Thymus Transplantation in DiGeorge Syndrome #668

• Sponsor: Enzyvant Therapeutics GmBH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00576407
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 26
• Location: 1
• Arm: 1
• Actual Duration (Months): 315
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study purpose is to determine whether cultured thymus tissue implantation (CTTI) is effective in treating typical complete DiGeorge syndrome.

Condition or Disease	Intervention/Treatment	Phase
DiGeorge Syndrome; Complete Typical DiGeorge Anomaly	Biological: Cultured Thymus Tissue for Implantation (CTTI)	Phase 2

Detailed Description

There is no safe and effective treatment for DiGeorge syndrome and most patients die by the age of two. Complete DiGeorge syndrome is characterized by very low T cell or very low naïve T cell numbers. In this study, typical complete DiGeorge syndrome subjects underwent human postnatal cultured thymus tissue implantation (CTTI). Thymus tissue that would otherwise be discarded was processed and then implanted into complete DiGeorge subjects in the operating room. At the time of CTTI, a skin biopsy may have been obtained to look for any preexisting T cells. After CTTI, subjects were followed by routine research immune evaluations, using blood samples obtained approximately every 2-4 weeks. At approximately 2-3 months post-CTTI subjects underwent an open biopsy of the allograft. The biopsy was done under general anesthesia in the operating room. At the time of the graft biopsy, another skin biopsy was obtained to look for clonal populations of T cells.

The protocol aims include: assessing thymopoiesis in the allograft biopsy; assessing immunoreconstitution of complete DiGeorge syndrome subjects after postnatal allogeneic cultured thymus tissue implantation; assessing minimally invasive methods of assessing thymopoiesis (flow cytometry and polymerase chain reaction (PCR); assessing pre-implant T cells which do not proliferate in response to mitogens (focusing on NK-T cells); and, assessing cultured thymus tissue implantation safety and toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Thymus Transplantation in Complete DiGeorge Syndrome #668
• Actual Study Start Date: Oct 1, 1991
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Cultured Thymus Tissue Implantation in Complete DiGeorge Participants with Complete DiGeorge Syndrome, who were eligible, received cultured thymus tissue implantation (CTTI). No specific dose was assigned. There was a one time administration of the cultured thymus tissue.

Biological: Cultured Thymus Tissue for Implantation (CTTI); Cultured thymus tissue for implantation (CTTI) (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated thymus donors. Thymus tissue, the thymus donor, & thymus donor's birth mother were screened for safety. Approximately 2-3 weeks post-harvest thymus slices were implanted into the recipient's quadriceps. Dose was number of grams of cultured thymus tissue divided by the recipient's weight in kilograms. Minimum dose was 4 g/m2. Maximum dose 18g/m2. At time of CTTI, a skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. Post-CTTI, subjects followed by routine research immune evaluations, using blood samples for approximately 2 years.; Other Names: Thymus Tissue Thymus Tissue Transplantation Thymus Transplant CTTI

Outcome Measures

Primary Outcome Measures

1. Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI) [1 year post-CTTI]

   Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.

Secondary Outcome Measures

1. Survival at 2 Years Post-CTTI [2 years post-CTTI]

   Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.

2. Immune Reconstitution Efficacy - Total CD3 T Cells [1 year post-CTTI]

   The development of total CD3 T cells at one year as measured using flow cytometry

3. Immune Reconstitution Efficacy - Total CD4 T Cells [1 year post-CTTI]

   The development of total CD4 T cells at one year as measured using flow cytometry

4. Immune Reconstitution Efficacy - Total CD8 T Cells [1 year post-CTTI]

   The development of total CD8 T cells at one year as measured using flow cytometry

5. Immune Reconstitution Efficacy - Naive CD4 T Cells [1 year post-CTTI]

   The development of naive CD4 T cells at one year as measured using flow cytometry

6. Immune Reconstitution Efficacy - Naive CD8 T Cells [1 year post-CTTI]

   The development of naive CD8 T cells at one year as measured using flow cytometry

7. Immune Reconstitution Efficacy - Response to Mitogens [1 year post-CTTI]

   The development of a T cell proliferative response to the mitogen phytohemagglutinin.

