Conditions: Poor Thymic Function Immunodeficiency Athymia Immunoreconstitution Thymus Transplantation Low T Cell Numbers
Keywords: Cultured Thymus Tissue Implantation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The primary purpose is to provide access for patients who have immunodeficiency or severe autoimmune disease related to poor thymic function to cultured thymus tissue for implantation. With no thymus function, bone marrow stem cells do not develop into educated T cells, which fight infection.

Eligible participants receive cultured thymus tissue for implantation and may undergo biopsy. Immune suppression may be given depending on the immune status and clinical condition of the participant. Immune function testing is continued for one year post-implantation.

Detailed description:
The patients enrolled have a high likelihood of death if they do not receive culture thymus tissue because of lack of thymus function. As there are many types of patients who may be enrolled, study results will not have statistical significance.

The study objective is to make cultured thymus tissue available for implantation on an expanded access basis. Data will be collected on survival, naïve T cell development, T cell chimerism, and implant related toxicities, as well as any unexpected study-related serious adverse events.

Eligible subjects receive cultured thymus tissue and may undergo allograft biopsy. Immune suppression may be given depending on the subject's immune status and clinical condition.

Protocol specified studies continue until approximately one year post-implantation. Study participation lasts approximately two years.

Arms:
arm 1: Cultured thymus tissue for the treatment of immunodeficiency and autoimmune disorders

Interventions: intervention 1: Cultured Thymus Tissue intervention 2: Blood Draw intervention 3: Rabbit Anti-Thymocyte Globulin and Cyclosporine or Tacrolimus
Intervention descriptions: intervention 1: Subjects receive cultured thymus tissue which is implanted into the quadriceps muscle. Subjects may receive pre and/or post-implantation immunosuppression.

Potential subjects are screened for eligibility. The thymus tissue (from an unrelated donor), the donor, and the donor's mother are screened for safety. Cultured thymus tissue is implanted into the subject's quadriceps muscle under general anesthesia in the operating room. Two to three months post-implantation, if medically stable, subjects may undergo an allograft biopsy. Subjects undergo laboratory testing for approximately one year post-implantation. At year 2 post-implantation, subjects are contacted for data collection. intervention 2: None intervention 3: RATGAM and Cyclosporine or Tacrolimus may be given, depending on the patient. The doses, timing, and trough levels will vary depending on the patient's clinical condition.

Protocol document:
Prot_000.pdf: 




Amended Version: 30Nov2021 
 
 
 
TABLE OF CONTENTS   
 
SPONSOR SIGNATURE PAGE ................................................................................. 2 
PROTOCOL SYNOPSIS ............................................................................................. 5 
Summary of Changes: Amendment Version 30Nov2021. ...................................... 5 
1 BACKGROUND AND RATIONALE ........................................................................ 6 
1.1 Risk/Benefit Analysis and Adverse Events ............................................................ 7 
1.2 Description of Subject Population ......................................................................... 10 
2 STUDY DESIGN .................................................................................................... 10 
2.1 Study Design ............................................................................................................ 10 
2.2 Eligibility .................................................................................................................... 10 
2.2.1 Cultured Thymus Tissue Implant Recipient Inclusion Criteria.................... 11 
2.2.2 Cultured Thymus Tissue Implant Recipient Exclusion Criteria .................. 11 
2.3 Consent Process ..................................................................................................... 11 
3 CULTURED THYMUS TISSUE IMPLANTATION PLAN ....................................... 12 
3.1 General ...................................................................................................................... 12 
3.2 Thymus Procurement .............................................................................................. 13 
3.3 Thymus Processing ................................................................................................. 13 
3.4 Thymus Donor Screening....................................................................................... 13 
3.5 Dose........................................................................................................................... 13 
3.6 Implantation Procedure .......................................................................................... 13 
3.7 Toxicities of Cultured Thymus Tissue Implantation Procedure & Thymus 
Tissue Biopsy .................................................................................................................. 13 
3.8 Venous Access ........................................................................................................ 13 
3.9 Cultured Thymus Tissue Implant Preparative Regimen .................................... 14 
3.10 Skin Biopsy ............................................................................................................. 14 
3.11 Thymus Tissue Biopsy ......................................................................................... 14 
3.12 Graft Versus Host Disease (GVHD) ................................................................... 14 
3.13 Prophylactic Medications ..................................................................................... 14 
3.14 Supportive Care ..................................................................................................... 14 
4 SUBJECT MONITORING AND SAFETY EVALUATION ...................................... 14 
4.1 Subject Monitoring ................................................................................................... 14 
4.2 Study Duration ......................................................................................................... 14 
4.3 Study Endpoints ....................................................................................................... 14 
4.4 Statistical Considerations ....................................................................................... 15 
4.5 Adverse Event Recording and Reporting ............................................................ 15 
4.6 Stopping Rules ......................................................................................................... 16 
4.7 References ............................................................................................................... 16 
APPENDICES ........................................................................................................... 17 
Appendix 1  Adverse Events Related to Treatment .................................................. 17 


Amended Version: 30Nov2021 
 
Appendix 2  Adverse Events Possibly Related to RVT-802 .................................... 20 
Appendix 3  RETHYMIC US Prescribing Information .............................................. 22 
Appendix 4  Persons responsible for conducting the study .................................... 44 
Appendix 5  Investigator Statement of Agreement. .................................................. 45 




