Statement_of_Work.pdf

STATEMENT OF WORK

1. INTRODUCTION/OVERVIEW

1.1. Project Title

Genomic Research Alliance for Transplantation (GRAfT) Project

1.2. Background

Heart and lung transplantation are well-established treatment options for selected patients with end-stage heart and lung disease. Advances in surgical techniques have significantly reduced post-operative complications, resulting in 1-year survival that often exceeds 90 percent.

Unfortunately, long-term graft viability is still limited by chronic rejection, which is manifested in heart grafts as chronic allograft vasculopathy (CAV) and in lung grafts as chronic lung allograft dysfunction (CLAD).

The most common CAV risk factor is acute rejection (AR), which occurs in up to 20 percent of heart-transplant patients within the first 6 months after transplantation. Given this high prevalence, heart-transplant patients undergo repeated invasive endomysial biopsies (EMB) to monitor for the presence of AR. Unfortunately, AR can often occur in a non-uniform pattern in the heart, and since EMB only sample a small percentage of the heart, this results in a high false-negative rate in addition to high cost and procedure-related complications. A low concordance rate between pathologists’ biopsy grading presents further problems.

There is little understood about the nature of AR. For this reason, Dr. Hannah Valantine, Director of the Laboratory of Transplantation Genomics in the National Heart Lung and Blood Institute (NHLBI) established a local research consortium—Genomic Research Alliance for Transplantation (GRAfT)—dedicated to learning more about the disease. GRAfT is comprised of various heart/lung-transplant centers throughout the Washington, D.C. metropolitan area.

Each center contributes biological samples from consenting heart/lung-transplant patients to GRAfT’s bio-bank located at NHLBI’s facilities for further sequencing and analysis.

1.3. Scope

The Contractor shall provide the Government with additional biological samples to further research in AR.

1.4. Purpose and Objectives

The Laboratory of Transplantation Genomics is in need of 620 biological samples from heart/lung-transplant patients in order to allow GRAfT to effectively observe AR and begin validating the predictive accuracy and ROC characteristics of %ccfdDNA. Samples collected from the Contractor will be sequenced by NHLBI, and the resultant data will be added to an existing data set for further analysis. Effective analysis cannot occur without the full quantity of samples.

2. REQUIREMENTS

2.1. Contractor Requirements

Independently and not as an agent of the Government, the Contractor shall provide the NHLBI with clinical samples according to the following guidelines:

2.1.1. Sample Processing

The Contractor shall use the NHLBI’s collection/processing kit to process each sample as per NHLBI protocol Standard Operation Procedures (SOPs), within two (2) hours of collection as follows:

2.1.1.1. Collect RNA-Later

Add 5 mL of total blood to a solution to preserve RNA-Later for later RNA purification at NIH.

2.1.1.2. Centrifuge to collect plasma

Spin the remaining whole blood twice (1500G followed by 15,000 G) to isolate plasma.

2.1.1.3. Collect Peripheral Blood Mononuclear Cells (PBMNC)

Use the cell pellet to purify mononuclear cells on a Ficoll gradient. (Only technicians who have undergone CHI standard operating procedure training at NIH shall perform this step).

2.1.1.4. Scan Pathology slides into NHLBI’s online repository

2.1.1.5. Enter data into NHLBI’s clinical database

(See Section 2.1.2, Data Entry).

2.1.1.6. Freeze sample

Once all the necessary data has been recorded, freeze the sample and prepare the sample for shipment. (See 2.1.3., Sample Shipment).

2.1.2. Data Entry

Unless otherwise provided by the NHLBI, the Contractor shall upload the following information onto the NHLBI’s online database per protocol SOP.

