Clinical trial NCT04420195
Conditions: Lung Transplant
Sponsor: NYU Langone Health
Start date: 2020-10-23; Completion date: 2022-11-30
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients undergoing a lung transplant will be enrolled. All patients will undergo lung transplantation with standard post-operative management, including triple immunosuppression. As soon as the patient is deemed appropriate to take medications via the oral route, they will be converted from IR tacrolimus to Envarsus XR. Patients will be followed per site's standard of care.

Detailed description:
Lung transplantation will be performed per standard-of-care techniques. All post-transplant management, including initial triple immunosuppression, will be carried out per standard of care. Once the patient is able to take medications via the oral route, they will be converted to Envarsus XR, which will be maintained for the first year post-lung transplant.

Arms: arm 1: Envarsus XR to be initiated once patient is tolerating oral medications arm 2: Historical cohort of patients maintained on IR tacrolimus following transplant
Interventions: intervention 1: Extended-Release Tacrolimus intervention 2: Immediate-Release Tacrolimus
Intervention descriptions: intervention 1: Envarsus XR is an FDA-approved drug for the prophylaxis of organ rejection in de novo kidney transplant patients or in kidney transplant patients converted from IR tacrolimus when used with other immunosuppressants. Envarsus XR is a novel extended-release formulation of tacrolimus created using MeltDose technology. Envarsus XR is available in tablet form. It is available in 0.75, 1, and 4 mg tablets. intervention 2: Historical cohort of 20 subjects who will be maintained on IR tacrolimus following transplant. Dosing will be converted on an individual basis (Capsules: 0.5 mg, 1 mg and 5 mg or Injection: 5 mg) . All patients will be initiated on IR tacrolimus either under the tongue (sublingual) or as a solution given through a tube placed through the nose into the stomach, which is standard of care for all lung transplant recipients.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Pilot Study Comparing Early Conversion to Extended-Release 
Tacrolimus (ENVARSUS XR) to Immediate-Release Tacrolimus in Lung 
Transplant Recipients   
NCT Number: 
NCT04420195 
Study Number: 
19-01247 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
 December 21, 2021 
 
 


 
 
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authorized in writing by the study sponsor 
 
 
 
 
 
 
 
PILOT STUDY COMPARING EARLY CONVERSION TO EXTENDED-
RELEASE TACROLIMUS (ENVARSUS XR) TO IMMEDIATE-RELEASE 
TACROLIMUS IN LUNG TRANSPLANT RECIPIENTS 
 
Principal Investigator: 
 
Luis F Angel, MD 
Professor of Medicine and Cardiothoracic Surgery 
Medical Director, Lung Transplant Program 
530 First Avenue, HCC Suite 7A 
New York, NY 10016 
646-501-9884 
luis.angel@nyulangone.org 
Additional Investigators: 
Co-investigators: 
Tyler Lewis, PharmD (tyler.lewis@nyulangone.org) 
Zachary Kon, MD (zachary.kon@nyulangone.org) 
Melissa Lesko, DO (melissa.lesko@nyulangone.org) 
Darya Rudym, MD (darya.rudym@nyulangone.org 
Kimberly Sureau, DNP (kimberly.sureau@nyulangone.org)  
Stephanie Chang, MD (stephanie.chang@nyulangone.org) 
NYULMC Study Number: 
i19-01247  
Funding Sponsor: 
Veloxis Pharmaceuticals Inc. 
1001 Winstead Drive, Suite 310, Cary, NC 27513 
1-919-591-3090 
IND/IDE Number: 
None 
Regulatory Sponsor:  
None 
Study Product: 
Extended-release Tacrolimus (Envarsus XR) 
Study Product Provider: 
Veloxis Pharmaceuticals, Inc, Cary, North Carolina 
ClinicalTrials.gov 
Number                 
To be assigned. 
 
Initial version: January 28, 2020 
1st Addendum: July 6, 2020 
2nd Addendum: July 23, 2020 
3rd Addendum: October 30, 2020 
4th Addendum: November 30, 2020 
5th Addendum: January 27, 2021 
6th Addendum: March 25, 2021 
7th Addendum: May 18, 2021  
8th Addendum: December 10, 2021


 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 


Study number: i19-01247 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................. II 
LIST OF ABBREVIATIONS......................................................................................................................... VI 
PROTOCOL SUMMARY .............................................................................................................................. 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 2 
1 
KEY ROLES ............................................................................ ERROR! BOOKMARK NOT DEFINED. 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 4 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 4 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT .............................................................. 5 
2.2.1 
Preclinical Data........................................................................................................................ 6 
2.2.2 
Clinical Data to Date ................................................................................................................ 6 
2.2.3 
Dose Rationale (if applicable) ................................................................................................. 6 
2.3 
RATIONALE .................................................................................................................................... 6 
2.4 
POTENTIAL RISKS & BENEFITS ........................................................................................................ 7 
2.4.1 
Known Potential Risks ............................................................................................................. 7 
2.4.2 
Known Potential Benefits ........................................................................................................ 7 
3 
OBJECTIVES AND PURPOSE ........................................................................................................... 7 
3.1 
PRIMARY OBJECTIVE ...................................................................................................................... 7 
3.2 
SECONDARY OBJECTIVES (IF APPLICABLE) ...................................................................................... 7 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................... 7 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................... 7 
4.2 
STUDY ENDPOINTS......................................................................................................................... 7 
4.2.1 
Primary Study Endpoints ......................................................................................................... 7 
4.2.2 
Secondary Study Endpoints .................................................................................................... 7 
4.2.3 
Exploratory Endpoints ............................................................. Error! Bookmark not defined. 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................... 8 
5.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
5.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
5.3 
VULNERABLE POPULATIONS ........................................................................................................... 8 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................................................ 8 
5.5 
DURATION OF STUDY PARTICIPATION .............................................................................................. 8 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES .................................................................................. 9 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION .................................................................................. 9 
5.7.1 
Reasons for Withdrawal or Termination .................................................................................. 9 
5.7.2 
Handling of Participant Withdrawals or Termination ............................................................... 9 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................... 9 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 10 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 10 
6.1.1 
Acquisition ............................................................................................................................. 10 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 10 
6.1.3 
Product Storage and Stability ................................................................................................ 10 
6.1.4 
Preparation ............................................................................................................................ 10 
6.1.5 
Dosing and Administration .................................................................................................... 10 
6.1.6 
Route of Administration ......................................................................................................... 11 
6.1.7 
Starting Dose and Dose Escalation Schedule ...................................................................... 11 
6.1.8 
Dose Adjustments/Modifications/Delays ............................................................................... 11 
6.1.9 
Duration of Therapy ............................................................................................................... 11 


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6.1.10 
Tracking of Dose ............................................................................................................... 11 
6.1.11 
Device Specific Considerations .......................................... Error! Bookmark not defined. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 11 
6.3 
STUDY BEHAVIORAL OR SOCIAL INTERVENTION(S) ......................... ERROR! BOOKMARK NOT DEFINED. 
6.3.1 
Administration of Intervention .................................................. Error! Bookmark not defined. 
6.3.2 
Procedures for Training Interventionalists and Monitoring Intervention Fidelity ............. Error! 
Bookmark not defined. 
6.3.3 
Assessment of Subject Compliance with Study Intervention ................................................ 11 
6.4 
STUDY PROCEDURAL INTERVENTION(S) DESCRIPTION ................... ERROR! BOOKMARK NOT DEFINED. 
6.4.1 
Administration of Procedural Intervention ............................... Error! Bookmark not defined. 
6.4.2 
Procedures for Training of Clinicians on Procedural InterventionError! 
Bookmark 
not 
defined. 
6.4.3 
Assessment of Clinician and/or Participant Compliance with Study Procedural Intervention
 
