, potential risks, alternatives and potential benefits, and all other information contained in the informed consent document. In addition, they will review the experimental participant’s bill of rights and the HIPAA research authorization form. Prospective research participants will be informed that they may withdraw from the study at any time and for any reason without prejudice. Prospective research participants will be afforded sufficient time to consider whether or not to participate in the research.

A LAR/Authorized Representative will be used to sign the informed consent document if the patient is not able to provide consent because of an impairment or being unable to communicate (i.e., on a ventilator and sedated). If the LAR/designee is unable to be physically in the room with the patient at the time of written informed consent, the Physician/PI or their designee trained to get informed consent can speak with the LAR via a telemedicine or telephone device, and ask them to sign the consent form. They can photograph the consent form and email it with signature to the physician/PI.

10.5 Registration

Participants will be registered into COH Clinical Trial Management System (CTMS) per COH policy.

10.6 Participant Withdrawal

Participants may withdraw from the study at any time and for any reason without prejudice. The withdrawal must be documented per institutional policies.

Participant withdrawal may consist of any of the following with regard to study procedures and data collection:

o Withdrawal from all active procedures, but agreement for medical record review and survival follow-up.

http://www.conquercovidtogether.com/


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o Withdrawal from all active procedures and any future data collection.

Participants who agreed to the collection of research specimens may withdraw consent to use their specimens, if they are not yet processed as detailed in the consent form. Once the PI and site PI is notified of this withdrawal of informed consent, the research specimens will not be used in any research. At that time, any of the existing specimens will be destroyed.

10.7 Special and Vulnerable Populations

The study is open to anyone regardless of gender, race or ethnicity. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be performed to investigate those differences more fully.

45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, mentally incapacitated persons, or economically or educationally disadvantaged persons. This study will not enroll any children or prisoners.

Lower income workers are more likely to be uninsured, underinsure, and have irregular access to health care. To address the need for improved outreach to such patients, an approach will be developed based on COH experience with sickle cell disease patient outreach, which can reach all California centers/sites, even those located in disproportionately affected communities such as Riverside. The COVID-19 Coordination Program will initiate identification of donors in such centers currently receiving COVID-19 patients, and support those physicians committed to registering to the EAP necessary to implement treatment protocols involving convalescent plasma in these underserved communities.

10.8 Participant Confidentiality

This research will be conducted in compliance with federal and state requirements relating to protected health information (PHI).

Participant confidentiality will be strictly held in trust by the investigators, the patient’s treating physicians, study staff, and the sponsor(s) and their agents.

All study related forms/ documents including informed consent documents will be stored in locked and secure locations. All electronic data will be stored on secure, password-protected computers.

Medical records of participants will be securely maintained in the strictest confidence, according to current legal requirements. Results from this study will not be placed in the participant’s medical records nor communicated to the participant.

All information will be treated confidentially. No identifiers will be used in any subsequent publication of these results.

10.8.1 OnRamp portal

Questionnaires, donor and patient information, and clinical and laboratory results will be stored on an online portal managed by OnRamp. OnRamp Portals leverage world-class encryption based on industry standards for data security as well as compliant infrastructure provided by the Google Cloud Platform. The Google Cloud Platform is certified for NIST 800-53, NIST 800-171, COBIT-5. The Google Cloud Platform conducts rigorous internal continuous testing of our application surface through various types of penetration exercises. In addition, The Google Cloud Platform coordinates external 3rd party penetration testing using qualified and certified penetration testers. The Google Cloud Platform


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undergoes several independent third-party audits to test for data safety, privacy, and security, as noted: SOC 1 / 2 / 3 (Formerly SSAE16 or SAS 70) ISO 27001 ISO 27017 / 27018 PCI-DSS HIPAA.

All users, participants and study administrators require authentication using verification of Email Address or Cell Phone authorization and access to the Portal is only permitted with the use of a user id/password. The Portal maintains secure, time-stamped audit trails that can't be modified by system users, and no external application is allowed to modify or access records within the system. All patient and donor data will be anonymized and stored in a single system with a unique identifier that will be established thereafter (currently, it is in discussion whether this identifier will be provided by TGen or by OnRamp). As per HIPAA standards and 21 CFR guidelines, all data transmission will be encrypted in transit as well as at rest.