Amended Version: 30Nov2021 
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The appendices have been updated and renumbered. 
Summary of changes: 
 Section 1  Sponsor updated 
 Section 1.1  Reference to US Prescribing Information for RETHYMIC added 
 Section  2.2 Comment on current status of the study added 
 Section 3.1  Comment on current status of the study added 
 Section 4.5  Sponsor and site responsibilities added, reporting to the DSMB 
removed and reference made to USPI in identifying unexpected adverse events 
 Section 4.6 DSMB description removed  
 Section 4.7 now becomes Section 4.6 and sponsor replaced DSMB in 
responsibilities 
 Section 4.8 now becomes Section 4.7 
 Appendices 5.1 and 5.2 changed to Appendix 1 and Appendix 2. New Appendix 3 
is the RETHYMIC USPI, new Appendix 4 is persons responsible for conducting 
the study and new Appendix 5 is the Investigator Agreement 
 
 
  
 
1 BACKGROUND AND RATIONALE    
Data accumulated over the last 20 years has shown that cultured thymus tissue 
implantation leads to survival and naïve T cell development in young children with 
athymia.  An integrated database for all patients treated under IND 9836 with data 
available through August 2020 has been prepared by Enzyvant Therapeutics, Inc. 
(Enzyvant), the US authorized representative of Enzyvant Therapeutics GmbH (now the 
IND holder). Enzyvant was the licensing partner of Duke University responsible for the 
development and commercialization of the product under BLA 125685. Adverse events in 
this dataset were coded using MedDRA version 19.1.  
 
The database includes data from a total of 105 subjects (complete DiGeorge anomaly 
and other immunodeficient conditions).  Analyses have been conducted for 3 populations.  
Efficacy analysis sets included 1) patients with complete DiGeorge anomaly (EAS-cDGA; 
n=93) and 2) patients with cDGA and FOXN1 mutations (EAS; n=95).  These patients 
were all treated under thymus implantation protocols.  The survival of patients in both 
EAS populations has been evaluated using Kaplan-Meier estimated survival rates.  The 
survival rates at year 1 and year 2 after implantation for congenital athymia (complete 
DiGeorge anomaly and FOXN1 deficiency (EAS) were 77% and 76%, respectively. 
The patients in the Full Analysis Set (FAS) population included the 95 patients with 
complete DiGeorge anomaly and FOXN1 mutation patients and an additional 10 subjects 
(n=105).  These 10 subjects had prior transplants, or severe combined immunodeficiency 
(SCID), or unknown causes of immune dysfunction.  Of these 10 patients, seven are 
alive, 1 died and 2 were withdrawn. 
 
Patients similar to these 10 subjects and other subjects who are not eligible for Protocol 
00025966 Safety and Efficacy may be treated under this protocol.   
 
Three examples (unpublished) of patients who may enrolled in this protocol follows: 


Amended Version: 30Nov2021 
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1. A pediatric patient with Foxn1 deficiency1 who was initially treated with 
hematopoietic cell transplantation.  The patient developed pulmonary and renal 
failure with 2 months on the ventilator and dialysis.  Less than 100 T cells 
developed and no naïve T cells.  A cultured thymus tissue implant (CTTI; RVT-
802) was given and on day 406 post CTTI, the patient had 219/mm3 naïve T cells.   
This patient is alive over 2.5 years post-CTTI.  
 
2. A pediatric patient who was initially thought to have severe combined 
immunodeficiency (SCID).  That patient received an ablative bone marrow 
transplant and then peripheral blood from the donor but did not develop naïve T 
cells.  On approximately day 1000, the patient was given a CTTI.  On 
approximately day 306 post CTTI, the naïve T cell number was 140/mm3 and the 
number increased to 650/mm3 by the end of the 2nd year.  The patient is over 8.2 
years post CTTI. 
 
3. A pediatric patient was born with no T cells, hypoparathyroidism, and a small 
ventricular septal defect.  As the patient did not have a 22q11.2 deletion, the 
patient was given a cord blood transplant.  When the cord blood transplant was 
not successful, the patient was given a myeloablative transplant, but again, no T 
cells developed.  The patient was referred for CTTI.  The patient was treated with 
pre-implant rabbit anti-thymocyte globulin (RATGAM) and received CTTI at 
approximately 2.5 years of age.  The pa
-operative course was 
uneventful.  However, a few months after returning home he developed 
pancytopenias.  The bone marrow showed multiple non-necrotizing granulomas.  
The patient was not given steroids because of the concern for mycobacterial 
disease.  The cytopenias were so severe that eventually immunosuppression was 
given.  The spleen also had to be removed.  With time the cytopenias were 
controlled and the patient has subsequently done well with follow up of 5 years.   
 
The above cases demonstrate some of the diversity of patients who might benefit from 
CTTI under this protocol.  The patients listed above all met the enrollment criteria: 
immunodeficiency or severe autoimmune disease related to poor thymic function.  The 
patients had very low naïve T cells thought to be secondary to thymus hypoplasia or 
thymus dysfunction.   
 
1.1 Risk/Benefit Analysis and Adverse Events  
The potential benefits of CTTI (RVT-802) include development of functional T cells and 
the ability of these cells to protect against infection and severe autoimmune disease.  
RETHYMIC (RVT-802) was approved for the treatment of pediatric congenital athymia in 
October 2021. The major risks and benefits relevant to the treatment of congenital 
athymia is in the US prescribing information (Appendix 3). 
 
The consent document thoroughly discusses risks and adverse events that the sponsor 
has seen in CTTI recipients, and the risks associated with immune suppression.   
  


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As there have been few patients in the Expanded Access protocol, to assess adverse 
events, we are reporting here on the safety of all subjects who received a cultured 
thymus tissue implantation (FAS, n=105).   
 