8. Thymus Allograft Biopsy [2 to 3 months post-CTTI]

   Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The subject's parent(s) signed the ICF.

• For a diagnosis of DiGeorge Syndrome (DGS), the subject had one of the following:

• Heart defect

• Hypoparathyroidism

• 22q11 hemizygosity

• 10p13 hemizygosity

• Coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear anomalies/ deafness CHARGE association mutation (CHD7 deletion);

• PHA proliferative responses less than 20-fold above background.

• Subjects with typical Complete DiGeorge Anomaly (cDGA) had to have one of the following on 2 separate occasions:

• Circulating CD3+ T cells by flow cytometry < 50/mm3 or PHA < 20-fold over background

• If CD3+ were > 50/mm3, then CD45RA+ (cluster of differentiation 45RA) CD62L+ had to be < 50/mm3

• Or T cell receptor rearrangement excision circles (TRECs) by PCR had to be < 100 per 100,000 CD3+ cells.

• Subjects with atypical cDGA had to have both of the following with 2 studies each:

• Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.

• T cell proliferative response to PHA more than 20-fold over background. Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.

• T cell proliferative response to PHA more than 20-fold over background. While T cell response to PHA might have been seen, eligible subjects were to have no T cell proliferative response to antigens (less than 20-fold response) and were to have serious clinical problems related to immunodeficiency, such as opportunistic infection or failure to thrive.

Exclusion Criteria:

• Subjects on ventilators, with tracheostomies, with cytomegalovirus (CMV) infections, or requiring ongoing steroids could still be enrolled, but their data were to be analyzed separately

• Subjects who had heart surgery < 4 weeks prior to transplant

• Heart surgery anticipated within 3 months of the proposed time of transplantation

• Ongoing parenteral steroid therapy between enrollment and transplantation

• Present or past lymphadenopathy

• Rash associated with T cell infiltration of the dermis and epidermis

• Rejection by the surgeon or anesthesiologist as surgical candidates

• Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area (BSA) of the recipient

• Prior attempts at immune reconstitution, such as bone marrow transplantation or previous thymus transplantation

• Human immunodeficiency virus (HIV) infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Enzyvant Therapeutics GmBH
• National Institutes of Health (NIH)
• National Institute of Allergy and Infectious Diseases (NIAID)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: M. Louise Markert, MD, PhD, Duke University Medical Center, Pediatrics, Allergy & Immunology

Study Documents (Full-Text)

None provided.

More Information

Publications

• Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088.
• Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15.
• Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011 Sep;140(3):244-59. doi: 10.1016/j.clim.2011.04.004. Epub 2011 Apr 16.

• Responsible Party: Enzyvant Therapeutics GmBH
• ClinicalTrials.gov Identifier: NCT00576407
• Other Study ID Numbers: Pro00009955; 2R01AI047040-11A2; R56 Bridge R01AI4704011A1; 5K12HD043494-09; R01AI047040; 3R56AI047040-11A1S1; R01AI054843; #668
• First Posted: Dec 19, 2007
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Enzyvant Therapeutics GmBH: Thymus Transplantation; DiGeorge Syndrome; Athymia; Low T cell numbers; Immunoreconstitution; Primary immunodeficiency; DiGeorge Anomaly; Complete DiGeorge; Typical DiGeorge; Cultured Thymus Tissue Implantation (CTTI)
• Additional relevant MeSH terms: DiGeorge Syndrome; Syndrome

Study Results

Participant Flow

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Period Title: Overall Study
STARTED	26
COMPLETED	18
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation is done using allogeneic cultured postnatal thymus tissue from unrelated donors.
Overall Participants	26
Age (Count of Participants)
<=18 years	26 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	153 (102)
Sex: Female, Male (Count of Participants)
Female	11 42.3%
Male	15 57.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 34.6%
White	16 61.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%