Error! Bookmark not defined. 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 11 
7.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 11 
7.1.1 
Study Specific Procedures .................................................................................................... 11 
7.1.2 
Standard of Care Study Procedures ..................................................................................... 12 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 12 
7.2.1 
Clinical Laboratory Evaluations ............................................................................................. 12 
7.2.2 
Other Assays or Procedures ................................................... Error! Bookmark not defined. 
7.2.3 
Specimen Preparation, Handling, and Storage ....................... Error! Bookmark not defined. 
7.2.4 
Specimen Shipment ................................................................ Error! Bookmark not defined. 
7.3 
STUDY SCHEDULE ........................................................................ ERROR! BOOKMARK NOT DEFINED. 
7.3.1 
Screening ................................................................................ Error! Bookmark not defined. 
7.3.2 
Enrollment/Baseline ................................................................ Error! Bookmark not defined. 
7.3.3 
Intermediate Visits ................................................................... Error! Bookmark not defined. 
7.3.4 
Final Study Visit ....................................................................... Error! Bookmark not defined. 
7.3.5 
Withdrawal/Early Termination Visit.......................................... Error! Bookmark not defined. 
7.3.6 
Unscheduled Visit .................................................................... Error! Bookmark not defined. 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 12 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................ ERROR! BOOKMARK NOT DEFINED. 
7.5.1 
Precautionary Medications, Treatments, and Procedures .................................................... 12 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 13 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ... ERROR! BOOKMARK NOT DEFINED. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............. ERROR! BOOKMARK NOT DEFINED. 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................................................ 13 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 13 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 13 
8.1.1 
Definition of Adverse Events (AE) ......................................................................................... 13 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 13 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 14 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 14 
8.2.1 
Severity of Event ................................................................................................................... 14 
8.2.2 
Relationship to Study Agent .................................................................................................. 14 
8.2.3 
Expectedness ........................................................................................................................ 15 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 15 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 16 
8.4.1 
Adverse Event Reporting ...................................................................................................... 16 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 16 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 16 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 16 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 16 
8.6 
REPORTING PROCEDURES – NOTIFYING THE FDA ......................... ERROR! BOOKMARK NOT DEFINED. 
8.7 
REPORTING PROCEDURES – PARTICIPATING INVESTIGATORS ......... ERROR! BOOKMARK NOT DEFINED. 


Study number: i19-01247 
 
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8.8 
STUDY HALTING RULES ................................................................ ERROR! BOOKMARK NOT DEFINED. 
8.9 
SAFETY OVERSIGHT ..................................................................................................................... 17 
9 
CLINICAL MONITORING .................................................................................................................. 17 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 17 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 17 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................... 18 
10.3 
ANALYSIS DATASETS .................................................................................................................... 18 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 18 
10.4.1 
General Approach ............................................................................................................. 18 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) .................................................................... 18 
10.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 18 
10.4.4 
Safety Analyses ................................................................................................................ 18 
10.4.5 
Adherence and Retention Analyses .................................................................................. 18 
10.4.6 
Baseline Descriptive Statistics .......................................................................................... 19 
10.4.7 
Planned Interim Analysis .................................................................................................. 19 
10.4.8 
Additional Sub-Group Analyses .......................................... Error! Bookmark not defined. 
10.4.9 
Multiple Comparison/Multiplicity .......................................... Error! Bookmark not defined. 
10.4.10 
Tabulation of Individual Response Data ............................. Error! Bookmark not defined. 
10.4.11 
Exploratory Analyses .......................................................... Error! Bookmark not defined. 
10.5 
SAMPLE SIZE ............................................................................................................................... 19 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................... ERROR! BOOKMARK NOT DEFINED. 
10.6.1 
Enrollment/Randomization/Masking Procedures ................ Error! Bookmark not defined. 
10.6.2 
Evaluation of Success of Blinding ....................................... Error! Bookmark not defined. 
10.6.3 
Breaking the Study Blind/Participant Code ......................... Error! Bookmark not defined. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 19 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 20 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 20 
13.1 
ETHICAL STANDARD ..................................................................................................................... 20 
13.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 20 
13.3 
INFORMED CONSENT PROCESS .................................................................................................... 20 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 20 
13.3.2 
Consent Procedures and Documentation ......................................................................... 44 
13.4 
POSTING OF CLINICAL TRIAL CONSENT FORM................................................................................. 45 
13.5 
PARTICIPANT AND DATA CONFIDENTIALITY ...................................................................................... 45 
13.5.1 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 47 
13.6       FUTURE USE OF STORED SPECIMENS .........................................................................................47 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 22 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 22 
14.2 
STUDY RECORDS RETENTION ....................................................................................................... 22 
14.3 
PROTOCOL DEVIATIONS ............................................................................................................... 22 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 23 
15 
STUDY FINANCES ............................................................................................................................ 23 
15.1 
FUNDING SOURCE ........................................................................................................................ 23 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 23 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................ ERROR! BOOKMARK NOT DEFINED. 
16 
STUDY ADMINISTRATION ............................................................................................................... 23 
16.1 
STUDY LEADERSHIP ..................................................................................................................... 23 
17 
CONFLICT OF INTEREST POLICY .................................................................................................. 24 
18 
REFERENCES ................................................................................................................................... 24 


Study number: i19-01247 
 
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19 
ATTACHMENTS ................................................................................................................................ 26 
20 
SCHEDULE OF EVENTS .................................................................................................................. 27 
 
List of Abbreviations 
 
ACR 
Acute Cellular Rejection 
AE 
Adverse Event/Adverse Experience 
AMR 
Antibody-mediated Rejection 
CFR 
Code of Federal Regulations 
CKD 
Chronic Kidney Disease 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSA 
Donor-Specific Antibody 
DSMB 
Data and Safety Monitoring Board 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 


Study number: i19-01247 
 
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Protocol Summary 
Title 
Pilot Study Comparing early conversion to Extended-release Tacrolimus 
(ENVARSUS XR) to immediate-release Tacrolimus in lung transplant 
recipients 
Short Title 
Envarsus XR in Lung Transplant 
Brief Summary 
Patients undergoing a lung transplant will be enrolled. All patients will 
undergo lung transplantation with standard post-operative management, 
including triple immunosuppression. As soon as the patient is deemed 
appropriate to take medications via the oral route, they will be converted from 
IR tacrolimus to Envarsus XR. Patients will be followed per site’s standard of 
care.  
Phase 
Pilot study 
Objectives 
To determine the feasibility of early conversion to Envarsus XR in patients 
who receive a lung transplant. To compare the impact of tacrolimus 
formulation on CKD, ACR, AMR, and de novo DSA within the first year post-
lung transplant.  
Methodology 
Single-center, open-label study 
Endpoint 
Incidence of CKD, ACR, AMR, and de novo DSA in the first year post-lung 
transplant 
Study Duration 
Two years 
Participant Duration 
One year 
Duration of IP 
administration 
One year 
Population 
Adult patients undergoing lung transplantation 
Study Sites 
NYU Langone Hospital 
Number of participants 
Sixty patients (20 patients who received IR tacrolimus and 40 patients who 
will receive Envarsus XR) 
Description of Study 
Agent/Procedure 
Lung transplantation will be performed per standard-of-care techniques. All 
post-transplant management, including initial triple immunosuppression, will 
be carried out per standard of care. Once the patient is able to take 
medications via the oral route, they will be converted to Envarsus XR, which 
will be maintained for the first year post-lung transplant. 
Reference Therapy 
IR tacrolimus 
Key Procedures 
Patients in the Prospective Cohort will receive lung transplantation and post-
operative management per standard protocol, including frequency of 
laboratory assays, surveillance bronchoscopy, and DSA assessment by 
single-antigen bead assay.  
Statistical Analysis 
Categorical variables will be compared using chi-square test or Fisher’s exact 
test, as appropriate. Continuous variables will be compared using the Mann-
Whitney U test for nonparametric data. 
 