As of August 2020 an analysis of all adverse events reported in all subjects (FAS, n=105) 
that have received cultured thymus tissue implant treatment under IND 9836 found that 
44 (42%) subjects out of 105 subjects that were treated experienced 87 events that were 
considered by the Sponsor/Investigator to be possibly related to cultured thymus tissue 
implantation.  
 
Overall, the related events generally were distributed into three main categories:  
autoimmune diseases, complications associated with the implantation procedure itself, 
and events considered specifically related to T cells (e.g. rash and GVHD).  
 
The most severe post-CTTI adverse events have been i.) autologous GVHD, ii.) maternal 
GVHD, iii.) transverse myelitis, iv.) autoimmune hepatitis, and v.) autoimmune 
cytopenias.   
 
i) Autologous GVHD: Many patients with complete DiGeorge anomaly have pre-
existing recipient T cells causing rash, potential organ damage, and other 
symptoms, a condition 
 
Autologous GVHD from pre-existing recipient T cells is a risk for these patients, 
before or in the initial months after CTTI.   
 
A patient with complete DiGeorge Anomaly, developed autologous GVHD 
post CTTI manifested as enterocolitis.  The sponsor thought the autologous 
GVHD might have been associated with the high thymus dose given.  The 
patient developed host T cells that did not express naïve T cell markers and 
did not have detectable T regulatory cells.  Despite attempts to treat the 
autologous GVHD, the patient died from disseminated candidal disease.   
 
ii.) Maternal GVHD:  
A patient with severe combined immunodeficiency (SCID) who received 
CTTI developed GVHD post-thymus and maternal stem cell transplant.  The 
SCID patient had received a paternal Bone Marrow Transplant (BMT) at 
approximately age 6 months and a maternal BMT at approximately 1 year.  
When neither BMT worked, it was thought that the patient might have both 
a bone marrow defect and a thymus defect.  A BMT from the mother was 
attempted again along with a CTTI.  Five months later genetically maternal 
T cells appeared in the child.  The maternal T cells attacked the patient, 
similar to what happens in GVHD.  The patient was withdrawn.  The genetic 
defect of that patient is unknown.  The reason for the GVHD is not well 
understood. 
 
Another patient with complete DiGeorge anomaly presented with maternal 
GVHD pre-implantation.  The patient developed acute Epstein Barr Virus 


Amended Version: 30Nov2021 
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(EBV) infection post CTTI.  The maternal T cells expanded and fought the 
EBV infection.  When the EBV was under control, the maternal T cells 
attacked the child.  The maternal GVHD led to severe skin and gut disease.  
Two years post implantation, the patient had no signs of GVHD or EBV 
infection.  As of day 783 post CTTI, the patient had only 13.8% maternal 
cells, the rest were recipient T cells.  As of day 2340 post CTTI, the patient 
had 487/mm3 naïve CD4T cells.  
 
iii.) Transverse Myelitis: Post-CTTI, transverse myelitis developed in one patient 
who developed Human Herpesvirus 6 (HHV6) infection after CTTI.  There was no 
evidence that HHV6 contributed to the transverse myelitis.  The transverse myelitis 
was accompanied by demyelination of white matter in the brain.  The patient could 
not stand up or walk during this illness.  The patient was found to carry a mutation 
in CD45.  That mutation is associated with multiple sclerosis.2  It is unknown if the 
CD45 mutation was associated with the demyelination or if the demyelination was 
secondary to immune dysregulation after cultured thymus tissue implantation.  The 
etiology could be the latter (immune dysregulation) as the demyelination 
developed at 9 months post CTTI, when T cells were developing and the T cell 
receptor repertoire is usually still oligoclonal.  The patient has improved and is now 
ambulatory. 
 
iv.) Autoimmune Hepatitis: Autoimmune hepatitis developed in two patients post 
implantation.   
In one patient, the autoimmune hepatitis was confirmed on day 245 after 
CTTI.  Per reports from the local physicians, the patient never developed 
more than 50/mm3 naïve T cells.  The sponsor
that the 
donor thymus tissue may have been damaged after the patient returned to 
the local physicians and had a cardiorespiratory arrest possibly secondary 
to hypocalcemia. Thus, autoimmunity likely was secondary to the lack of 
function of the donor thymus. The autoimmune hepatitis resolved with 
treatment.   
 
Another patient also developed autoimmune hepatitis.  On day 409 after 
CTTI, the patient developed 112/mm3 naïve CD4 T cells. The patient 
developed autoimmune hepatitis on day 949 after CTTI.  The patient was 
treated with immunosuppression. The autoimmune hepatitis resolved by 
Day 1116 after CTTI.  Per report from local physician, at 8.1 years after 
CTTI, the patient had 280/mm3 CD4+RA+ T cells.   
 
v.) Autoimmune Cytopenias:  As of August 2020 in the population of all subjects 
treated with cultured thymus tissue implantation (CTTI) (FAS, n=105) 21 subjects 
reported 32 autoimmune cytopenias which were considered possibly related to 
CTTI. Twelve subjects experienced thrombocytopenia (11%), 8 subjects 
experienced neutropenia (8%), and 9 subjects experienced anemia (includes 
anemia, Coombs positive hemolytic anemia, hemolytic anemia, and hemolysis 
(9%). The cytopenias usually occurred in the first 2 years after CTTI, suggesting 




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2.2.1 Cultured Thymus Tissue Implant Recipient Inclusion Criteria  
Patients with poor thymus function will be eligible for this protocol.   
 
Eligibility screening for cultured thymus tissue implantation includes the 
review of 
medical testing, laboratory studies, and physical examinations. The PI uses the data, 
examinations, and consultations to determine whether the patient is clinically stable and 
will potentially benefit from cultured thymus tissue implantation.  The PI reviews each 
patient with the DSMB prior to enrollment. 
 