10.8.2 Subject-specific study ID and master list

Participants will be given a sequential subject-specific study ID upon registration on the OnRamp portal. The link between the COH research patient number (RPN) and the subject-specific study ID (i.e. master list) will be maintained on the secure, password-protected OnRamp portal and only accessible to the Study PI/ PI designee.

10.8.3 Distribution of biospecimens and clinical data to non-COH collaborators

Processed biospecimens will be coded with a sequential study subject ID. Anonymized data set devoid of HIPAA-identifiers (sequential study subject ID and timepoint of sample (e.g. Day + 0)) will be established. Data transmittal forms will not accompany the processed anonymized samples.

Clinical data will be collected from non-COH sites, but if data is collected at COH from the electronic health records, these data will not be disclosed to non-COH collaborators. Clinical data analysis will be performed by the study biostatistican, Paul Frankel, and by the Study PI/ PI designee.

10.9 Potential Risks and Benefits to Participation

10.9.1 Potential risks to participation

Blood specimens requested for this study will be collected by medical professionals, and the risk to the participants will be minimized. There will not be any additional needle stick (when not obtained by catheter) for research blood collection.

Nasopharyngeal swabbing can cause discomfort and epistaxis.

The risk of breach in confidentiality will be mitigated by following procedures detailed in Section 10.8.

10.9.2 Potential benefits to participation

There is no direct significant benefit to the research participant for the research done in this study. However, the participant may benefit from the knowledge that his/her participation may help others.

10.9.3 Potential benefits to others

It is expected, however, that the information learned from this study will benefit future patients by assessing whether serologic parameters in CCP predicts clinical outcome in COVID-19 recipients.


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10.10 Alternatives to Participation

Convalescent donors consent to join the study by a voluntary online interaction, but after this, they, or the collection site, can choose not to have their plasma collected. In such cases, the screening data would remain in the study unless requested to be removed by the donor. Convalescent donors can choose not to participate, and this will not impact their medical care in any way since they are healthy donors. Data from such subjects would be removed from analysis.

The COVID-19 patients will have already consented to participate in the expanded access trial and could choose to leave that trial at any time, in which case they would not be treated and would pari passu leave this study.

10.11 Conflict of Interest

Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in this study. All City of Hope investigators will follow the City of Hope conflict of interest policy.

10.12 Future Use of Unused (Leftover) Samples Collected for This Study

Unused processed blood samples will be banked in a repository at TGen under the supervision of J. Altin. Unused plasma samples will also be banked in a repository at COH in the Laboratory of Cellular Medicine under the supervision of A. Cardoso. These samples will be anonymized, cryopreserved, archived, and retained for future research purposes (eg, future exploratory analysis). All stored samples will be accessible only authorized members. Samples will be stored in freezers equipped with locks and located in the building behind locked doors with cypher or key pad entry.

When requested, and after approval by Dr. Altin and Dr. Zaia, anonymized samples may be shared with collaborators for secondary research. An MTA will be executed for such transfer of specimens.

10.13 Financial Obligations, Compensation, and Reimbursement of Participants

Neither the research participants nor the insurance carrier will be responsible for the research procedures related to this study. Patient treatment is directed independent of this study by the patient’s physician, and this study only collects biospecimens and data pre- and post-treatment. This study does not include plasmapheresis and does not contain research treatment.

The study monitors the treatment of patient-subjects, but is not a treatment study per se. The standard of care drugs or procedures provided to the patient during the course of study participation will be the responsibility of the research participant and/or the insurance carrier. The participant will be responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by the insurance carrier. The participant and/or the insurance carrier will be billed for the costs of treatment and diagnostic procedures in the same way as if the participant were not in a research study.

There are no plans for City of Hope or TGen to provide financial compensation in the event of physical injury to a participant.

The research participant may be eligible for reimbursement for up to $50 for travel expenses.