 
 


Study number: i19-01247 
 
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Schematic of Study Design 
 
 
Envarsus XR 
ARM 1 
n=40 
Envarsus XR to be 
initiated once 
patient is tolerating 
oral medications  
IR tacrolimus 
(historical control) 
ARM 2 
n=20 
Historical cohort of 
patients maintained 
on IR tacrolimus 
following transplant 
 
 
 
 


Study number: i19-01247 
 
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1 Key Roles 
 
Principal Investigator: 
Luis Angel, MD 
Professor of Medicine and Cardiothoracic Surgery 
Director, Lung Transplant Program 
530 First Avenue, HCC Suite 7A 
New York, NY 10016 
646-501-9884 
Luis.Angel@nyulangone.org 
 
Co-Investigators: 
Tyler Lewis, PharmD 
Clinical Assistant Professor, Department of Cardiothoracic Surgery 
Clinical Pharmacotherapy Specialist, Lung Transplant 
Clinical Pharmacy Manager, Solid Organ Transplant 
545 First Avenue, GBH SC2-097 
New York, NY 10016 
646-501-6978 
Tyler.Lewis@nyulangone.org 
 
Zachary Kon, MD 
Assistant Professor of Cardiothoracic Surgery 
Surgical Director, Lung Transplant Program and Mechanical Circulatory Support 
NYU Langone Cardiothoracic Surgery Associates 
530 First Avenue, Suite 9V 
New York, NY 10016 
212-263-7835 
Zachary.Kon@nyulangone.org 
 
Melissa Lesko, DO 
Instructor, Department of Medicine 
NYU Langone Transplant Institute 
530 First Avenue, HCC12 
New York, NY 10016 
866-838-5864 
Melissa.Lesko@nyulangone.org 
 
Darya Rudym, MD 
Clinical Assistant Professor, Department of Medicine 
NYU Langone Transplant Institute 
530 First Avenue, HCC12 
New York, NY 10016 
866-838-5864 
Darya.Rudym@nyulangone.org 
 
Stephanie Chang, MD 
Assistant Professor, Department of Cardiothoracic Surgery 
NYU Langone Cardiothoracic Surgery Associates 
530 First Avenue, Suite 9V 
New York, NY 10016 
212-263-0695 
Stephanie.Chang@nyulangone.org 
 
 


Study number: i19-01247 
 
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Kim Sureau, DNP, ACNP-BC, MA, RN 
Program Manager, Lung Transplant 
NYU Langone Transplant Institute 
530 First Avenue, HCC12 
New York, NY 10016 
646- 501-8996 
 
Research Coordinators: 
Elaina Weldon, MSN, ACNP-BC 
Transplant Research Nurse Practitioner 
NYU Langone Transplant Institute  
403 E. 34th St, 4th Floor 
New York, NY 10016 
646-385-0920 
Elaina.Weldon@nyulangone.org 
 
Cecilia Deterville, MS, CCRC 
Senior Clinical Research Coordinator 
NYU Langone Transplant Institute  
403 E. 34th St, 4th Floor 
New York, NY 10016 
212-263-3630 
Cecilia.Deterville@nyulangone.org 
 
2 Introduction, Background Information and Scientific Rationale 
 
2.1 Background Information and Relevant Literature 
Lung transplantation remains the definitive cure for many end-stage lung diseases. Despite advances in 
surgical technique and medical therapy, morbidity and mortality remain unacceptably high.1 Chronic lung 
allograft dysfunction (CLAD) is the major barrier to long-term survival in lung transplant recipients.2  The 
risk for CLAD is heterogenous, yet acute cellular rejection (ACR) has consistently been identified as a risk 
factor for the development of CLAD, with just one episode of A1 ACR portending a higher likelihood of 
CLAD.3-5 Minimizing ACR in the first year post-lung transplant may therefore reduce the incidence of 
CLAD. 
 
Tacrolimus is the backbone of rejection prevention following lung transplantation. Interpatient variability in 
tacrolimus pharmacokinetics make achieving consistent systemic exposure challenging and necessitate 
the use of therapeutic drug monitoring (TDM).6 Even with TDM, tacrolimus trough levels will vary over 
time potentially leaving patients at increased risk for ACR. 
 
Tacrolimus trough level variability was first described as a risk for ACR in lung transplant recipients by 
Chiang and colleagues.7 They measured trough level variability utilizing the standard deviation (SD). In 
their cohort, the risk of ACR was increased by 23% for every 1 unit increase in SD within the first 3 
months post-transplant. Counterintuitively, the mean tacrolimus trough level was higher in patients who 
had rejection, and the mean tacrolimus trough level pre-rejection was not predictive of rejection.7 A similar 
study retrospectively reviewed 110 lung transplant recipients to evaluate the effect of tacrolimus SD on 
CLAD.8 Tacrolimus SD was greatest in the first 6 months post-transplant, but was similar between months 
6-12 and 12-24. Again it was observed that for each 1 unit increase in tacrolimus SD the risk of CLAD 
and death was significantly increased.8 Recent data in lung transplant recipients found that increasing the 
time-in-therapeutic range for tacrolimus by 10% within the first year post-transplant reduced the burden of 
ACR by 54%.9 Similar data was recently published in heart transplant recipients where patients with high 
tacrolimus variability had an increased rate of chronic rejection despite similar mean C0 levels.10 Taken 


Study number: i19-01247 
 
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together, this data suggests that the tacrolimus trough level in and of itself is not sufficient monitoring to 
protect against rejection and that trends in trough levels should be monitored as well.  
 
Envarsus XR is a once-daily, extended-release formulation of tacrolimus that utilizes MeltDose 
technology optimize the pharmacokinetics of tacrolimus.11,12 Pharmacokinetic studies in kidney transplant 
recipients demonstrated more consistent peak and peak-to-trough levels, decreased Cmax and increased 
Tmax for Envarsus XR as compared to IR tacrolimus. Additionally, bioavailability was improved with a 
stronger correlation between trough concentration (C0) and AUC.13-15 The randomized, phase III MELT 
trial was the first to compare the efficacy and safety of IR tacrolimus with conversion to Envarsus XR in 
kidney transplant recipients. The primary efficacy endpoint was a composite of death, graft failure, biopsy-
proven acute rejection (BPAR), or loss to follow-up over a 12 month period. Tacrolimus TDD was 
decreased by 30% in patients converted to Envarsus XR. There was a significant decrease in TDD with 
conversion to Envarsus XR despite similar trough levels. The efficacy endpoint was similar between 
groups (2.5 vs. 2.5%, p>0.999). Additionally, there were no differences between individual components of 
the composite endpoint. A subsequent prospective, double-blind, double-dummy, multicenter, phase III 
comparison of IR tacolimus and de novo Envarsus XR was conducted to demonstrate non-inferiority at 
24-months follow-up. Treatment failure defined as death, transplant failure, BPAR, or loss to follow-up 
was similar between the two drugs (Envarsus XR 23.1%, IR tacrolimus 27.3%) and well below the 10% 
non-inferiority margin. There was no significant difference in safety outcomes, including changes in 
estimated glomerular filtration rate (eGFR) and serum creatinine (Scr) was similar between groups. 
Certain subgroup populations (African-American race, age > 65, female gender) demonstrated trends 
towards significant efficacy benefit with Envarsus XR, however these groups were too small reach 
statistical significance.16 
 
A phase II study comparing the pharmacokinetics of Envarsus XR to another unique prolonged-release 
tacrolimus formulation (Advagraf) is the only published experience to date in lung transplant recipients. 
This open-label, single-arm, prospective evaluated 20 lung transplant recipients stable on Advagraf who 
were then converted to Envarsus XR at a conversion dose of 1:0.7. Mean AUC was similar despite 
significantly lower dosing requirements in the Envarsus XR arm (5.05 vs. 3.36 mg, p=0.00002). Time to 
peak concentration was prolonged with Envarsus XR compared to Advagraf (325 vs. 125 minutes, 
p<0.001). Adverse events did not differ between the two formulations over the 6 month follow-up, and no 
major adverse events were considered related to the tacrolimus formulation or required withdrawal of 
therapy.17 It is unknown if Envarsus XR would improve immunologic outcomes in lung transplant 
recipients by providing a stable pharmacokinetic profile and minimizing variability. 
 