To be eligible for cultured thymus tissue implantation, patients must: 
 Have an immunodeficiency or severe autoimmunity for which development of naïve T 
cells would be expected to lead to clinical improvement.  Examples of underlying 
conditions may include the following: 
o An immunodeficiency secondary to primary or acquired thymus deficiency 
o An autoimmune disease likely secondary to primary or acquired thymus deficiency 
 Have given written consent (or consent of parent/legal guardian as applicable). 
 
2.2.2 Cultured Thymus Tissue Implant Recipient Exclusion Criteria  
Any one of the following items excludes a patient from enrollment or implantation: 
 Unrepaired cyanotic congenital heart disease 
 Uncontrolled infections
vasopressor support or anticipated as requiring such support within 6 months.  
 Pregnancy 
 For females of child-bearing potential, a serum pregnancy test is done after 
consent, at the same time another blood draw is done if possible.    
 Females of child-bearing potential must agree to contraceptive measures as 
indicated in the consent form.  
 A second serum pregnancy test is done within 48 hours prior to administration of 
study interventions involving FDA pregnancy class D drugs, chemotherapy drugs, 
or other drugs or interventions known to pose risks to a potential fetus.  
 History of malignancy 
 CMV Infection 
 For subjects receiving immunosuppression as part of the implantation 
protocol, CMV infection as documented by >500 copies/ml in blood by PCR 
on two consecutive assays is an exclusion 
 HIV Positive  
 
2.3 Consent Process 
The consent process may begin at recognition of 
eligibility. Consent is 
requested and obtained per institutional practices before study interventions are initiated.   
All subjects and/or the legal guardian must sign a consent document consistent with local 
institutional and Federal guidelines stating that they are aware of the investigational 
nature of this protocol and the possible side effects and risks. Subjects (parent/guardian) 
are informed that no efficacy is guaranteed, and that unforeseen toxicities may occur. 
Subjects may withdraw from this protocol at any time. Confidentiality of subjects and 
subject records are protected to the full extent possible according to federal, state, and 


Amended Version: 30Nov2021 
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institutional guidelines. The consent document reviews different forms of 
immunosuppression and associated risks.  During the consent process, the 
subject/parent/guardian is told which medications are likely to be used. The 
subject/parent/guardian is told that the immunosuppression plan may be altered and 
other drug
status.   
 
3 CULTURED THYMUS TISSUE IMPLANTATION PLAN  
 
3.1 General 
Note that at the time of this amendment (November 2021) the clinical study is closed to 
enrollment. Patients currently remaining in the trial are in the post-transplantation period 
and have returned to the care of the referring/local physician. 
 
Adjunctive therapies are allowed.  Adjunctive therapies may include bone marrow 
transplantation with myeloablation and cytotoxic lymphocyte infusions for viral infections.  
Subjects may receive immunosuppression depending on the immune status of the 
subject.  These regimens will be based on standard of care practices, patient condition, 
and history of other chemotherapy administration.  The DSMB will review the plan for 
each subject prior to enrollment, including administration of immunosuppression 
drugs/chemotherapy and cultured thymus tissue implantation. 
 
The entire cultured thymus tissue implantation procedure will be carried out under the 
supervision of the Duke Thymus Transplant Center, including but not limited to the 
following:  
 pre-transplant work-up,  
 selection of cultured thymus tissue for implantation,  
 administration of immunosuppression if necessary,  
 administration of medications to treat the immunodeficiency or autoimmune 
symptoms,  
 inpatient care during the immediate post-implantation period, and  
 inpatient or outpatient follow-up post-implant until the subject is stable enough to 
return to care of the referring physician 
 
After cultured thymus tissue implantation, standard blood counts should be done at least 
once a week for 2 months, or for as long as the recipient subject is on 
immunosuppression.  After 2 months and after immunosuppression is stopped, standard 
blood counts should be done once a month for the first year after implantation. 
 
Blood samples for flow cytometry immune testing, including naïve T cell numbers, will be 
obtained at 3, 6, 9 and 12 months post cultured thymus tissue implantation.  Immune 
tests may be done more frequently if medically necessary.  Yearly follow-up clinic visits 
are strongly encouraged. 
 
At 2 to 3 months after cultured thymus tissue implantation, blood for T cell chimerism will 
be obtained.  Chimerism may be repeated if necessary. If thymus donor T cells are 


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present, chimerism testing should be repeated at 6 months after cultured thymus tissue 
implantation, and may be repeated at intervals, until the donor T cells disappear.  
 
After the subject leaves the Duke area, all recommended medications, monitoring, and 
testing is entirely dependent upon the subject, parent/guardian, and/or local physicians. 
 
3.2 Thymus Procurement 
Thymus tissue, which would otherwise be discarded, will be obtained from pediatric heart 
surgery cases in which the heart surgery patient is less than or equal to 9 months of age. 
Consent for use of thymus is obtained from the parent/guardian of the thymus donor 
under an IRB approved protocol.        
 
3.3 Thymus Processing 
Thymus processing occurs as detailed in IND 9836.  The thymus tissue must meet lot 
release criteria.   
 
3.4 Thymus Donor Screening 
Screening of the donor and the 
 birth mother is performed as detailed in the IRB 
approved thymus donor protocol and under IND 9836.  
 
