CLINICAL TRIAL / NCT06305286
Safety, Tolerability, and Efficacy of Immunomodulation With A Monoclonal Antibody Against CD40L in Combination With Transplanted Islet Cells in Adults With Brittle Type 1 Diabetes Mellitus (T1D)
- Interventional
- Recruiting
- NCT06305286
Contact Information
A Pilot Study Assessing the Safety of Using a Monoclonal Antibody Against Cluster of Differentiation 40 (CD40) Ligand to Achieve a Calcineurin Inhibitor-free Immunosuppression Regimen in Patients With Type 1 Diabetes Mellitus (T1D) and Problematic Hypoglycemia Undergoing Islet Cell Transplantation
AT-1501 is a monoclonal antibody. Antibodies are Y-shaped proteins that are produced naturally by the subject's immune system to attack and fight foreign substances that cause illness. Monoclonal antibodies are man-made proteins manufactured to serve as substitute antibodies to fight diseases. Monoclonal antibodies can restore, enhance, or mimic (copy) the immune system's attack process; they can also tone down the immune system. AT-1501 is thought to work by dampening down the immune system so that it will be less likely to attack the transplanted cells. For other types of transplants, like kidney, a drug called a calcineurin inhibitor is usually used to prevent rejection. That class of drugs can be toxic to islet cells. AT-1501 is an experimental agent that is anticipated to prevent rejection without harming the islet cells.
By doing this study, the study team is studying an investigational regimen containing 2
experimental components:
- An investigational drug called AT-1501 and
- Human pancreatic islet cells
Both AT-1501 and human pancreatic islet cells are considered investigational because they
are not currently approved for use in the United States.
Islet cells are the specialized cells in the pancreas that produce insulin. In this
study, islet cells will be collected from the pancreas of a deceased organ donor and
transplanted into the body. The goal of this study is to see whether these transplanted
islet cells can take over insulin production. The study team will evaluate how well the
subject makes insulin and how well-controlled blood sugar is after the transplant.
The islet transplant procedure involves inserting a thin, flexible tube called a catheter
through a small cut in the upper abdomen. A radiologist uses X-rays and ultrasound to
guide the catheter into the portal vein of the liver where the islet cells are delivered.
This study of islet transplantation will test to see if islet transplantation is safe and
effective.
Because these islet cells come from another person, the subject's immune system may
recognize them as foreign and attack them. Standard immunosuppressive medicines
(Anti-thymocyte globulin [ATG] or Basiliximab, mycophenolate mofetil/mycophenolate sodium
(MMF/MPS) (CellCept®), and Etanercept) will be used to help prevent the body from
attacking the transplanted islet cells. AT-1501 will be given in combination with these
standard immunosuppressive medicines to test whether the investigational drug is safe,
tolerable, and efficacious. The effect of the combination of AT-1501 with other
immunosuppressant medications has not been previously tested.
Gender
All
Age Group
18 Years to 65 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
1. Men and women 18-65 years of age.
2. A diagnosis of T1D ≥5 years with onset of disease at <40 years of age.
3. Ability to provide informed consent.
4. Able to comply with study procedures, including the requirement to utilize
continuous glucose monitoring (CGM).
5. Involvement in appropriate diabetes management in accordance with the standard of
care, as directed by an endocrinologist or diabetologist with at least 4 (quarterly)
clinical evaluations within the 12 months prior to Screening; using CGM*: using an
insulin pump or multiple daily injection (MDI) of insulin therapy; and, unable to
achieve acceptable metabolic control because of the occurrence of unexplained SHEs-
at least 3 unexplained SHEs not secondary to a missed meal or dosing error, in the
12 months prior to Screening.
*CGM will be provide to subjects who otherwise qualify for study participation but
have not used CGM previously.
6. At least 3 unexplained SHEs not secondary to a missed meal or dosing error, in the
12 months prior to Screening.
7. HbA1c level 7.0% (48 mmol/mol) to 9.5% (80 mmol/mol), inclusive.
8. Absence of stimulated C-peptide (<0.3 ng/mL) in response to a 240-minute mixed- meal
tolerance test (MMTT).
9. Impaired awareness of hypoglycemia (IAH) as defined by a Clarke Score [Clarke 1995]
of 4 or more at the time of Screening, during the Screening period, and within the
last 6 months prior to the transplant.
10. If female, must be surgically sterile or 2 years postmenopausal. Women of
childbearing potential may be enrolled if a serum pregnancy test is negative at
screening/baseline. Women of childbearing potential and men with partners that are
of childbearing potential must agree to use 2 forms of highly effective methods of
contraception from Screening, throughout the study, and while receiving
immunosuppressive therapy for the functioning graft after the conclusion of the
study. Contraception use must continue for 90 days after the last administration of
the study drug (see Appendix 5). Male participants must refrain from donating sperm
for the duration of the study and agree to not donate sperm for 90 days after last
administration of the study drug.