Currently at NYU Langone Health (NYULH), our practice has been to convert lung transplant recipients 
from IR tacrolimus to Envarsus XR following discharge from the hospital because of our observations of 
improved adherence and reduced side effects in this population. The only deterrent to inpatient use is the 
lack of availability on NYULH formulary. We have however experienced subtherapeutic tacrolimus C0 
during the outpatient conversion due to the inability to measure frequent C0 concentrations. Early 
conversion to Envarsus XR in the hospital would allow for daily monitoring of C0 levels and appropriate 
dose adjustments to be made leading to stable Envarsus XR dosing and potentially minimizing the risk of 
rejection during the early post-transplant period. 
2.2 Name and Description of the Investigational Agent  
Envarsus XR (tacrolimus extended-release tablets) 
Manufactured by Rottendorf Pharma GmbH, North Rhine-Westphalia, Germany 
Manufactured for Veloxis Pharmaceuticals, Cary, NC 
 
Envarsus XR is an FDA-approved drug for the prophylaxis of organ rejection in de novo kidney transplant 
patients or in kidney transplant patients converted from IR tacrolimus when used with other 
immunosuppressants.  
 
Envarsus XR is a novel extended-release formulation of tacrolimus created using MeltDose technology. 


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2.2.1 
Preclinical Data 
Compared to IR tacrolimus, Envarsus XR has improved bioavailability, a lower peak concentration (Cmax), 
similar area-under-the-concentration-time curve (AUC) despite lower total daily dosing (TDD).18 
2.2.2 
Clinical Data to Date 
A phase II study comparing the pharmacokinetics of Envarsus XR to another unique prolonged-release 
tacrolimus formulation (Advagraf) is the only experience to date in lung transplant recipients. This open-
label, single-arm, prospective evaluated 20 lung transplant recipients stable on Advagraf who were then 
converted to Envarsus XR at a conversion dose of 1:0.7. Mean AUC was similar despite significantly 
lower dosing requirements in the Envarsus XR arm (5.05 vs. 3.36 mg, p=0.00002). Time to peak 
concentration was prolonged with Envarsus XR compared to Advagraf (325 vs. 125 minutes, p<0.001).17 
 
The randomized, phase III MELT trial was the first to compare the efficacy and safety of IR tacrolimus 
with conversion to Envarsus XR in kidney transplant recipients. The primary efficacy endpoint was a 
composite of death, graft failure, biopsy-proven acute rejection (BPAR), or loss to follow-up over a 12 
month period. Tacrolimus TDD was decreased by 30% in patients converted to Envarsus XR. There was 
a significant decrease in TDD with conversion to Envarsus XR despite similar trough levels. The efficacy 
endpoint was similar between groups (2.5 vs. 2.5%, p>0.999). Additionally, there were no differences 
between individual components of the composite endpoint. A subsequent prospective, double-blind, 
double-dummy, multicenter, phase III comparison of IR tacolimus and de novo Envarsus XR was 
conducted to demonstrate non-inferiority at 24-months follow-up. Treatment failure defined as death, 
transplant failure, BPAR, or loss to follow-up was similar between the two drugs (Envarsus XR 23.1%, IR 
tacrolimus 27.3%) and well below the 10% non-inferiority margin. There was no significant difference in 
safety outcomes, including changes in estimated glomerular filtration rate (eGFR) and serum creatinine 
(Scr) was similar between groups. Certain subgroup populations (African-American race, age > 65, 
female gender) demonstrated trends towards significant efficacy benefit with Envarsus XR, however 
these groups were too small reach statistical significance.16 
 
A phase IIIb prospective study compared continuation of IR tacrolimus to Envarsus XR conversion in 
patients on IR tacrolimus with significant tremor. Improvement in tremor with conversion to Envarsus XR 
was documented by two separate clinical scoring systems and by patient-reported quality-of-life (78.9% 
reported improvement with conversion).19  
2.2.3 
Dose Rationale (if applicable)  
Dosing will be converted on an individual basis. Because all patients will be initiated on IR tacrolimus via 
the sublingual or enteral route, conversion will be dependent on several factors: tacrolimus TDD, tacrolimus 
trough level, and patient clinical status (i.e. infection, rejection, acute kidney injury, etc.). Envarsus XR 
conversion dose will be decided upon by the attending pulmonologist and the clinical pharmacotherapy 
specialist caring for the patient, who are also members of the study team. 
2.3 Rationale 
Tacrolimus is the primary immunosuppressant medication administered following lung transplant. Despite 
its widespread use, tacrolimus is limited by inconsistent pharmacokinetics (PK), variability in systemic 
exposure, difficulties with therapeutic drug monitoring, concentration-related neurologic side effects, and 
poor patient adherence. Envarsus XR is a once-daily, extended-release formulation of tacrolimus that 
utilizes MeltDose technology to optimize the pharmacokinetics of tacrolimus. Phase II studies in kidney 
transplant recipients demonstrated more consistent peak and peak-to-trough levels for Envarsus XR as 
compared to IR tacrolimus. Additionally, bioavailability was improved to 30% from 17% with a stronger 
correlation between trough concentration (C0) and AUC.  
 
Recent data in lung transplant recipients found that increasing the time-in-therapeutic range for tacrolimus 
by 10% within the first year post-transplant reduced the burden of ACR by 54%.9 Similar data was recently 
published in heart transplant recipients where patients with high tacrolimus variability had an increased rate 
of chronic rejection despite similar mean C0 levels.10 Taken together, these data highlight the clinical 


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consequences of inconsistency in systemic exposure to tacrolimus. Envarsus XR may improve 
immunologic outcomes in lung transplant recipients by providing a stable pharmacokinetic profile and 
minimizing variability. 
2.4 Potential Risks & Benefits 
2.4.1 
Known Potential Risks 
There is likely to be no potential risk to the patient as Envarsus XR has been shown to produce equivalent 
outcomes to IR tacrolimus in stable kidney transplant recipients. Adverse effects have similarly been 
equivocal or typically improved compared to IR tacrolimus.19 This study involves minimal to no risk to 
individual patients as it is a retrospective review of medical records and will involve collection and storage 
of de-identified patient data only.  
 
2.4.2 
Known Potential Benefits 
The potential benefits of this study include improved adherence and convenience of maintenance 
immunosuppressive therapy, reduction in neurologic adverse effects (e.g. tremor) as demonstrated in the 
STRATO trial,19 and a decrease in the burden of ACR within the first-year post-transplant. There is no 
direct benefit to the historical control cohort. 
3 Objectives and Purpose 
3.1 Primary Objective 
The primary objective will be to assess the feasibility of early conversion to Envarsus XR at 1-year follow-
up. 
3.2 Secondary Objectives (if applicable) 
Secondary objectives will be to assess immunologic outcomes that may be impacted by conversion to 
Envarsus XR and potential mitigation of concentration-related side effects.  
4 Study Design and Endpoints 
4.1 Description of Study Design 
This study will be a prospective, open-label, non-randomized, parallel arm, single-center trial comparing 
new lung transplant recipients converted to Envarsus XR to a historical cohort of patients who received IR 
tacrolimus.  
4.2 Study Endpoints 
4.2.1 
Primary Study Endpoints 
The primary endpoint will be percentage of patients remaining on Envarsus XR at 1-year follow-up. 
4.2.2 
Secondary Study Endpoints 
Secondary endpoints will include freedom from ACR at 1-year follow-up, ACR burden at 1-year follow-up 
as assessed by the composite rejection standardized score (CRSS),20 treated episodes of rejection, the 
incidence of chronic lung allograft dysfunction (CLAD) at 1-year, incidence of de novo DSA in the first 
postoperative year, change in estimated glomerular filtration rate (eGFR) over the first post-operative 
year, and 1-year survival. 


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5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
Prospective arm: 
1. Age ≥ 18 years 
2. Received a lung or heart-lung transplant at NYU Langone Health 
3. Be able to convert to Envarsus XR within the first month post-transplant 
4. Able and willing to provide informed consent 
Historical control: 
1. Age ≥ 18 years 
2. Received a lung or heart-lung transplant at NYU Langone Health 
3. Completed one year from transplant on IR tacrolimus 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
Prospective arm: 
1. Contraindication to tacrolimus due to allergic or adverse reactions 
2. Pregnant or nursing women 
Historical control: 
1. Contraindication to tacrolimus due to allergic or adverse reactions (not including chronic kidney 
disease) 
5.3 Vulnerable Subjects 
Vulnerable subjects will not be eligible for enrollment. 
5.4 Strategies for Recruitment and Retention 
Recruitment of patients in the Prospective Cohort will occur during routine evaluation visits to determine 
candidacy for a lung transplant at NYU Langone Health by a member of the study team. Patients will be 
informed of the option to enroll in this study, and if interested, detailed information pertaining to the risks 
and benefits of the trial will be provided. Historical control patients will be reviewed retrospectively 
because they have already completed the study period and thus will not require recruitment into the 
study. 
 