3.5 Dose 
The thymus tissue dose used in implantation is 4,500 to 22,000mm2 of thymus tissue per 
recipient BSA in m2.  
 
3.6 Implantation Procedure 
The cultured thymus tissue implantation is performed in the operating room by a general 
surgeon.  The cultured thymus tissue slices are inserted into pockets made in the 
quadriceps muscles in one or both legs depending on the amount of tissue to be 
implanted and the size of the recipient.    
 
3.7 Toxicities of Cultured Thymus Tissue Implantation Procedure & Thymus Tissue 
Biopsy 
Risks based on the safety experience of 105 patients (FAS) who received a cultured 
thymus tissue implant are detailed in the consent document.  The procedure risks are 
detailed in the consent document.  
 
See Appendix 1 for adverse events related to treatment by system organ class and 
preferred term.  See Appendix 2 for adverse events possibly related to RVT-802 by 
system organ class and preferred term.  
 
3.8 Venous Access 
All subjects require venous access (central or peripheral) for cultured thymus tissue 
implantation surgery.  Central venous access is required for subjects receiving rabbit anti-
thymocyte globulin (RATGAM) and other chemotherapy.  The type of venous access is 
dependent on the medical condition for each individual subject. 
 


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3.9 Cultured Thymus Tissue Implant Preparative Regimen 
Subjects will receive immunosuppression depending on the immune status of the subject.  
These regimens will be based on standard of care practices, patient condition, and 
history of other chemotherapy administration.  The DSMB will review and approve the 
plan for each subject prior to initiation of that plan. 
 
 
3.10 Skin Biopsy 
A skin biopsy may be done pre and/or post cultured thymus tissue implantation.  If skin 
rashes develop, the skin biopsies may be examined for the presence of T cells.  
 
3.11 Thymus Tissue Biopsy   
A thymus tissue biopsy may be obtained approximately 2 months after cultured thymus 
tissue implantation. Biopsies are done at the discretion of the PI and if the subject is 
medically stable.  The graft biopsy, if done, is evaluated for thymopoiesis by 
immunohistochemistry. 
 
3.12 Graft Versus Host Disease (GVHD) 
GVHD prophylaxis will not be included, as GVHD from thymus donor cells has not been 
seen to date in any thymus tissue recipient.  Standard of care management of GVHD will 
be initiated if GVHD occurs.  The medications may include cyclosporine or tacrolimus, 
steroids, and/or mycophenylate mofetil (MMF) depending on the severity and organs 
affected by the GVHD.  
 
3.13 Prophylactic Medications 
Prophylactic medications will be given as clinically indicated to protect against infection.   
 
3.14 Supportive Care 
Subjects will receive supportive care such as blood components, antibiotics, 
immunoglobulin replacement, and other interventions as appropriate for medical care.   
 
4 SUBJECT MONITORING AND SAFETY EVALUATION  
 
4.1 Subject Monitoring  
While at Duke, subjects will receive standard-of-care monitoring.  The exact schedule will 
 
 
 
 
4.2 Study Duration  
Subjects will be followed for approximately two years post-implantation. Recipients of 
cultured thymus tissue implants are encouraged to have annual follow-up appointments 
for ongoing medical care and evaluation.   
 
4.3 Study Endpoints 
This is an expanded access descriptive study.  Survival of subjects at one-year post-
implantation is the primary safety and efficacy endpoint.     
 


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We will record survival and collect data on CD3, CD4, CD8, and naïve T cells at 3, 6, and 
9 months and 1 year post implantation.  Chimerism will be assessed at 2 to 3 months
post implantation.  
4.4 Statistical Considerations
This is an expanded access study so there is no formal sample size or statistical 
analysis.  Post cultured thymus tissue implantation data will be reviewed on the naïve T 
cell count at 3, 6, and 9 months and 1 year (engraftment), T cell chimerism at 2 to 3 
months, and unexpected, study related serious adverse events.  After the subject leaves
Duke, data collection is dependent upon the subject/parent/guardian and local 
physicians. 
4.5 Adverse Event Recording and Reporting 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. All adverse events that meet the criteria 
for serious (see Definitions below) and deaths are to be entered into the clinical database 
and to be forwarded to the SAE contact. Review of SAEs and any that require expedited 
reporting will be conducted according to the procedures at Enzyvant and responsible 
safety vendor (Appendix 4).
The criteria listed in the NCI Common Terminology Criteria for Adverse Events v 4.0 
(CTCAE) will be used in grading toxicity. 
US Regulations require that an IND sponsor report Serious Adverse Events (SAEs) 
occurring with use of its product in a clinical trial if it is unexpected, and felt to be likely 
related to use of the investigational agent. In this study, all SAEs that occur will be 
evaluated by the PI and sponsor for assessment regarding the need for reporting to the 
FDA, and the IRB. After an Adverse Event is identified, the classification and relationship 
to the study procedures will be determined and assessed by the investigator and sponsor 
using the definitions that follow: 
Definitions
An Adverse Event is any undesirable experience occurring to a subject during the 
clinical trial, whether or not the event is considered related to the study interventions. 
Pre-existing conditions are not recorded as Adverse Events.
A Serious Adverse Event is any untoward medical occurrence that is fatal, life-
threatening, disabling, or results in inpatient hospitalization or prolongation of 
hospitalization. Occurrence of malignancy and adverse events resulting from overdose 
are considered serious adverse events. Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations, 
such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
CD3, CD4, CD8, a


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Note: The term "life-threatening" in the definition of "Serious Adverse Event" refers to 
an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe. 
 
An Unexpected Adverse Event is an event not listed in this document, in the consent 
form, in the US prescribing information (Appendix 3) or not associated with expected 
  
 
Expected adverse events are those generally associated with CTTI and/or 
chemotherapy/radiation therapy. Subjects undergoing high dose chemotherapy are 
anticipated to experience anorexia, nausea, vomiting, mucositis; pancytopenia and 
associated infections while neutropenic. Some may develop organ toxicities from high 
dose therapy.  
 