2.1.2.1. Lung-transplant Patient Samples

2.1.2.1.1. Pre-transplantation Data Collection (Recipient demographics)

Study-specific identification number Date enrolled (date when consent form signed), UNOS status at enrollment, UNOS status at transplantation Transplant center Gender, race, ethnicity Date of birth, weight at enrollment, height, body mass index Primary diagnosis for transplantation Co-morbid conditions pre-transplant [diseases, hospitalization, ventilator, inotropes, ECMO, VAD, IABP, HD, creatinine, smoker status, NO, inhaled prostacyclin, prostaglandins, supplemental oxygen (also dose), infection requiring antibiotics, other medications]

Pre-transplant spirogram: FEV1. FVC, FEV1/FVC. TLC, RV/TLC, DLCO, DLCO/VA

Pre-transplant echocardiogram Pre-transplant medications Blood type HLA type IgG cPRA, C1q cPRA, Transplant listing date CMV status Physical capacity pre-transplant measured by 6 minute-walk test

2.1.2.1.2. Pre-transplantation Data Collection (Donor demographics)

OPO

Age, weight, height, Gender, race, ethnicity Blood type, HLA type Graft PaO2, FIO2 Pulmonary artery catheter measurements Donor bronchoscopy results Donor cultures from BAL Donor CXR results: abnormalities (mass, infiltrates,) and location CMV status Comorbidities (diseases, CAD status, smoking, chest trauma, EtOH use, IVDU).

High risk status per CDC guidelines Ex-vivo lung perfusion Cause of death Donor sample collected for DNA isolation

2.1.2.1.3. Peri-transplantation Data Collection

Ischemic time per lung for double lung transplant Induction regimen Duration of mechanical ventilation Primary Graft Dysfunction: diagnosis, grade and duration of symptoms 6mwt, oxygen requirement at discharge Spirogram prior to discharge Echocardiogram prior to discharge Discharge medication (dose, levels) Blood sample collected twice a week during hospitalization

2.1.2.1.4. Post-transplantation Data Collection (Routine follow-up clinical data collection) Last hospitalization: diagnosis, treatment, bronchoscopy report, imaging data, pathology report, microbiology results, immunosuppression drug levels)

Symptoms (cough, sputum, sputum color, sob, chest pain) Imaging (CXR or CT chest): indication, findings and location of findings Spirogram data Echocardiogram data Baseline oxygen requirement, SpO2 6mwt, ABG Post-transplant complications: diabetes, bronchial stenosis, renal failure, depression, etc… Prior history of acute rejection: date of diagnosis, symptoms, biopsy-grade, treatment CMV/RSV, respiratory virus status BOS status: diagnosis and severity

DSA status and titer Medications: dose and levels

2.1.2.1.5. Post-transplantation Data Collection (Biopsy visit and sample collections) Time point (weeks/months after transplant) Biopsy visit: routine or emergent/urgent Procedures performed (BAL, TBBx, stent placement) BAL cell count and differential, immunocompromised viral panel, culture results Biopsy results: infection, rejection type: antibody vs. cellular rejection Biopsy grade: 2004 ISHLT classification Amount of excess BAL collected Blood sample collected.

Blood product isolated: plasma, PBMNC, RNA-later Sample shipping date

2.1.2.1.6. Post-transplantation Data Collection (Rejection/infection event

Date of diagnosis Specific symptoms: cough, sputum (color, blood), chest pain, sob CT chest data/CXR data: indication, findings and location of findings Echo performed Spirometry, 6mwt (admission and discharge) Medications on admissions and levels Bronchoscopy: BAL, biopsy, stent Biopsy results (infection, ACR, AMR) and grade Microbiology (sputum/BAL/biopsy culture results, respiratory virus immunocompromised panel results) Rejection treatment: steroid (dose), ATG, IVIg, Plasmapheresis, Rituximab, other Antibiotic treatment Medication changes at discharge, drug levels Hospitalization data: duration, supplemental oxygen, discharge oxygen requirement and FEV1 Outcome: resolved, no sequel, improving, death, etc…

2.1.2.1.7. Post-transplantation Data Collection (Spirogram data collection)

Scheduled or urgent

FEV1, FEV1/FVC, FVC, TLC, TLC/RV, DLCO, DLCO

2.1.2.2. Heart-transplant Patient Samples

2.1.2.2.1. Pre-transplantation Data Collection (Recipient demographics)

Study specific identification number Date enrolled (date when consent form signed), UNOS status at enrollment, UNOS status at transplantation Transplant center Gender, race, ethnicity