 
No additional information about potential candidates will be collected to determine interest or 
candidacy for this trial than would otherwise be normally collected as per standard of care for 
evaluation for a lung transplant. 
 
Written informed consent for enrollment in the study will occur once the patient has been listed for 
lung transplantation in a private patient clinic room. Timing of consent for enrollment in relation to 
transplant date will vary between patients as acuity of disease is variable and waiting time to 
transplant is unpredictable.  
 
The target sample size for the Prospective Cohort is 40 patients with early conversion to Envarsus 
XR. 
5.4.1 
Use of DataCore/Epic Information for Recruitment 
Purposes 
This study will utilize EPIC to identify subjects.  
 
Any recruitment information sent by email will utilize Send Safe email.  
 


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Potential subjects will already be known to the study team, as they will be under their care as candidates 
and/or waitlist registrants for lung transplant. The study team will conduct an in person consultation with 
the patients to explain the study as well as discuss the risks, benefits, and alternatives 
 
Approved recruitment language will be used to communicate the reason they are being contacted 
and subjects will be asked if they are interested in participating in this specific study. Should the 
potential subjects agree, the study team will provide the subjects with information regarding the next 
steps for participation. 
 
If a subject requests information regarding opting out of further recruitment for all research, subjects 
will be directed to contact research-contact-optout@nyumc.org or 1-855-777-7858. 
5.5 Duration of Study Participation 
Duration of study participation is expected to be 12 months minimum. 
5.6 Total Number of Participants and Sites  
Forty patients are expected to be enrolled and switched to Envarsus XR post-transplant. No sites outside 
of NYU Langone Health will enroll patients. 
5.7 Participant Withdrawal or Termination 
5.7.1 
Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
5.7.2 
Handling 
of 
Participant 
Withdrawals 
or 
Termination 
In the event a patient requests to withdrawal or is terminated from the study, the patient will either be 
continued on Envarsus XR or converted back to IR tacrolimus at the discretion of the transplant 
pulmonologist. If a patient withdrawals from the trial due to a hypersensitivity or severe adverse reaction 
to tacrolimus, future anti-rejection regimen will be determined by the transplant pulmonologist. 
5.8 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to investigator, funding agency, and regulatory authorities. If the 
study is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the sponsor, IRB and/or FDA. 


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6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
6.1 Study Agent(s) and Control Description 
Envarsus XR is available in tablet form. It is available in 0.75, 1, and 4 mg tablets.  
 
In accordance with 21 CFR 312.2(b)(1): 
 
(i) 
The investigation is not intended to be reported to FDA as a well-controlled study in support of 
a new indication for use nor intended to be used to support any other significant change in the 
labeling for the drug; 
  
(ii) 
the investigation is not intended to support a significant change in the advertising for the 
product;  
 
 
(iii) 
The investigation does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability 
of the risks) associated with the use of the drug product;  
 
(iv) 
The investigation is conducted in compliance with the requirements for institutional review set 
forth in part 56 and with the requirements for informed consent set forth in part 50; and  
 
The investigation is conducted in compliance with the requirements of 312.7. 
 
6.1.1 
Acquisition 
The study agent will be shipped to the Investigational Pharmacy from the manufacturer and stored 
according to standard protocols. 
 
6.1.2 
Formulation, 
Appearance, 
Packaging, 
and 
Labeling 
This is an open label study and the drug will appear as it provided directly from the manufacturer, Veloxis 
Pharmaceuticals, Inc. The tablets are oval, white to off-white uncoated extended-release tablets, 
debossed with “TCS” on one side and “0.75”, “1”, or “4” on the other side depending on the strength of the 
tablet. The drug will be packed in the standard manufacturer’s packing and all standard package inserts 
will be retained. This product is commercially available and is FDA-approved for use in kidney transplant 
recipients in the proposed dosage form. 
6.1.3 
Product Storage and Stability 
Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F). 
6.1.4 
Preparation 
The drug is a tablet for oral ingestion, which requires no preparation.  
6.1.5 
Dosing and Administration 
The dose of Envarsus XR is administered once daily, most commonly prior to the morning meal. The 
precise dose will be determined by TDM of tacrolimus C0 levels with dose adjustments to achieve the goal 
prescribed by the transplant pulmonologist. The dose can include any combination of the 0.75, 1 and 4 
mg tablets. The tablet should be swallowed whole, and should not be split, chewed or crushed.  


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6.1.6 
Route of Administration 
Tablets are administered orally. 
6.1.7 
Starting Dose and Dose Escalation Schedule 
The initial dose of Envarsus XR will be determined by the transplant pulmonologist and the clinical 
pharmacotherapy specialist based on the patients current dose of sublingual or enteral IR tacrolimus and 
the corresponding C0 level. 
6.1.8 
Dose Adjustments/Modifications/Delays 
Dose adjustments will be made based on corresponding C0 tacrolimus levels to achieve the goal 
prescribed by the transplant pulmonologist. 
6.1.9 
Duration of Therapy 
Duration of therapy will be a minimum of 12 months. 
6.1.10 
Tracking of Dose 
While in the hospital, nursing staff will give any doses and accountability will be maintained in the 
electronic medical record. Once outpatient, patients will attend regularly scheduled clinic appointments for 
routine care following a lung transplant and medication review will occur on each of these visits to ensure 
that the medication is being taken properly. Tacrolimus C0 levels will be followed per routine post-
operative care to ensure therapeutic levels are maintained. 
6.2 Study Agent Accountability Procedures 
The Investigational Pharmacist must complete the study drug accountability record. Any deviations or 
discrepancies must be reported to the PI immediately. The PI or co-investigator will review drug 
accountability during routine monitoring visits. 
 
The accountability records will contain complete records of receipt, storage, dispensation and return for 
all used and unused tablets of Envarsus XR. Documentation will include batch numbers, expiry dates, 
and quantities received/dispensed/returned/destroyed. The accountability records and the study drug 
must be reconciled and discrepancies between the amount received, dispensed and returned/destroyed 
drug must be accounted for. This is applicable for unused, used and partially used and deliberately or 
accidentally damaged tablets of study drug.  
 
Unused or damaged study drug must be kept at the Investigational Pharmacy until study closure and then 
returned to Veloxis Pharmaceuticals unless otherwise agreed upon with Veloxis Pharmaceuticals. Used 
study drug will be destroyed by the Investigational Pharmacist according to local guidelines after reviewed 
by the PI and confirmed by Veloxis Pharmaceuticals. 
6.2.1 
Assessment of Subject Compliance with Study 
Intervention 
Assessment of compliance to study intervention will be performed during routine clinic follow-up post-lung 
transplantation. Tacrolimus C0 levels will be followed per routine post-operative care to ensure therapeutic 
levels are maintained. 
7 Study Procedures and Schedule 
7.1 Study Procedures/Evaluations 
7.1.1 
Study Specific Procedures 
Note that the medical history and medication history that pertains to candidacy for lung transplantation, 
physicals, height, weight, and vital signs are considered standard-of-care procedures and evaluations 


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for lung transplantation, and are not considered here as study specific procedures. Patients are not 
considered candidates for this trial if there is any contraindication to their standard candidacy for a lung 
transplant. As such, there are no procedures and evaluations specific to participation in this study that 
are outside of routine post-lung transplant management 
7.1.2 
Standard of Care Study Procedures 
Lung transplantation and all associated procedures will be considered standard-of-care including: the 
transplant procedure itself and requisite intra-operative procedures and hemodynamic monitoring, 
post-operative ICU-level care, inpatient hospital unit care, outpatient post-operative care including, 
standard induction and maintenance immunosuppression, and standard post-transplant anti-infectious 
prophylaxis (anti-fungal, anti-pneumocystis, and anti-CMV prophylaxis). In accordance, clinical data 
resulting from these procedures will be collected at the following timepoints: 
 