Causality 
Cultured Thymus Tissue Implantation  is a 
determination of whether there is reasonable possibility that the investigational product 
may have caused or contributed to an adverse event. It includes assessing temporal 
relationships, dechallenge/rechallenge information, association (or lack of association) 
with underlying diseases, and the presence (or absence) or a lack of one or more likely 
causes. The assessment of the relationship of an adverse event to implantation 
(possible, probable, or definitely related) is a clinical decision based on all available 
information. 
 
4.6 Stopping Rules       
All serious adverse events (SAEs) that are unanticipated but related to the investigational 
interventions are reviewed by the IRB, sponsor, and FDA. SAEs do not stop enrollment 
or interventions unless requested by the PI, Sponsor, FDA, or IRB. Examples of SAEs 
are GVHD and cancer. 
 
4.7 References        
1. 
Markert ML, Marques JG, Neven B, et al. First use of thymus transplantation 
therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood 2011; 
117(2): 688-96. 
2. 
Jacobsen M, Schweer D, Ziegler A, et al. A point mutation in PTPRC is associated 
with the development of multiple sclerosis. Nat Genet 2000; 26(4): 495-9. 
 


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APPENDICES  
 
Appendix 1  Adverse Events Related to Treatment  
 
 
 
FAS  
(N=105) 
System Organ Class (SOC) 
   Preferred Term (PT) 
  n 
   (%) 
   E 
Number of Related Adverse Events1  
 82 
( 78.1) 
264
 
Blood and lymphatic system disorders  
 
 25 
 
( 23.8) 
 
  40
   Thrombocytopenia 
12 
( 11.4) 
  15
   Neutropenia 
  9 
(  8.6) 
    9
   Coombs positive haemolytic anaemia 
  3 
(  2.9) 
    3
   Autoimmune haemolytic anaemia 
  2 
(  1.9) 
    3
   Anaemia 
  2 
(  1.9) 
    2
   Haemolysis 
  2 
(  1.9) 
    2
   Haemolytic anaemia 
  2 
(  1.9) 
    2
   Lymphadenopathy 
  2 
(  1.9) 
    2
   Immune thrombocytopenic purpura 
  1 
(  1.0) 
    1
   Splenomegaly  
Skin and subcutaneous tissue disorders  
  1 
25 
(  1.0) 
( 23.8) 
    1
  29
   Rash 
11 
( 10.5) 
  11
   Urticaria 
  5 
(  4.8) 
    6
   Alopecia 
  4 
(  3.8) 
    4
   Dermatitis atopic 
  1 
(  1.0) 
    1
   Erythema 
  1 
(  1.0) 
    1
   Granuloma skin 
  1 
(  1.0) 
    1
   Pigmentation disorder 
  1 
(  1.0) 
    1
   Psoriasis 
  1 
(  1.0) 
    1
   Rash papular 
  1 
(  1.0) 
    1
   Skin mass 
  1 
(  1.0) 
    1
   Stevens Johnson Syndrome 
Immune system disorders  
  1 
 23 
(  1.0) 
( 21.9) 
    1
  26
   Cytokine release syndrome 
 19 
( 18.1) 
  20
   Graft versus Host Disease 
   Graft versus Host Disease in gastrointestinal tract 
   Graft versus Host Disease in skin 
   Hypersensitivity 
  2 
  2 
  1 
  1 
(  1.9) 
(  1.9) 
(  1.0) 
(  1.0) 
    2
    2
    1
    1
Metabolism and nutrition disorders  
 22 
( 21.0) 
  32
   Hypomagnesaemia 
 17 
( 16.2) 
  17
   Hyperglycaemia 
  4 
(  3.8) 
    4
   Acidosis 
  3 
(  2.9) 
    3
   Hypoalbuminaemia 
  2 
(  1.9) 
    2
   Decreased appetite 
  1 
(  1.0) 
    1
   Fluid retention 
  1 
(  1.0) 
    1
   Hyperkalaemia 
  1 
(  1.0) 
    1
   Hypokalaemia 
   Hyponatraemia 
  1 
  1 
(  1.0) 
(  1.0) 
    1
    1
   Lactase deficiency  
Vascular disorders 
  1 
 21 
(  1.0) 
( 20.0) 
    1
  24
   Hypertension 
 20 
( 19.0) 
  21
   Thrombosis 
  2 
(  1.9) 
    2
   Haematoma 
  1 
(  1.0) 
    1


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FAS  
(N=105) 
System Organ Class (SOC) 
   Preferred Term (PT) 
  n 
   (%) 
   E 
 
Investigations 
 
17 
 
( 16.2) 
 