Outcome Measures

1. Primary Outcome

Title	Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI)
Description	Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Of the 26 participants, 2 subjects did not have cDGA (1 SCID and 1 FoxN1) and underwent CTTI as enrollment exceptions. The FoxN1 participant is included in the efficacy analysis, thus n=25. The SCID participant is not included in the efficacy analysis as CTTI cannot lead to T cell development in SCID.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	25
Number (95% Confidence Interval) [% of participants who survive to 1 year]	72 276.9%

2. Secondary Outcome

Title	Survival at 2 Years Post-CTTI
Description	Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
Time Frame	2 years post-CTTI

Outcome Measure Data

Analysis Population Description

Of the 26 participants, 2 subjects did not have cDGA (1 SCID and 1 FoxN1) and underwent CTTI as enrollment exceptions. The FoxN1 participant is included in the efficacy analysis, thus n=25. The SCID participant is not included in the efficacy analysis as CTTI cannot lead to T cell development in SCID.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	25
Number (95% Confidence Interval) [% of participants who survive to 2 years]	72 276.9%

3. Secondary Outcome

Title	Immune Reconstitution Efficacy - Total CD3 T Cells
Description	The development of total CD3 T cells at one year as measured using flow cytometry
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD3 T cell count was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	17
Median (Full Range) [cells/mm3]	770

4. Secondary Outcome

Title	Immune Reconstitution Efficacy - Total CD4 T Cells
Description	The development of total CD4 T cells at one year as measured using flow cytometry
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD4 T cell count was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation)is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	17
Median (Full Range) [cells/mm3]	570

5. Secondary Outcome

Title	Immune Reconstitution Efficacy - Total CD8 T Cells
Description	The development of total CD8 T cells at one year as measured using flow cytometry
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD8 T cell count was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	16
Median (Full Range) [cells/mm3]	122

6. Secondary Outcome

Title	Immune Reconstitution Efficacy - Naive CD4 T Cells
Description	The development of naive CD4 T cells at one year as measured using flow cytometry
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if a T cell count was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	13
Median (Full Range) [cells/mm3]	270

7. Secondary Outcome

Title	Immune Reconstitution Efficacy - Naive CD8 T Cells
Description	The development of naive CD8 T cells at one year as measured using flow cytometry
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if a T cell count was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	11
Median (Full Range) [cells/mm3]	65

8. Secondary Outcome

Title	Immune Reconstitution Efficacy - Response to Mitogens
Description	The development of a T cell proliferative response to the mitogen phytohemagglutinin.
Time Frame	1 year post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants for the 1 year time point if testing was performed in the relevant time period.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	13
Median (Full Range) [counts/minute (cpm)]	133000

9. Secondary Outcome

Title	Thymus Allograft Biopsy
Description	Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.
Time Frame	2 to 3 months post-CTTI

Outcome Measure Data

Analysis Population Description

Data were only included on cDGA and FoxN1 participants if the participant had a biopsy of the thymus tissue implanted.

Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
Measure Participants	19
Evidence of thymopoiesis	17 65.4%
Evidence of rejection	1 3.8%
Inconclusive for thymopoiesis	1 3.8%