• 
Pathological rejection grading from transbronchial biopsies performed at 1, 3, 6, and 12 
months post-transplant 
• 
Any requirement for augmented immunosuppression for treatment of documented or 
presumed rejection 
• 
Forced expiratory volume in 1 second (FEV1) measurements monthly 
• 
De novo DSA as assessed by single antigen bead assay measured at 1, 3, 6, 9, and 12 
months post-transplant 
7.2 Laboratory Procedures/Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
The following tests will be reviewed for patients who are included in the study but will be performed as 
standard of care for lung transplant recipients: 
 
• 
Hematology:white blood cells (WBC)  collected weekly for the first 3 
months and monthly for months 4-12 
• 
Biochemistry: potassium and creatinine collected weekly for the first 3 
months and monthly for months 4-12 
• 
Tacrolimus: C0 levels will be obtained at all routine post-transplant follow-
up visits and more frequently as needed for sub- or supra-therapeutic levels 
collected weekly for the first 3 months and monthly for months 4-12 
 
 
7.2.2 
Retrospective data to be collected in the Historical 
Control Cohort 
Specific data pertaining to primary and secondary outcomes to be collected in the 
Historical Control Cohort is the same as listed above in the Prospective Cohort and at 
the same time points.  
 
7.3 Concomitant Medications, Treatments, and Procedures 
The subjects will receive concomitant medications, which would otherwise be given as standard of care 
for patients undergoing a lung transplant. 
7.3.1 
Precautionary 
Medications, 
Treatments, 
and 
Procedures 
Treatment with potent CYP3A4 inducers (e.g. rifampin, St. John’s Wort, efavirenz, carbamazepine, 
phenytoin, phenobarbital, etc.) or inhibitors (ritonavir, cobicistat, darunavir, lopinavir, atazanavir, etc.) 
requires special dosing considerations and potentially more frequent monitoring of tacrolimus C0 levels. 


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Management of these significant drug interactions will be discussed by the study team and any dose 
adjustment plan documented. 
7.4 Prohibited Medications, Treatments, and Procedures 
As frequent tacrolimus C0 level monitoring is available, no medications will be explicitly prohibited from 
the study. 
7.5 Participant Access to Study Agent at Study Closure 
Patients will be eligible to continue Envarsus XR through standard prescription coverage at completion of 
the study. The study team will assist with ensuring continuance of therapy is secured. Based on our 
current experience, Envarsus XR is readily obtainable for lung transplant recipients with the assistance of 
pharmacy liaisons who provide prior authorization support. The cost of any copayment for Envarsus XR 
past the one year study window would be the responsibility of the patient. If insurance coverage of 
Envarsus XR is not able to be obtained, the patient would then be converted back to IR tacrolimus at the 
discretion of the treating transplant pulmonologist, who would also be a study team member.  
 
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
8.1.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
8.1.2 
Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  


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8.1.3 
Definition of Unanticipated Problems (UP) 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
8.2 Classification of an Adverse Event 
8.2.1 
Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
8.2.2 
Relationship to Study Agent 
The clinician’s assessment of an AE's relationship to study drug is part of the documentation process, but 
it is not a factor in determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. All AEs must have their relationship to study 
agent assessed. In a clinical trial, the study product must always be suspect. To help assess, the 
following guidelines are used. 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease 


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or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
8.2.3 
Expectedness 
The Principal Investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study agent. 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  


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8.4 Reporting Procedures – Notifying the IRB  
8.4.1 
Adverse Event Reporting 
All AEs will be recorded in AE CRFs by a member of the study team only if they are related to the study 
drug. AEs will be recorded within 3 business days of the study team being made aware of the AE. The 
relationship of the AE to the study drug will be noted by the PI. AEs that are deemed definitely related 
or probably related to the study drug will be reported to the IRB. within 3 days of their designation as 
such. AEs that are deemed unrelated or not likely related to the study drug will be recorded on CRFs 
as described above and will be reviewed at quarterly safety review meetings with the Safety Monitor, 
and at annual review by the IRB. 
8.4.2 
Serious Adverse Event Reporting 
All SAEs will be recorded in SAE CRFs by a member of the study team. SAEs will be recorded within 
3 business days of the study team being made aware of the SAE. The relationship of the SAE to the 
study drug will be noted by the PI. SAEs that are both unexpected and deemed related to the study 
drug will be reported to the IRB and the Safety Monitor within 24 hours of the PI designation as such. 
The Safety Monitor will determine the need for an emergency meeting between the Safety Monitor 
and the study team (see safety oversight below) or whether these can be reviewed at quarterly 
meetings. SAEs that are deemed unrelated or not likely related to the study drug will be recorded on 
CRFs, will be reported to IRB and Safety Monitor within 3 days of their designation as such and will 
be reviewed at quarterly safety meetings. 
8.4.3 
Unanticipated Problem Reporting 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the PI’s responsibility to report UPs to their IRB and notify the Safety Monitor. The UP 
report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB within 3 days the investigator becoming aware 
of the event. 
• Any other UP will be reported to the IRB within 3 days of the investigator becoming aware of 
the problem. 
8.4.4 
Reporting of Pregnancy 
If any pregnancy occurs in a study subject, the PI will be notified immediately and the IRB will be 
notified within 3 days of discovery of the pregnancy. Data regarding safety of tacrolimus in pregnant 
women suggests an increased risk of premature delivery and potential for fetal harm. Standard of 
care medications utilized for lung transplant recipients have known contraindications in pregnancies 
therefore any pregnancies will need to be managed as per standard of care with the lung transplant 
team. Counseling of pregnant subjects with regard to the risks of continuing versus discontinuing 
Envarsus XR will occur with patients once counseling with regard to the contraindications of the 
standard of care transplant medications has occurred. 
8.5 Reporting Procedures – Notifying the Study Sponsor 
 


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The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the study sponsor within 24 hours of site awareness. See 
Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the study sponsor within 72 hours of 
site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the study sponsor and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative.  This should include a copy of the completed Unanticipated Problem form, 
and any other diagnostic information that will assist the understanding of the event.  Significant new 
information on ongoing unanticipated adverse effects shall be provided promptly to the study sponsor. 
 
8.6 Safety Oversight 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan. 
Medical monitoring will include a regular assessment of the number and type of serious adverse 
events.  
 
The study will not have a formal DSMB as there are no anticipated SAE from routine testing and 
monitoring post-lung transplant, along with the off-label use of an approved FDA medication 
(Envarsus XR) for prevention of acute rejection following lung transplant and with the 
recommended dosing. Additionally, this trial will not be looking for a new indication or use of 
Envarsus XR. 
 
Safety oversight will be under the direction of the PI and a Safety Monitor with expertise in 
transplantation (Claudia Gidea, MD – Transplant Cardiology). This individual will be involved as a 
consultant but not as an investigator of the trial and will provide an independent evaluation of each 
one of the SAE related to the treatment with Envarsus XR. Furthermore, the PI and the Safety 
Monitor will meet at least quarterly to discuss patient progress and any relevant study related 
events that meet criteria for routine review. The Safety Monitor will review de-identified data only. 
9 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with 
applicable regulatory requirement(s). 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
No formal SAP is required as the study will employ only a single prospective arm with comparison to a 
historical control. 