  25
   Alanine aminotransferase increased 
  4 
(  3.8) 
    4
   Aspartate aminotransferase increased 
  4 
(  3.8) 
    4
   Blood bicarbonate decreased 
  3 
(  2.9) 
    3
   Blood creatinine increased 
  3 
(  2.9) 
    3
   Lymphocyte morphology abnormal 
  1 
(  1.0) 
    2
   Blood alkaline phosphatase increased 
  1 
(  1.0) 
    1
   Blood chloride decreased 
  1 
(  1.0) 
    1
   Blood cortisol decreased 
  1 
(  1.0) 
    1
   Blood immunoglobulin E increased 
  1 
(  1.0) 
    1
   Blood magnesium decreased 
  1 
(  1.0) 
    1
   Lipase increased 
  1 
(  1.0) 
    1
   Lymphocyte count abnormal 
   Weight decreased 
   White blood cell count decreased 
  1 
  1 
  1 
(  1.0) 
(  1.0) 
(  1.0) 
    1
    1
    1
Renal and urinary disorders
11 
( 10.5) 
  16
   Proteinuria 
  7 
(  6.7) 
    7
   Acute kidney injury 
  3 
(  2.9) 
    3
   Renal failure 
  3 
(  2.9) 
    3
   Glomerulonephritis minimal lesion 
  1 
(  1.0) 
    1
   Glycosuria  
   Renal tubular acidosis 
  1 
  1 
(  1.0) 
(  1.0) 
    1
    1
Gastrointestinal disorders 
11 
( 10.5) 
  14
   Diarrhoea 
  4 
(  3.8) 
    4
   Pancreatitis 
  3 
(  2.9) 
    3
   Abdominal distension 
  1 
(  1.0) 
    1
   Diarrhoea haemorrhagic 
  1 
(  1.0) 
    1
   Enteritis 
  1 
(  1.0) 
    1
   Gastrointestinal haemorrhage 
  1 
(  1.0) 
    1
   Gingival hypertrophy 
   Ileus 
  1 
  1 
(  1.0) 
(  1.0) 
    1
    1
   Nausea 
Respiratory, thoracic and mediastinal disorders 
  1 
11 
(  1.0) 
( 10.5) 
    1
  11
   Hypoxia 
  5 
(  4.8) 
    5
   Respiratory failure 
  2 
(  1.9) 
    2
   Respiratory distress 
  1 
(  1.0) 
    1
   Sleep apnoea syndrome 
  1 
(  1.0) 
    1
   Stridor 
  1 
(  1.0) 
    1
   Tachypnoea 
  1 
(  1.0) 
    1
General disorders and administration site conditions 
  8 
(  7.6) 
    9  
   Pyrexia 
  6 
(  5.7) 
    7  
   Face oedema 
  1 
(  1.0) 
    1  
   Oedema peripheral 
  1 
(  1.0) 
    1  
Infections and infestations 
  8 
(  7.6) 
    8  
   Cytomegalovirus infection 
  2 
(  1.9) 
    2  
   Cellulitis staphylococcal 
  1 
(  1.0) 
    1  
   Device related infection 
  1 
(  1.0) 
    1  
   Staphylococcal skin infection 
  1 
(  1.0) 
    1  
   Stitch abscess 
  1 
(  1.0) 
    1  
   Varicella zoster virus infection 
   Wound infection staphylococcal 
  1 
  1 
(  1.0) 
(  1.0) 
    1
    1
 


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Page 19 of 45 
 
FAS  
(N=105) 
System Organ Class (SOC) 
   Preferred Term (PT) 
  n 
   (%) 
   E 
 
Injury, poisoning and procedural complications 
 
  6 
 
(  5.7) 
 
    6
   Wound dehiscence 
  4 
(  3.8) 
    4
   Graft haemorrhage 
   Venous injury 
  1 
  1 
(  1.0) 
(  1.0) 
    1
    1
Nervous system disorders
  6 
(  5.7) 
    6
   Seizure 
  3 
(  2.9) 
    3
   Febrile convulsion 
  1 
(  1.0) 
    1
   Infantile spasms 
  1 
(  1.0) 
    1
   Myelitis transverse 
  1 
(  1.0) 
    1
Hepatobiliary disorders 
  4 
(  3.8) 
    4
   Autoimmune Hepatitis 
   Hepatomegaly 
   Hepatosplenomegaly 
  2 
  1 
  1 
(  1.9) 
(  1.0) 
(  1.0) 
    2
    1
    1
Endocrine disorders 
  3 
(  2.9) 
    5
   Hypothyroidism 
  2 
(  1.9) 
    2
   Adrenal insufficiency 
  1 
(  1.0) 
    1
   Basedow's disease 
  1 
(  1.0) 
    1
   Hyperthyroidism 
  1 
(  1.0) 
    1
Musculoskeletal and connective tissue disorders 
  3 
(  2.9) 
    3
   Growth retardation 
  1 
(  1.0) 
    1
   Juvenile idiopathic arthritis 
  1 
(  1.0) 
    1
   Psoriatic arthropathy 
  1 
(  1.0) 
    1
Cardiac disorders 
  2 
(  1.9) 
    2
   Sinus Tachycardia 
Congenital, familial and genetic disorders 
   Albinism 
Neoplasms benign, malignant and unspecified  
(inc cysts and polyps) 
   Epstein-Barr virus associated lymphoma 
Psychiatric disorders 
   Irritability 
Reproductive system and breast disorders  
   Ovarian failure  
 
  2 
  1 
  1 
..1 
 
  1 
  1 
  1 
  1 
  1 
(  1.9) 
(  1.0) 
(  1.0) 
(  1.0) 
 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
    2
    1
    1
    1
 
    1
    1
    1
    1
    1
 
 
Abbreviations:  AE = adverse event; E = number of events; FAS = full analysis set; 
MedDRA = Medical Dictionary for Regulatory Activities; N = number of subjects included in the 
analysis set; n = number of subjects with events; PT = preferred term; SOC = system organ 
class 
Note:  If a subject had multiple occurrences of an AE, the subject was presented only once in 
the subject count for a given SOC and PT. Adverse events were coded using MedDRA version 
19.1.  
1Related events were defined as events that were definitely, probably or possibly related to 
RVT-802 or study procedures or with an unknown relationship based on investigator review. 
Source: Table 14.3.1.8.1    Adverse Events Related to Treatment by System Organ Class and Preferred Term 


