Induction dose of 270 mg Stelara (ustekinumab),followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) through Week 40

Gastrointestinal Inflammation Associated With CVID

CVID Enteropathy

The purpose of this study is to assess the safety/tolerability and efficacy of using Stelara (ustekinumab) in subjects with common variable immunodeficiency or selective IgG subclass deficiency (functional agammaglobulinemia) who have associated symptomatic gastrointestinal inflammation (CVID enteropathy). Subjects will receive a treatment dose of 270 mg will be injected subcutaneously in subjects by qualified nursing staff on the Day 0 study visit. Subjects will then receive a follow up treatment dose of 90 mg at Week 8, Week 16, Week 24, Week 32 and Week 40 and be followed for a total of 48 weeks.

Stelara (ustekinumab)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency

An Open-Label Phase I/II Pilot Study to Assess the Safety/Tolerability and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency

The primary endpoint of the study is whether treatment with ustekinumab is safe and tolerated in CVID enteropathy patients anddoes not cause a significant increase in infection or result in any serious adverse events (SAEs) that are determined to be definitely,probably or possibly related to administration of the study agent.

To assess the efficacy of the study agent in alleviating symptoms of CVID enteropathy by comparing measurements of weight and stool frequency at Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 with Day 0 baseline values.

To assess changes in gut absorption and protein loss (D-xylose absorption, 48 hour stool fat collection, fecal alpha-1 antitrypsin (A1AT) clearance) at Week 24 and Week 48 by comparison to baseline studies.

To assess changes in mucosal histology score (modified D haens scoring) at Week 48 by comparison to baseline score.

To measure changes in stimulated cytokine production and mRNAexpression microarray by LPMCs at Week 48 by comparison to baseline studies.

To measure changes in gut microbiota and global gene expression of inducible interferon and metabolic genes in LPMCs at Week 48 by comparison to baseline studies.

To measure changes in laboratory surrogate efficacy markers of inflammatory bowel disease treatments (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], albumin,hemoglobin, platelets) at Week 8, Week 16, Week 24, Week 32, Week 40 and Week 48.

National Institute of Allergy and Infectious Diseases (NIAID)

A single arm multi-drug regimen is used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates. The intervention includes a protocol of Thymoglobulin, Rituximab, plasmapheresis and Bortezomib.

A Multi-drug regimen is used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates.
Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol): Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis

Elimination of Immunologic Memory

Sex: Female, Male

Heart transplant candidates with CPRA > 50%

Region of Enrollment

Percentage of highly sensitized heart transplant candidates, (patients with a CPRA greater than 50%), who have desensitization therapy, and then achieve a reduction in alloantibody such that their CPRA falls below 20%. For an individual patient, the outcome measure time frame is the one year of the Recovery Phase which begins after 218 days from the time that the patient begins the Induction Immunotherapy Phase, which is the same as the end of the Bortezomib Treatment Phase.

The percentage of patients with a CPRA less than 20% during the Recovery Phase of the protocol

Highly Sensitized Heart Transplant Candidates

Percentage of Patients With a Reduction in CPRA to Less Than 20%

Percentage of patients, who are transplanted within one year of finishing the Bortezomib treatment phase.

Highly sensitized heart transplant candidates with a CPRA greater than 50% that complete the Bortezomib treatment phase and are transplanted within one year

Percentage of Patients Transplanted

Percentage of study patients who experience a serious safety issue during the three phases of the study as measured by all cause mortality, serious adverse reactions and other adverse reactions.

Mortality for any reason during the study period

All Cause Mortality

The number of study patients with serious adverse events.

Serious Adverse Events

The number of study patients who had adverse events other than serious.

Other Adverse Events

Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period

Percentage of patients who experience of grade 3 and above non-hematologic toxicities as measured by the incidence of hypersensitivity reaction, fever, nausea and vomiting or dehydration during the study period.

Percentage of patients who experienced a Grade 3 or above non-hematologic toxicity during any phase of the study

Percentage of Patients With Grade and Above Non-Hematologic Ti

Percentage of Patients Who Experience Grade 3 and Above Non-Hematologic Toxicities

The percentage of patients in the study who experience any grade of peripheral neuropathy during the study period

Percentage of study patients with all grades of peripheral neuropathy during the study period

The Percentage of Patients Who Experience Any Grade of Peripheral Neuropathy

Percentage of patients who experience cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD), or progressive multifocal leukoencephalopathy (PML) during the study period.

Percentage of patients who experience CMV, PTLD or PML within the study period

Incidnce of CMV, PTLD, PML

Percentage of Patients Who Experience CMV, PTLD, and PML

The percentage of study patients who experience infectious complications in either the respiratory or urinary tracts during the study period.

Number of Participants with Respiratory Tract Infections

Respiratory Tract Infections

Number of participants with urinary tract infections

Urinary Tract Infections

The Percentage of Patients Who Experience Either a Respiratory Tract Infection or a Urinary Tract Infection

The percentage of study patients who experience an exacerbation of cardiac dysrhythmias and heart failure during the study period

The study patients, who all have heart failure and need a heart transplant, but experience an exacerbation of their heart failure during the study period.

Percentage of Patients With Exacerbation of Heart Failure

The percentage of study patients who experienced an exacerbation of the incidence of cardiac dysrhythmias during the study period.