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10.2 Statistical Hypotheses 
We hypothesize that freedom from ACR within the first year post-lung transplant will be reduced by early 
and continued prescription of Envarsus XR as compared to IR tacrolimus. Additionally, we hypothesize 
that key related immunologic outcomes, de novo DSA and CLAD, may be reduced due to less frequent 
rejection. 
10.3 Analysis Datasets 
All subjects will be entered into a database containing de-identified information. All patients who take one 
dose of the study drug will be included in the safety analyses (intention-to-treat). However, only patients 
completing the full first year post-lung transplant will be included in the efficacy analysis (per-protocol 
analysis). 
10.4 Description of Statistical Methods 
10.4.1 
General Approach 
The study is a two-arm, non-randomized study comparing a prospective arm of patients receiving 
Envarsus XR to a historical control who received IR tacrolimus. Descriptive statistics will be used for 
baseline characteristics and to compare nominal outcomes such as de novo DSA and the incidence of 
CLAD at 1 year post-transplant. These data will be presented as frequencies and will be compared using 
Chi-square tests or Fishers exact test, as appropriate. The primary outcome freedom from ACR will be 
compared using Kaplan-Meier survival analysis and analyzed with the log-rank test. Continuous data will 
be presented as median (interquartile range) and compared using Mann-Whitney U test. A two-tailed P 
value of < 0.05 will be considered as significant for inferential tests.  
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoint, percentage of patients remaining on Envarsus XR at 1-year, will be measured as a 
single endpoint on a nominal scale. It will be analyzed using descriptive statistics. 
10.4.3 
Analysis of the Secondary Endpoint(s) 
 
1. Freedom from ACR will be compared using Kaplan-Meier survival analysis and the log-rank test. 
2. Composite rejection standardized score at 1 year follow-up will be presented as median (IQR) 
and will be compared using the Mann-Whitney U test 
3. Treated episodes of rejection will be presented as frequencies and compared using chi-square 
test 
4. Incidence of CLAD at 1 year will be presented as odds ratio with 95% confidence intervals and 
compared between groups using logistic regression. 
5. Incidence of de novo DSA at 1 year will be presented as odds ratio with 95% confidence intervals 
and compared using between groups using logistic regression. 
6. Mortality a 1 year post-transplant will be compared using Kaplan-Meier survival curves and log-
rank analysis. 
10.4.4 
Safety Analyses 
Safety endpoints include worsening chronic kidney disease and discontinuation of therapy will be 
analyzed as changes from baselines and summary data during the course of treatment, respectively. 
These will be compared as linear regression and frequencies using the chi-square test, respectively. All 
AEs will be ascertained and reported by the PI. 
10.4.5 
Adherence and Retention Analyses 
Adherence to the protocol will be assessed by the study team in direct conversation with subjects during 
routine visits, and will be assessed clinically by evaluation tacrolimus C0 levels. Failure to maintain 
significant tacrolimus C0 levels will prompt more detailed direct patient inquiries regarding medication 
adherence. 


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10.4.6 
Baseline Descriptive Statistics 
Baseline statistics including but not limited to age, gender, etiology of lung disease, type of lung 
transplant, lung allocation score, details of the requirement for mechanical ventilation or extracorporeal 
membrane oxygenation, and ischemic time of the organ will be collected for each group. These data will 
be compared using chi-square tests to assess for baseline imbalances. 
10.4.7 
Planned Interim Analysis 
No interim analysis is planned. 
10.4.7.1 Safety Review 
Any patient death will result in halting of any further enrollment in the study and an assessment of 
whether the death was related to Envarsus XR exposure or complications thereof. Even in the event of a 
patient death, currently enrolled patients who are actively being treated with Envarsus XR and tolerating 
therapy will continue to receive therapy so as not to put them at risk for rejection as a consequence of 
converting therapy. If the patient death is deemed related to Envarsus XR, enrolled patients receiving 
Envarsus XR will be switched to an alternative therapy including, but not limited to: IR tacrolimus, 
cyclosporine, sirolimus, everolimus, mycophenolate, belatacept, or some combination thereof. 
10.4.7.2 Efficacy Review 
There will be no interim analyses performed due to the small sample size and anticipated short duration 
of enrollment for the study. 
10.5 Sample Size 
We plan to prospectively enroll 40 patients into the Envarsus XR arm to provide a 2:1 sample size with a 
historical control of patients who received IR tacrolimus. The sample size of 40 patients for the 
Prospective Cohort was chosen based on the expected number of lung transplants performed in one year 
at NYULH. The Historical Control Cohort sample size includes all patients who were transplanted at 
NYULH and completed one year of follow-up post lung transplant while maintained on IR tacrolimus. The 
2:1 sample size was chosen as the purpose of the study is to gain experience with Envarsus XR in lung 
transplant recipients and IR tacrolimus has many years of clinical use. As this is a pilot study, there will be 
no power calculations.   
 
11 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF is left 
blank because the procedure was not done or the question was not asked, write “N/D”. If the item is not 
applicable to the individual case, write “N/A”.  All entries will be stored in REDCap. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 


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documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
12 Quality Assurance and Quality Control 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
13.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
13.3 Informed Consent Process 
13.3.1 
Consent/Assent 
and 
Other 
Informational 
Documents Provided to Participants (Envarsus XR Prospective Cohort) 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The informed consent document to be used is submitted with 
this protocol. 
13.3.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should have 


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the opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. 
The participant will sign the informed consent document prior to any procedures being done specifically 
for the study. The participants may withdraw consent at any time throughout the course of the trial. A 
copy of the signed informed consent document will be given to the participants for their records. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The 
consent process, including the name of the individual obtaining consent, will be thoroughly documented in 
the subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, 
consent document presented orally, etc.) and the justification for such alteration will likewise be 
documented.  
13.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at the site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used by 
the site and by NYU Langone Medical Center research staff will be secured and password protected. At 
the end of the study, all study databases will be de-identified and archived at the NYU Langone Medical 
Center. 


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14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
Data will be  directly entered from the electronic medical record into electronic CRFs in the Institution-
approved HIPAA Compliant and Encrypted version of REDCap. The original CRFs will be provided for 
use as source documents and maintained for recording if and when study visits occurred for each 
participant enrolled in the study.  
 
Once all subjects have completed the study visits, Laboratory Evaluation windows will open up to +/-14 
days of the target date to allow for the retrospective collection of data that accurately reflects the status of 
these subjects month-to-month as there is variability in the scheduling of labs due to many clinical factors. 
This will also more closely align with the window, +/- 28 days, for the bronchoscopies and DSAs that 
happen at these monthly visits as well.  
 
The window for the Year 1 visits (Study Visit Week 52) will also open to +/- 30 days once all patients have 
completed the study for retrospective data collection. This enables Year 1 visits to properly capture data 1 
year post-transplant and balances out the enrollment window given that the enrollment window for the 
trial is within 30 days post-transplant. 
 
De-identified clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be assimilated in the study subject binders. Clinical data will be 
entered directly to electronic CRFs in REDCap. 
 
 
14.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the investigation is discontinued. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
14.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 3 working days of the scheduled 
protocol-required activity. 
 
All protocol deviations must be addressed in study source documents, reported to the PI and Safety 
Monitor. During the course of routine follow-up, certain adjustments from routine clinical, laboratory, and 
bronchoscopy schedules are deemed necessary per the clinical judgement of the treating transplant 


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pulmonologist. If study procedures or assessments are not performed based on clinical judgement, these 
routine adjustments shall not be deemed as protocol deviations or result in a report to the IRB. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOP. 
14.4 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility 
to register the trial in an acceptable registry, so the research results may be considered for publication in 
ICMJE member journals. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
15 Study Finances 
15.1 Funding Source 
This study will be financed by an investigator-initiated study grant from the manufacturer of Envarus XR, 
Veloxis Pharmaceuticals, Inc. 
15.2 Costs to the Participant 
Participants will not incur any costs associated with participating in this trial. 
16 Study Administration 
16.1 Study Leadership 
The Principal Investigator will govern the conduct of the study. The PI, together with at least one 
coinvestigator will meet in person or by teleconference with the Safety Monitor at least quarterly 


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and documentation of the meeting will be maintained. 
17 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership in conjunction with the 
<specify NIH IC> has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 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 the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
18 References 
 