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10.14 Publication/Data Sharing

Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information provided by City of Hope for the purposes of performing the study, will be published or passed on to any third party without the written approval of the Study PI. Any investigator involved with this study is obligated to provide City of Hope with complete test results and all data derived from the study.

The preparation and submittal for publication of manuscripts containing the study results shall be in accordance with a process determined by mutual written agreement between City of Hope and participating institutions/ co-investigators. The publication or presentation of any study results shall comply with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 1996.

11.0 DATA AND SAFETY MONITORING AND UP REPORTING

This is a Risk Level 1 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, because this study involves minimal risk specimen collection (blood and NP swab) and data collection.

Monitoring and Personnel Responsible for Monitoring The Principal Investigator (PI) is responsible for monitoring protocol conduct and reporting to the City of Hope (COH) Data and Safety Monitoring Committee (DSMC) and Institutional Review Board (IRB) as indicated in the sections below. Unanticipated Problems (UP) Involving Risks to Subjects or Others An unanticipated problem is any incident, experience or outcome that meets all three of the following criteria:

1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research procedures that are described in the protocol-related documents such as the IRB approved research protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of the subject population being studied; AND

2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcomes may have been caused by the procedures involved in the research); AND

3. Suggests that the research places participants or others at greater risk of harm (including physical, psychological, economic, or social harm) than previously known or recognized.

Any UP that occurs during the study conduct will be reported to the DSMC and IRB in accordance with the City of Hope’s Institutional policy [policy effective date: 05/14/14] using the electronic submission system, iRIS. Deviations A deviation is a divergence from a specific element of a protocol and that occurred without prior IRB approval. Deviations from the approved protocol will be avoided, except when necessary to eliminate an immediate hazard to a research participant. A Corrective and Preventative Action (CAPA) plan should be developed by the study staff and implemented promptly to avoid similar issues in the future. All deviations from the protocol must be documented in study source documents and promptly reported to the DSMC and IRB. Reporting Deviations

https://na14.salesforce.com/sfc/p/d0000000gcFM/a/d0000000XZmD/qzUUIf59yIoJrNUmJlNyEq6.GH2gCzXO9tQjcuvLKKchttps://na14.salesforce.com/sfc/p/d0000000gcFM/a/d0000000XZnk/h_UlRVZ7Nb0cZvBYiVazE6idX_BVYmTdju_hY7Vq2xEhttp://iris.coh.org/


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Investigators may deviate from the protocol to eliminate immediate hazards for the protection, safety, and well-being of the study subjects without prior IRB approval. For any such deviation, the PI will notify the DSMC and IRB, within 5 calendar days of its occurrence by electronic submission of a Deviation Notice via iRIS. Planned Protocol Deviation (PPD) Amendment Request Deviations from the written protocol that are not done to eliminate an immediate hazard(s) for the protection, safety and well-being of study subjects but may increase risk and/or alter the protocol integrity require prior IRB approval. The deviation is submitted as a Planned Protocol Deviation (PPD) amendment request. An IRB approved PPD does not need to be submitted as a protocol deviation to the DSMC. The PPD should be submitted according to the IRB guidelines and Clinical Research Protocol Deviation policy [policy effective date: 11/07/11] and submitted via iRIS. A deviation that is not a PPD (i.e., discovered after the occurrence) must be reported to the COH DSMC and IRB according to the Clinical Research Protocol Deviation policy [policy effective date: 11/07/11] and submitted via iRIS.

http://iris.coh.org/https://na14.salesforce.com/sfc/p/d0000000gcFM/a/d0000000XZnu/89t1NKrXYjae7w4dVOxnyOUhLAFqbbS_Yscwv0zKqlshttps://na14.salesforce.com/sfc/p/d0000000gcFM/a/d0000000XZnu/89t1NKrXYjae7w4dVOxnyOUhLAFqbbS_Yscwv0zKqlshttp://iris.coh.org/https://na14.salesforce.com/sfc/p/d0000000gcFM/a/d0000000XZnu/89t1NKrXYjae7w4dVOxnyOUhLAFqbbS_Yscwv0zKqlshttp://iris.coh.org/


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12.0 APPENDICES

12.1 Appendix A: Registration Questionnaire for Treating Physicians

Note: This online interaction will be linked to the online portal. Each treating physician will first create an account with a user id/password.