Adverse Events

Time Frame	2 years post-CTTI
Adverse Event Reporting Description	Adverse events reporting on all participants (cDGA, FoxN1, and SCID) who underwent cultured thymus tissue implantation (previously described as transplantation).
Arm/Group Title	Cultured Thymus Tissue Implantation
Arm/Group Description	Cultured Thymus Tissue Implantation (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated donors.
All Cause Mortality
	Cultured Thymus Tissue Implantation
	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)
Serious Adverse Events
	Cultured Thymus Tissue Implantation
	Affected / at Risk (%)	# Events
Total	23/26 (88.5%)
Blood and lymphatic system disorders
Thrombocytopenia	2/26 (7.7%)	4
Febrile neutropenia	1/26 (3.8%)	1
Cardiac disorders
Cyanosis	1/26 (3.8%)	1
Right ventricular hypertension	1/26 (3.8%)	1
Endocrine disorders
Hypothyroidism	2/26 (7.7%)	2
Gastrointestinal disorders
Diarrhoea	2/26 (7.7%)	3
Diarrhoea haemorrhagic	1/26 (3.8%)	1
Gastrooesophageal reflux disease	1/26 (3.8%)	1
Haematemesis	1/26 (3.8%)	1
Vomiting	1/26 (3.8%)	1
General disorders
Pyrexia	3/26 (11.5%)	3
Immune system disorders
Hypersensitivity	2/26 (7.7%)	2
Graft versus host disease in skin	1/26 (3.8%)	1
Infections and infestations
Device related infection	10/26 (38.5%)	19
Staphylococcal bacteraemia	3/26 (11.5%)	3
Sepsis	2/26 (7.7%)	3
Enterococcal sepsis	2/26 (7.7%)	2
Gastroenteritis rotavirus	2/26 (7.7%)	2
Influenza	2/26 (7.7%)	2
Parainfluenzae virus infection	2/26 (7.7%)	2
Viral upper respiratory tract infection	2/26 (7.7%)	2
Pneumonia klebsiella	1/26 (3.8%)	2
Bronchitis	1/26 (3.8%)	1
Croup infectious	1/26 (3.8%)	1
Cystitis escherichia	1/26 (3.8%)	1
Enterococcal bacteraemia	1/26 (3.8%)	1
Gastroenteritis adenovirus	1/26 (3.8%)	1
Gastroenteritis enteroviral	1/26 (3.8%)	1
Klebsiella sepsis	1/26 (3.8%)	1
Lower respiratory tract infection bacterial	1/26 (3.8%)	1
Pneumonia	1/26 (3.8%)	1
Pneumonia respiratory syncytial viral	1/26 (3.8%)	1
Pneumonia staphylococcal	1/26 (3.8%)	1
Pseudomonal bacteraemia	1/26 (3.8%)	1
Streptococcal bacteraemia	1/26 (3.8%)	1
Urinary tract infection viral	1/26 (3.8%)	1
Varicella	1/26 (3.8%)	1
Viraemia	1/26 (3.8%)	1
Injury, poisoning and procedural complications
Procedural haemorrhage	1/26 (3.8%)	1
Splenic rupture	1/26 (3.8%)	1
Investigations
Blood creatinine increased	1/26 (3.8%)	1
Weight decreased	1/26 (3.8%)	1
Metabolism and nutrition disorders
Feeding intolerance	1/26 (3.8%)	1
Hypocalcaemia	1/26 (3.8%)	1
Hypoglycaemia	1/26 (3.8%)	1
Metabolic acidosis	1/26 (3.8%)	1
Nervous system disorders
Seizure	2/26 (7.7%)	2
Central nervous system haemorrhage	1/26 (3.8%)	1
Cranial nerve disorder	1/26 (3.8%)	1
Febrile convulsion	1/26 (3.8%)	1
Hydrocephalus	1/26 (3.8%)	1
Hypertonia	1/26 (3.8%)	1
Hypocalcaemic seizure	1/26 (3.8%)	1
Infantile spasms	1/26 (3.8%)	1
Motor dysfunction	1/26 (3.8%)	1
Renal and urinary disorders
Glomerulonephritis minimal lesion	1/26 (3.8%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	5/26 (19.2%)	5
Hypoxia	2/26 (7.7%)	2