1. 
Chambers DC, Cherikh WS, Goldfarb SB, et al. The International Thoracic Organ Transplant 
Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung 
and heart-lung transplant report--2018; Focus theme: Multiorgan Transplantation. The Journal 
of Heart and Lung Transplantation 2018;37:1169-83. 
2. 
DerHovanessian A, Wallace WD, Lynch JP, Belperio JA, Weigt SS. Chronic Lung Allograft 
Dysfunction: Evolving Concepts and Therapies. Semin Respir Crit Care Med 2018;39:155-71. 
3. 
Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung 
transplantation. An analysis of risk factors and management. The Journal of thoracic and 
cardiovascular surgery 1995;110:4-13; discussion -4. 
4. 
Burton CM, Iversen M, Carlsen J, et al. Acute cellular rejection is a risk factor for bronchiolitis 
obliterans syndrome independent of post-transplant baseline FEV1. The Journal of heart and 
lung transplantation : the official publication of the International Society for Heart 
Transplantation 2009;28:888-93. 
5. 
Hachem RR, Khalifah AP, Chakinala MM, et al. The significance of a single episode of 
minimal acute rejection after lung transplantation. Transplantation 2005;80:1406-13. 
6. 
Monchaud C, Marquet P. Pharmacokinetic optimization of immunosuppressive therapy in 
thoracic transplantation: part I. Clinical pharmacokinetics 2009;48:419-62. 
7. 
Chiang CY, Schneider HG, Levvey B, Mitchell L, Snell GI. Tacrolimus Level Variability Is a 
Novel Measure Associated with Increased Acute Rejection in Lung Transplant (LTx) 
Recipients. The Journal of Heart and Lung Transplantation 2013;32:S170. 
8. 
Gallagher HM, Sarwar G, Tse T, et al. Erratic tacrolimus exposure, assessed using the 
standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and 
survival. The Journal of heart and lung transplantation : the official publication of the 
International Society for Heart Transplantation 2015;34:1442-8. 
9. 
Ensor CR, Iasella CJ, Harrigan KM, et al. Increasing tacrolimus time-in-therapeutic range is 
associated with superior one-year outcomes in lung transplant recipients. 2018;18:1527-33. 
10. 
Gueta I, Markovits N, Yarden-Bilavsky H, et al. High tacrolimus trough level variability is 
associated with rejections after heart transplant. 2018;18:2571-8. 
11. 
Nigro V GA, Weinberg J. Improved Bioavailability of MELTDOSE Once-Daily Formulation of 
Tacrolimus (LCP-Tacro) with Controlled Agglomeration Allows for Consistent Absorption over 
24 Hrs: A Scintigraphic and Pharmacokinetic Evaluation [abstract]. American journal of 
transplantation : official journal of the American Society of Transplantation and the American 
Society of Transplant Surgeons 2013;13. 


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CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
12. 
Staatz CE, Tett SEJCP. Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ 
Transplant Patients. 2015;54:993-1025. 
13. 
Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily 
tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT 
trial. American journal of transplantation : official journal of the American Society of 
Transplantation and the American Society of Transplant Surgeons 2013;13:760-9. 
14. 
Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion From Twice-Daily 
Tacrolimus Capsules to Once-Daily Extended-Release Tacrolimus (LCPT): A Phase 2 Trial of 
Stable Renal Transplant Recipients. 2013;96:191-7. 
15. 
Tremblay S, Nigro V, Weinberg J, Woodle ES, Alloway RR. A Steady-State Head-to-Head 
Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-
Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study. 2017;17:432-42. 
16. 
Rostaing L, Bunnapradist S, Grinyo JM, et al. Novel Once-Daily Extended-Release Tacrolimus 
Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results 
of Phase 3, Double-Blind, Randomized Trial. American journal of kidney diseases : the official 
journal of the National Kidney Foundation 2016;67:648-59. 
17. 
Sintes H, Sáez-Giménez B, Berastegui C, et al. Pharmacokinetic Study of Conversion 
Between 2 Formulations of Once-daily Extended-release Tacrolimus in Stable Lung 
Transplant Patients. 2018;102:e439-e46. 
18. 
Grinyo JM, Petruzzelli S. Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of 
organ rejection in kidney and liver transplantations. Expert review of clinical immunology 
2014;10:1567-79. 
19. 
Langone A, Steinberg SM, Gedaly R, et al. Switching STudy of Kidney TRansplant PAtients 
with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b 
study. 2015;29:796-805. 
20. 
Ensor CR, Rihtarchik LC, Morrell MR, et al. Rescue alemtuzumab for refractory acute cellular 
rejection and bronchiolitis obliterans syndrome after lung transplantation. 2017;31:e12899. 
 
 


Study number: i19-01247 
 
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Version: December 10, 2021 
 
 
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authorized in writing by the study sponsor 
19 Attachments 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They are 
stored and modified separately. As such, modifications to these documents do not require protocol 
amendments. 


Study number: i19-01247 
 
Page 27 
Version: December 10, 2021 
 
 
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This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in writing by the study sponsor 
20 Schedule of Events 
 
Activity 
Screening Visit 
(POD 0 to30) 
SVD0* 
SVW1 
(+/- 5 days) 
SVW2 
(+/- 5 days) 
SVW3 
(+/- 5 days) 
SVW4 
(+/- 5 days) 
SVW5 
(+/- 5 days) 
Study team procedures 
  
  
 
 
 
  
  
Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
Vitals signs 
X 
 
 
 
 
 
 
Review all recipient inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Study drug dispensation 
 
X 
 
 
 
 
 
Participant study drug compliance 
check and accountability 
 
 
 
 
 
X 
 
Bronchoscopy with biopsy 
 
 
 
 
 
X 
 
Spirometry (FEV1) 
 
 
 
 
 
X 
 
Donor-specific antibody 
 
 
 
 
 
X 
 
Laboratory Evaluations 
 
 
 
 
 
 
 
Biochemistry 
 
 
X 
X 
X 
X 
X 
Hematology 
 
 
X 
X 
X 
X 
X 
Tacrolimus C0 
 
 
X 
X 
X 
X 
X 
SVD=study visit day; SVW=study visit week 
*Study visit day 0 = day of first drug dispensation and may occur on the same day as screening visit.  
*For SVW4 and SVW12: Bronchoscopies and DSAs will be done per SOC and as close to the specified study visit week as possible with a window 
of +/- 14 days.   
 
 


Study number: i19-01247 
 
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Activity 
SVW6 
(+/- 5 days) 
SVW7 
(+/- 5 days) 
SVW8 
(+/- 5 days) 
SVW9 
(+/- 5 days) 
SVW10 
(+/- 5 days) 
SVW11 
(+/- 5 days) 
SVW12 
(+/- 5 days) 
Study team procedures 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
Participant study drug compliance 
check and accountability 
 
 
X 
 
 
 
X 
Bronchoscopy with biopsy 
 
 
 
 
 
 
X 
Spirometry (FEV1) 
 
 
X 
 
 
 
X 
Donor-specific antibody 
 
 
 
 
 
 
X 
Laboratory Evaluations 
 
 
 
 
 
 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Tacrolimus C0 
X 
X 
X 
X 
X 
X 
X 
Activity 
SVW16 
(+/- 5 days) 
SVW20 
(+/- 5 days) 
SVW24 
(+/- 5 days) 
SVW28 
(+/- 5 days) 
SVW32 
(+/- 5 days) 
SVW36 
(+/- 5 days) 
SVW40 
(+/- 5 days) 
Study team procedures 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
Participant study drug compliance 
check and accountability 
X 
X 
X 
X 
X 
X 
X 
Bronchoscopy with biopsy 
 
 
X 
 
 
 
 
Spirometry (FEV1) 
X 
X 
X 
X 
X 
X 
X 
Donor-specific antibody 
 
 
X 
 
 
X 
 
Laboratory Evaluations 
 
 
 
 
 
 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Tacrolimus C0 
X 
X 
X 
X 
X 
X 
X 
 
Activity 
SVW44 
(+/- 5 days) 
SVW48 
(+/- 5 days) 
SVW52 
(+/- 5 days) 
Study team procedures 
  
  
  
 
 
 
 
Participant study drug compliance check 
and accountability 
X 
X 
X 


Study number: i19-01247 
 
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Medical History 
 
 
X 
Physical Exam 
 
 
X 
Height 
 
 
X 
Weight 
 
 
X 
Vitals signs 
 
 
X 
Bronchoscopy with biopsy 
 
 
X 
Spirometry (FEV1) 
X 
X 
X 
Donor-specific antibody 
 
 
X 
Laboratory Evaluations 
 
 
 
Biochemistry 
X 
X 
X 
Hematology 
X 
X 
X 
Tacrolimus C0 
X 
X 
X 
*For SVW24, SVW36, and SVW52: Bronchoscopies and DSAs will be done per SOC and as close to the specified study visit week as possible 
with a window of +/- 28 days.