11. Patients with Coronavirus Disease 2019 (COVID-19) Polymerase chain reaction (PCR)
negative test result.
Exclusion Criteria:
1. Any previous solid organ or islet allotransplant.
2. Body mass index (BMI) >30 kg/m2.
3. Weight ≤50 kg.
4. Insulin requirement >1.0 unit/kg/day or <15 units/day.
5. Treatment with any anti-diabetic medication other than insulin within 4 weeks of
Screening.
6. Uncontrolled proliferative diabetic retinopathy.
7. Blood pressure: systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure
(DBP) >90 mmHg.
8. Estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation <60 mL/min/1.73 m2.
9. Diagnosis of macroalbuminuria (>300 mg/g creatinine).
10. For female participants: Positive pregnancy test, presently breast-feeding, or
unwillingness to use effective contraceptive measures for the duration of the study
and 90 days after discontinuation. For male participants: intent to procreate during
the duration of the study or within 90 days after discontinuation or unwillingness
to use effective measures of contraception.
11. History of malignancy except for completely resected squamous or basal cell
carcinoma of the skin.
12. History of a thromboembolic event (TE), known hypercoagulable state, or condition
requiring long-term anticoagulation.
a. Participants with a history of clotted venous access not requiring long- term
anticoagulation may be included at the Principal Investigator's discretion if they
have no other history of TEs or known hypercoagulable state.
13. Known heparin allergy.
14. Receiving treatment for a medical condition requiring chronic use of systemic
steroids, except for physiologic replacement for example in Addison disease.
15. Presence of ongoing active infection including tuberculosis (TB), human
immunodeficiency virus (HIV), hepatitis B, hepatitis C. Laboratory evidence of
active infection even in the absence of clinical symptoms of infection is
exclusionary.
16. Invasive aspergillus, histoplasmosis or coccidioidomycosis infection within one year
prior to Screening.
17. Negative screen for Epstein-Barr Virus (EBV) by immunoglobulin G (IgG)
determination.
18. Current treatment with any immunosuppressive regimen, and treatment with biologic
immune modulating agents, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate
(S1P) receptor agonists, azathioprine, Mercaptopurine (6- MP), or systemic
corticosteroids in the previous 5 years.
19. Persistent elevation of serum aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) value greater than 3 times the upper limit of normal (ULN);
elevation of total bilirubin >1.5 ULN.
20. Any history of receiving experimental cell or gene therapy. Exposure to any other
experimental or investigational agent within 30 days or 5 half-lives; whichever is
longer.
21. History of substance abuse within the past 2 years.
22. Allergy to the Boost drink necessary for MMTT
23. Severe cardiovascular disease characterized by any one of these conditions: a)
stroke;
b) recent myocardial infarction (within past 6 months); c) evidence of ischemia on
functional cardiac exam within the last year; d) left ventricular ejection fraction
<30%.
24. History of significant gastrointestinal disease such as symptomatic
cholecystolithiasis; acute or chronic pancreatitis; symptomatic peptic ulcer
disease; severe unremitting diarrhea, vomiting or other disorders potentially
interfering with the ability to absorb oral medications.
25. Significant hyperlipidemia despite medical therapy defined as fasting low-density
lipoprotein (LDL) cholesterol >130 mg/dL and/ or triglycerides >200 mg/dL.
26. History of any conditions that can interfere in the assessment of HbA1c due to
increased red blood cell turnover or requirement for regular blood transfusions such
as sickle cell disease (HbSS, hematopoietic blood stem cell (HbSC), HbS/beta
thalassemia); Beta thalassemia major; Alpha Thalassemia (HbH) disease, Hemoglobin
H-Constant Spring.
27. History of any other acute or chronic medical condition or pre-planned
medical/surgical procedure that, in the opinion of the Principal Investigator, would
compromise the safety of participants or the integrity of study results; non-
compliance with recommended diabetes care in the preceding 12 months.
28. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia
(<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL).
Participants with lymphopenia are allowed if the Principal Investigator determines
there is no additional risk and obtains clearance from a hematologist.
29. Any coagulopathy or medical condition requiring long-term anticoagulant therapy
(e.g., warfarin) after islet cell transplantation (low-dose aspirin treatment is
allowed) or participants with an international normalized ratio (INR) >1.5. The use
of Plavix is allowed only when portal vein access is obtained using a
mini-laparotomy procedure at the time of islet cell transplant.
30. History of factor V deficiency.
31. Administration of live attenuated vaccine(s) within 2 months of Screening.
32. Any previous treatment with AT-1501 or any other anti-CD40L therapy
33. Baseline Panel-reactive Antibody (PRA) over 20%
34. Patients with COVID-19 positive PCR tests.