Respiratory acidosis	2/26 (7.7%)	2
Respiratory distress	2/26 (7.7%)	2
Alveolar lung disease	1/26 (3.8%)	1
Aspiration	1/26 (3.8%)	1
Bronchospasm	1/26 (3.8%)	1
Cough	1/26 (3.8%)	1
Diaphragmatic paralysis	1/26 (3.8%)	1
Pleural effusion	1/26 (3.8%)	1
Respiratory arrest	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome	1/26 (3.8%)	1
Vascular disorders
Hypotension	3/26 (11.5%)	3
Superior vena cava syndrome	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Cultured Thymus Tissue Implantation
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	4/26 (15.4%)	4
Eosinophilia	3/26 (11.5%)	3
Lymphadenopathy	3/26 (11.5%)	3
Anaemia	2/26 (7.7%)	2
Disseminated intravascular coagulation	2/26 (7.7%)	2
Splenomegaly	2/26 (7.7%)	2
Cardiac disorders
Bundle branch block right	2/26 (7.7%)	2
Congenital, familial and genetic disorders
Hydrocele	2/26 (7.7%)	2
Endocrine disorders
Hypothyroidism	4/26 (15.4%)	4
Gastrointestinal disorders
Diarrhoea	4/26 (15.4%)	4
Vomiting	3/26 (11.5%)	4
Umbilical hernia	3/26 (11.5%)	3
Constipation	2/26 (7.7%)	2
Pancreatic insufficiency	2/26 (7.7%)	2
General disorders
Pyrexia	15/26 (57.7%)	26
Generalised oedema	2/26 (7.7%)	2
Hepatobiliary disorders
Hepatomegaly	5/26 (19.2%)	5
Immune system disorders
Hypersensitivity	3/26 (11.5%)	3
Infections and infestations
Device related infection	5/26 (19.2%)	11
Oropharyngeal candidiasis	5/26 (19.2%)	6
Staphylococcal bacteraemia	4/26 (15.4%)	8
Clostridium difficile colitis	4/26 (15.4%)	4
Eye infection staphylococcal	4/26 (15.4%)	4
Urinary tract infection enterococcal	3/26 (11.5%)	4
Ear infection	3/26 (11.5%)	3
Eye infection bacterial	3/26 (11.5%)	3
Gastrointestinal viral infection	3/26 (11.5%)	3
Otitis media	3/26 (11.5%)	3
Urinary tract infection fungal	3/26 (11.5%)	3
Cystitis klebsiella	2/26 (7.7%)	4
Candiduria	2/26 (7.7%)	3
Enterococcal bacteraemia	2/26 (7.7%)	2
Lower respiratory tract infection bacterial	2/26 (7.7%)	2
Pneumonia staphylococcal	2/26 (7.7%)	2
Injury, poisoning and procedural complications
Stoma site haemorrhage	2/26 (7.7%)	2
Wound dehiscence	2/26 (7.7%)	2
Investigations
Alanine aminotransferase increased	5/26 (19.2%)	6
Aspartate aminotransferase increased	4/26 (15.4%)	5
Activated partial thromboplastin time prolonged	2/26 (7.7%)	2
Occult blood positive	2/26 (7.7%)	2
Prothrombin time prolonged	2/26 (7.7%)	2
Metabolism and nutrition disorders
Feeding intolerance	2/26 (7.7%)	2
Hyperglycaemia	2/26 (7.7%)	2
Hypomagnesaemia	2/26 (7.7%)	2
Renal and urinary disorders
Hydronephrosis	5/26 (19.2%)	6
Nephrocalcinosis	2/26 (7.7%)	2
Proteinuria	2/26 (7.7%)	2
Respiratory, thoracic and mediastinal disorders
Hypoxia	5/26 (19.2%)	5
Atelectasis	4/26 (15.4%)	5
Pleural effusion	4/26 (15.4%)	4
Pneumothorax	2/26 (7.7%)	3
Cough	2/26 (7.7%)	2
Pulmonary oedema	2/26 (7.7%)	2
Rales	2/26 (7.7%)	2
Skin and subcutaneous tissue disorders
Rash	9/26 (34.6%)	17
Alopecia	2/26 (7.7%)	2
Eczema	2/26 (7.7%)	2
Skin exfoliation	2/26 (7.7%)	2
Urticaria	2/26 (7.7%)	2
Vascular disorders
Hypertension	3/26 (11.5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.