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Thank you for your interest in helping with this research effort! Please fill out this questionnaire and one of our MD Coordinators or designees will contact you as soon as possible.

12.1.1 Registration (only for first-time connection on the portal)

- Site/Medical Center name and address - Treating Physician/PI full name, email and phone number - NPI and DEA number - Contact Information for Office Nurse/Research Coordinator/Other Support Person

Provide full name, email and telephone number for an office nurse/research coordinator/other support person

- Are you and your patients registered under Mayo EAP? Yes/No - Did you register to an eIND? Yes/No - Did you register to a local IRB? Yes/No - List IND number (if you have one) - Site/Medical Center Regulatory or IRB Administrative Key Contact Information (For future

contact in case of emergency or serious non-compliance): Full name, email address and telephone number of Regulatory or IRB Administrative Key Contact

- Site/Medical Center Blood Bank Supervisor (This is the contact information for the local personnel who will be ordering the CCP): Provide full name, email and phone number

- Have you identified potential CCP donors? Yes/No - Medical Center Health Record System: EPIC, Cerner, Other - Do you have any questions/comments?

12.1.2 Treating physician agreement (only for first-time connection on the portal)

Please fill out the following questionnaire: - Do you agree to participate in the COH/TGen study? Yes/No

Your request to participate in the COH study, use of the product and the consent form indicates your willingness and that of your institution/hospital/practice/legal business entity to adhere to the protocol, to rely upon a local IRB, the Mayo Clinic IRB (IND#19832) or an eIND, that you will follow all federal and state regulations regarding use and administration of the investigational product and that you will conduct the EAP in accordance with the principles set forth in the Belmont Report. - Do you agree to provide medical information before CCP unit infusion, 12-24h post each CCP

unit infusion, 7 days (±3 days) post last CCP unit infusion, 28 days post last CCP UNIT infusion

and at discharge from the hospital?

Please review the CRF you or a designee will be asked to complete. - Do you agree to consent the patient for the COH/TGen study? Yes/No


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- If the patient consents, do you agree to collect blood samples (~10.5 mL) at the following

timepoints: before CCP unit infusion, 12-24h post each CCP unit infusion, and 7 days (±3 days)

post last CCP unit infusion? Yes/No

- Do you agree to collect a ~1 mL retaining sample of the CCP unit infused in the patient?

Yes/No

12.1.3 COVID-19 Patient Registration Form (for each patient treated)

After you consent the patient to be part of the COH/TGen study, please register him/her on our portal:

1. Confirm you have obtained patient consent to be part of the COH/TGen study

- Informed consent (IC) has been obtained: Yes/No

- Date informed consent obtained

2. Enroll Patient on the portal

- Patient's full name - Patient's Initials (First Middle Last) (If no middle name use "X" as the middle initial) - Medical Record Number - Gender of Patient: Female/Male/Other - Race (select all that apply)

o Asian o American Indian or Alaska Native o Black or African American o White o Native Hawaiian or Other Pacific Islander o Other or Unknown

- Ethnicity o Hispanic/Latino o Not Hispanic/Latino

- Patient's Date of Birth MM-DD-YYYY (ex. 05-18-1989) - Weight (kg) - Date of COVID-19 Diagnosis test MM-DD-YYYY - Is the patient a healthcare worker who has direct COVID-19 patient contact at work? Yes/No - Is the patient pregnant? If yes: Gestational weeks assessment [___]weeks

3. Confirm the patient is eligible to be treated with CCP

All must be present: - Age at least 18 years - Laboratory confirmed diagnosis of infection with SARS-CoV-2 - Patient qualifies for a clinical trial involving the infusion of CCP for the treatment of COVI

city of hope national medical center 1500 e. duarte road … cirm covi… · irb institutional...

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