DOB, weight at enrollment, height, BMI Primary diagnosis for transplantation Prior sternotomy Co-morbid conditions pre-transplant (disease, ICU stay, in-hospital, ventilator, inotropes, ECMO, VAD (LVAD, LVAD Type, BiVADs, TAH), IABP, HD, creatinine, GFR, smoker status)

Pre-transplant echocardiogram, pre-transplant spirogram Pre-transplant medications Blood type HLA type IgG cPRA, C1q cPRA Transplant listing date CMV status

2.1.2.2.2. Pre-transplantation Data Collection (Donor demographics)

OPO

Age, weight, height, Gender, race, ethnicity ECHO: EF, LVEDD, IVSd, PWd Pa catheter measurements Inotropes / Vasopressors Blood type, HLA type CMV status Comorbidities (diseases, CAD status, smoking, chest trauma, EtOH use, IVDU).

High risk status per CDC guidelines Cause of death Donor sample collected for DNA isolation

2.1.2.2.3. Peri-transplantation Data Collection

Ischemic time Induction regimen Duration of mechanical ventilation PGD: diagnosis, grade, duration 6 mwt, oxygen requirement at discharge Spirogram prior to discharge Echocardiogram at discharge: EF, LVEDD, IVSd, PWd Discharge medication (dose, levels) Blood samples collected twice weekly

2.1.2.2.4. Post-transplantation Data Collection (Routine follow-up clinical

Last hospitalization diagnosis, treatment, bronchoscopy report, imaging data, pathology Symptoms (cough, sob, chest pain) Hemodynamics (vital signs) CXR/CT chest: indication, findings and location of findings Echocardiogram: EF, LVEDD, IVSd, PWd Spirogram data Baseline oxygen requirement, SpO2 6mwt, ABG

Post-transplant complications: diabetes, bronchial stenosis, renal failure, depression, etc

Prior history of acute rejection: date of diagnosis, symptoms, biopsy-grade, treatment

CMV status CAV status DSA status and titer Drug and dose, drug levels where applicable, dose change

2.1.2.2.5. Post-transplantation Data Collection (Biopsy visit and sample collections) Time point (weeks/months after transplant) Biopsy visit: routine or emergent/urgent Biopsy grade: 2004 ISHLT classification Rejection type: antibody vs. cellular rejection Allomap score Amount of blood sample collected Blood product isolated: plasma, PBMNC, RNA-later Sample shipping date

2.1.2.2.6. Post-transplantation Data Collection (Rejection/infection event

Date of diagnosis Specific symptoms: None, chest pain, sob, etc Admission drugs and levels Echocardiogram: EF, LVEDD, IVSd, PWd Spirometry Imaging data (CXR, CT chest) CMV status, viral load Biopsy performed Biopsy grade: 2004 ISHLT classification Echocardiogram: EF, LVEDD, IVSd, PWd Rejection treatment: steroid (dose), ATG, IVIg, Plasmapheresis, Rituximab, Bortezomib, other Medication changes and levels Hospitalization data: duration, supplemental oxygen, mechanical ventilation, diuresis, CVVH, iHD, discharge oxygen requirement, Outcome: resolved, no sequel, improving, death, etc…

2.1.2.2.7. Post-transplantation Data Collection (Spirogram data collection)

Scheduled or urgent Angiography CAV grade IVUS CAV grade if performed

2.1.3. Sample Shipment

After ensuring the sample has been properly frozen per protocol SOP, the Contractor shall complete a Sample Collection Form provided by the NHLBI. Samples should be shipped to NHLBI per protocol SOP.

2.2. Reporting Requirements and Deliverables

The Contractor shall email a monthly progress report in PDF format to the Contracting Officer’s

Representative (COR). The reports will be due to the COR within the first week of each calendar month. The reports shall include the following information:

Total number of patients enrolled in the protocol (since protocol inception).

Total number of patients withdrawn from the protocol (since protocol inception) Total number of active (post-transplant) patients as of date of report Total number of heart/lung-transplants performed (since protocol inception) Total number of samples shipped to NHLBI (since protocol inception) Total number of new patients enrolled in the protocol during reporting period Total number of heart/lung-transplants performed by during reporting period Total number of samples shipped to NHLBI during reporting period