Stem Cell Mobilization (Plerixafor) and Immunologic Reset in Type 1 Diabetes (T1DM)

• Status: Recruiting
• Trial end date: 2022-12-31
• Target enrollment: 0
• Participant gender: All

Summary

Type 1 diabetes is an autoimmune disease characterized by destruction of pancreatic beta-cells, resulting in absolute deficiency of insulin. Presently there is no known cure.

Our proposed interventional trial is based on 'immunological reset' approach: T-depletion therapy and anti-inflammatory treatment will restore self-tolerance in T1DM; Autologous, peripheral-blood mobilized hematopoietic CD34+-enriched stem cells and a long-acting GLP-1 analogue will promote pancreatic islet regeneration and repair.

The short-term goals of this protocol is to demonstrate that subjects with new-onset T1DM undergoing autologous hematopoietic stem cell mobilization and immunologic reset will have greater preservation of endogenous insulin secretion compared to controls, and foremost that this nonmyeloablative treatment is safe, without the need for chronic immune suppression.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Alberta
• Collaborator: Alberta Innovates Health Solutions
• Treatments: Alemtuzumab; Etanercept; Interleukin 1 Receptor Antagonist Protein; JM 3100; Liraglutide; Plerixafor

Criteria

Inclusion Criteria:

Patient is aged 18-45

To be eligible participants must have:

• A clinical diagnosis of type 1 diabetes using the diagnostic criteria of the CDA

• Residual β-cell function, defined by a stimulated C-peptide > 0.6 but ≤10.5 ng/mL on MMTT;

• One or more positive autoantibodies: (GAD, ICA512, IA2A, ZnT8, mIAA) to confirm T1DM;

• No underlying condition that would preclude enrolment at PI's discretion.

Participants must be capable of understanding the purpose and risks of the study and must sign a statement of informed consent, with additional parental consent where required.

Exclusion Criteria:

• Duration of T1DM longer than 180 days

• Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent myocardial infarction (within past 6 months); (b) left ventricular ejection fraction <30%; or (c) evidence of ischemia on functional cardiac exam.

• Active alcohol or substance abuse, including cigarette smoking (must be abstinent for 6 months prior to study enrolment).

• Psychiatric disorder making the subject not a suitable candidate for this study (e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication).

• History of non-adherence to prescribed regimens.

• Hypersensitivity to any of the required study medications.

• Significant systemic infection during the 3 weeks before the start of study intervention (e.g., infection requiring hospitalization, major surgery, or IV antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localized cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion).

• Active infection including Hepatitis C, Hepatitis B, HIV, tuberculosis (subjects with a positive PPD performed within one year of enrollment, and no history of adequate chemoprophylaxis).

• Any history of, current malignancies, other than non-melanoma skin cancer (To be included to the study, subject must have had fewer than 5 occurrences of non-melanoma skin cancer, and the last occurrence must not be within 3 months of study entry).

• BMI > 35 kg/m2 at screening visit.

• Age less than 18 or greater than 45 years.

• Measured glomerular filtration rate (GFR) < 60 m/min/1.73m2

• Presence or history of macroalbuminuria (>300 mg/g creatinine)

• Clinical suspicion of nephritic (hematuria, active urinary sediment) or rapidly progressing renal impairment (e.g. Increase in serum creatinine of 25% within the last 3-6 months).

• Baseline Hb < 105g/L in women, or < 120 g/L in men.

• Baseline screening liver function tests outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial LFT panel with any values >1.5 times the upper limit of normal (ULN) will exclude a patient without a re-test; a re test for any values between ULN and 1.5 times ULN should be made, and if the values remain elevated above normal limits, the patient will be excluded.

• Untreated proliferative retinopathy.

• Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast feeding.

• EBV viral load of > 10,000 copies per 106 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR). If there is any clinical suspicion that a subject who is EBV seronegative and with EBV PCR < 10,000 copies per 106 PBMCs has symptoms consistent with infectious mononucleosis prior to administration of study treatment, then a monospot test result must be negative before the subject can be enrolled.

• Positive result on the Rapid Plasma Reagin (RPR) test for syphilis; except if result of RPR test is positive, a negative confirmatory test (for example, fluorescent treponemal antibody absorbed [FTA-ABS] test).

• History of using any investigational drug within the 3 months before enrollment of this study.

• History of using any potent immunosuppressive agent (e.g., systemic high-dose corticosteroids on a chronic basis, methotrexate, cyclosporine, or anti-TNF agents) within the 30 days before the study treatment.

• History of receiving any live vaccine within the 30 days before the study treatment.

• Any major surgical procedure within 30 days before the study treatment.

• Insulin requirement >1.0 U/kg/day

• HbA1C >12% at screening.

• Uncontrolled hyperlipidemia [fasting LDL cholesterol > 3.4 mmol/L, treated or untreated; and/or fasting triglycerides > 2.3 mmol/L]

• Under treatment for a medical condition requiring chronic use of steroids.

• Use of coumadin or other anticoagulant therapy (except aspirin) or subject with PT INR > 1.5.

• Untreated Celiac disease.

• Patients with Graves disease unless previously adequately treated with radioiodine ablative therapy.

• Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.

• Hypersensitive to E. coli derived protein.

• Clinically significant abnormal lab values during the screening period, other than those due to T1DM. Permitted ranges for selected lab values are shown in the Table below. A clinically significant abnormal value will not result in exclusion if, upon re-test, the abnormality is resolved or becomes clinically insignificant.