Percentage of Patients With Exacerbation of Dysrythmias

The Percentage of Patients Who Experience Exacerbations Cardiac Dysrhythmias or Heart Failure

A Grade 4 hematologic toxicity includes a platelet count < 25,000/mm3 or an absolute neutrophil count < 500/mm3

The percentage of patients who experienced a grade 4 hematologic toxicity as manifested by a platelet count < 25,000 mm3 or an absolute neutrophil count of < 500/mm3

Percentage of Patients With Grade 4 Hemotologic Toxicities

Percentage of Patients With Grade 4 Hematologic Toxicities

The percentage of patients who experience antibody mediated rejection at 6 months and 1 year post transplant. The study period was 583 days, during which a patient was eligible for transplant during the last 365 days. If a patient was transplanted on day 583, then the patient is followed for one year after the transplant, then the total time to assess the two patients would have been a period of two years or 730 days. In fact, neither patient was transplanted within the study period.

Percentage of study patients who were transplanted and then developed AMR by 6 months after transplant

Percentage of TX Patients With AMR at 6 Months

The percentage of study patients who have developed AMR within 12 months of their transplant. This number includes those patients who had AMR diagnosed within 6 months of transplant.

Percentage of TX Patients With AMR at 12 Months

The Percentage of Patients With Antibody Mediated Rejection After Transplantation

Percentage of patients who are transplanted with the study period who then develop de novo or donor-specific alloantibody (DSA) within one year post-transplant. The patients would be eligible for transplant after day 218 in the study protocol and the study had 365 days in which to be transplanted. If a patient was transplant on day 583,( the last day of eligibility), and then followed for one year, then the outcome time frame would be a total of two years. No patient was transplanted within the study period.

Study patients who received a transplant and then developed de novo or donor specific antibodies after transplant.

Percentage of Pts. Who Develope De Novo or DSA < 1 yr After TX

Percentage of Patients Who Develop De Novo Alloantibody or DSA Alloantibody After Transplant

Percentage of patients who receive a transplant within the study period who are then DSA negative at 1 year following transplantation.

Study patients who received a transplant during the study period and then are negative for donor specific antibodies at one year after transplant

Percentage of Transplanted Pt That Are DSA Negative at 1 Year

Percentage of Patients Post-Transplant That Are DSA Negative

The percentage of allografts transplanted during the study period that survive to 6 and 12 months post transplant.

Study patients who receive a heart transplant within the study period whose allografts survive to 6 months.

Allograft Survival at 6 Months

Study patients who are transplanted and whose allografts survive to one year. This number includes those allografts that survived to 6 months that then survived to 12 months.

Allograft Survival at 12 Months

Percentage of Allograft Survival

The percentage of allografts that have an acute rejection episode per the criteria of the International Society of Heart and Lung Transplantation (ISHLT) within one year of transplantation. Allografts implanted during the Recovery Phase are monitored for a year for acute rejection per the study protocol. An allograft potentially implanted on the last day of a patient's recovery period would still be monitored for a year, so the potential outcome measure time would be 730 days. Since no allografts were implanted during the recovery period, there are no results to report.

Allografts implanted within the study period are followed for one year after transplantation and are routinely monitored for allograft rejection.

Percentage of Allografts With Acute Rejection

The Percentage of Allografts That Endure Acute Rejection Within One Year of Transplantation

Proportion of patients who achieve a Calculated Panel Reactive Antibody test CPRA of < 20%, but are not transplanted within the study period.

Percentage of patients with a CPRA < 20% but not transplanted within one year

Patients With CPRA < 20% Who Were Not Transplanted

Percentage of Patients With a CPRA <20%, But Were Not Transplanted During the Study Period

Percentage of study patients who receive transplants within the study period who then experience death, allograft loss, hospitalization due to infection, and non-fatal serious adverse cardiac event (defined as acute myocardial infarction, congestive heart failure, need for percutaneous cardiac intervention, coronary artery bypass grafting, cardiac defibrillator placement, cerebral vascular accident, peripheral vascular disease) within 1 year of transplantation.

The incidence of death in transplanted patients at one year from transplant

Transplant Patient Death

Study patients who were transplanted and lost their allografts

Allograft Loss in Transplanted Patients

Study patients who were transplanted and then required hospitalization for infection within one year of the transplant

Hospitalization Due to Infection in Transplanted Patients

Study patients who were transplanted and had a non-fatal cardiac event(acute MI, congestive heart failure, coronary intervention, etc) at one year

Non-fatal Serious Cardiac Event

Percentage of Patients Who Receive Transplants Who Then Suffer Serious Post-transplant Complications

This was a Single Group Assignment Interventional Study to determine if a multi-drug regimen could be used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates. It was a non-randomized, open label, safety/efficacy (pilot) treatment study. It was hoped that if the calculated panel reactivity antibody (CPRA) was reduced to less than 20% via the protocol, then the patients could become functionally transplantable. There were three phases of the study, an Induction Immunotherapy Phase, a Bortezomib Treatment Phase, and a Recovery Phase. Both patients completed each of the three phases.

Induction Immunotherapy

Bortezomib Treatment Phase

Recovery Phase

Timothy B Icenogle MD

All subjects will receive the study treatment. This is a non-randomized, open label study. The study treatment consists of an Induction phase with Thymoglobulin, Rituximab and Methylprednisolone, a Treatment phase with Bortezomib and a Recovery phase to follow-up and re-immunize and transplant the subject.

agammaglobulinemia/carbohydrate

Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency

Multi-Drug Desensitization Protocol for Heart Transplant Candidates

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