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Page 20 of 45 
Appendix 2  Adverse Events Possibly Related to RVT-802 
 
 
FAS 
(N=105) 
System Organ Class (SOC) 
   Preferred Term (PT) 
  n 
   (%) 
   E 
Number of Related Adverse Events1  
 44 
( 41.9)  
  87
Blood and lymphatic system disorders  
 21 
( 20.0) 
  32
   Thrombocytopenia 
 11 
( 10.5) 
  13
   Neutropenia 
  8 
(  7.6) 
    8
   Coombs positive haemolytic anaemia 
  3 
(  2.9) 
    3
   Autoimmune haemolytic anaemia 
  2 
(  1.9) 
    3
   Haemolysis 
  2 
(  1.9) 
    2
   Haemolytic anaemia 
  2 
(  1.9) 
    2
   Immune thrombocytopenic purpura 
  1 
(  1.0) 
    1
Skin and subcutaneous tissue disorders  
  9 
(  8.6) 
  10
   Alopecia 
  4 
(  3.8) 
    4
   Rash 
  2 
(  1.9) 
    2
   Granuloma skin 
  1 
(  1.0) 
    1
   Psoriasis 
   Skin mass 
   Stephens-Johnson syndrome 
  1 
  1 
  1 
(  1.0) 
(  1.0) 
(  1.0) 
    1
    1
    1
General disorders and administration site conditions 
   Pyrexia 
   Oedema peripheral 
Renal and urinary disorders 
   Proteinuria 
   Glomerulonephritis minimal lesion 
Gastrointestinal disorders 
   Diarrhoea 
   Enteritis 
   Ileus 
Injury, poisoning and procedural complications 
   Wound dehiscence 
   Graft haemorrhage 
Investigations  
   Blood bicarbonate decreased 
   Lymphocyte morphology abnormal 
   Blood immunoglobulin E increased 
   Lymphocyte count abnormal 
Infections and infestations  
   Cytomegalovirus infection  
   Staphylococcal skin infection 
   Stitch abscess 
   Wound infection staphylococcal 
Immune system disorders  
  6 
  5 
  1 
  5 
  5 
  1 
  5 
  3 
  1 
  1 
  5 
  4 
  1 
  4 
  2 
  1 
  1 
  1 
  4 
  1 
  1 
  1 
  1 
  2 
(  5.7) 
(  4.8) 
(  1.0) 
(  4.8) 
(  4.8) 
(  1.0) 
(  4.8) 
(  2.9) 
(  1.0) 
(  1.0) 
(  4.8) 
(  3.8) 
(  1.0) 
(  3.8) 
(  1.9) 
(  1.0) 
(  1.0) 
(  1.0) 
(  3.8) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.9) 
    6
    5
    1
    6
    5
    1
    5
    3
    1
    1
    5
    4
    1
    6
    2
    2
    1
    1
    4
    1
    1
    1
    1
    3
 
   Graft versus Host Disease 
   Graft versus Host Disease in gastrointestinal tract 
   Graft versus Host Disease in skin 
Hepatobiliary disorders 
   Autoimmune hepatitis 
Musculoskeletal and connective tissue disorders 
   Juvenile idiopathic arthritis 
   Psoriatic arthropathy 
  1 
  1 
  1 
  2 
  2 
  2 
  1 
  1 
 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.9) 
(  1.9) 
(  1.9) 
(  1.0) 
(  1.0) 
    1
    1
    1
    2
    2
    2
    1
    1
 


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Page 21 of 45 
 
FAS  
(N=105) 
System Organ Class (SOC) 
   Preferred Term (PT) 
  n 
   (%) 
   E 
Endocrine disorders 
   
 
   Hyperthyroidism 
Congenital, familial and genetic disorders 
   Albinism 
Nervous system disorders 
   Myelitis transverse 
Reproductive system and breast disorders 
   Ovarian failure 
Vascular disorders 
  1 
  1 
  1 
  1 
  1 
  1 
  1 
  1 
  1 
  1 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
(  1.0) 
    2
    1
    1
    1
    1
    1
    1
    1
    1
    1
 
   Haematoma 
  1 
(  1.0) 
    1  
 
Abbreviations:  AE = adverse event; E = number of events; FAS = full analysis set; 
MedDRA = Medical Dictionary for Regulatory Activities; N = number of subjects included in the 
analysis set; n = number of subjects with events; PT = preferred term; SOC = system organ 
class 
Note:  If a subject had multiple occurrences of an AE, the subject was presented only once in 
the subject count for a given SOC and PT. Adverse events were coded using MedDRA version 
19.1.  
1Related events were defined as events that were definitely, probably or possibly related to 
RVT-802 or study procedures or with an unknown relationship based on investigator review. 
Source: Table 14.3.1.8.9    Adverse Events Possibly Related to RVT-802 by System Organ Class and Preferred Term 
 


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Appendix 3  RETHYMIC US Prescribing Information 


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Appendix 5  Investigator Statement of Agreement. 
 
 I agree to conduct the study in compliance with the protocol. 
 I agree that I am aware of and will comply with international ethical and quality standards of 
Good Clinical Practice (GCP). 
 I agree not to make changes to the protocol without prior agreement from Enzyvant and 
documentation that the Institutional Review Board (IRB) or its equivalent has reviewed and 
approved these changes. 
 I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described study. 
 I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about and fulfil their obligations. Mechanisms are in place to ensure that 
site staff receives the appropriate information throughout the study. 
 
 
 
 
Principal Investigator Name (Printed) 
 
Principal Investigator Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
Site 
 

SAP_001.pdf: