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

NCT03182426 | Completed Phase 1 DMC

• 1 other identifier: Pro00053082
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (2)

• Change of 2-hour mixed meal stimulated C-peptide AUC

  This AUC will be normalized by dividing it by 120 minutes (the number of minutes over which it is determined), and will be adjusted by inclusion of baseline C-peptide AUC as a covariate in the analysis.

  Baseline, Month 3, 6, 9, 12, 18 and 24

• Rate of Serious Adverse Event/Medical Event of Special Interest

  Within 24 months

Secondary Outcomes (9)

• "Responder" status

  Month 3, 6, 9, 12, 18 and 24

• Exogenous insulin usage

  Baseline, Month 3, 6, 9, 12, 18 and 24

• Proportion of subjects with HbA1c ≤6.5%

  Baseline, Month 3, 6, 9, 12, 18 and 24

• Proportion of subjects with HbA1c ≤7.0%

  Baseline, Month 3, 6, 9, 12, 18 and 24

• Proportion of subjects free from severe hypoglycaemia

  Baseline, Month 3, 6, 9, 12, 18 and 24

Study Arms (2)

Treated arm

EXPERIMENTAL

For participants assigned to the treated arm, they will follow study regime below: Intervention treatment will last from Day 0 up to Month 24. Day 0: Subjects will receive alemtuzumab (30mg iv single dose); anakinra (100 mg sc.); etanercept (50 mg sc.) and liraglutide (0.6 mg sc.). Day 1: Subjects will receive plerixafor (0.24 mg/kg/day) sc. to mobilize CD34+ stem cells to peripheral blood. Day 1: Continuing with anakinra 100mg sc. daily for 12 month; etanercept 50mg sc. twice weekly for first 3 months, and 50mg sc. weekly for another 9 months; liraglutide 0.6 mg sc. daily for 7 days, then 1.2 mg sc. daily (or up to 1.8mg daily) as tolerated for 24 months.

Drug: Plerixafor; Drug: Alemtuzumab; Drug: Anakinra; Drug: Etanercept; Drug: Liraglutide

Control arm

EXPERIMENTAL

For participant assigned to the control arm, they will be monitored and tested for the first 12 months, and receive intervention treatment from Month 12 up to Month 24. Month 12: Subjects will receive alemtuzumab (30mg iv single dose); anakinra (100 mg sc.); etanercept (50 mg sc.) and liraglutide (0.6 mg sc.). Month 12 + 1 day: Subjects will receive plerixafor (0.24 mg/kg/day) sc.. Month 12 + 1 day: Continuing with anakinra 100mg sc. daily for 12 month; etanercept 50mg sc. twice weekly for first 3 months, and 50mg sc. weekly for another 9 months; liraglutide 0.6 mg sc. daily for 7 days, then 1.2 mg sc. daily (or up to 1.8mg daily) as tolerated for 12 months.

Drug: Plerixafor; Drug: Alemtuzumab; Drug: Anakinra; Drug: Etanercept; Drug: Liraglutide

Interventions

Plerixafor DRUG

Systemic CD34+ stem cell mobilization for beta-cell repair

Also known as: Mozobil

Control arm; Treated arm

Alemtuzumab DRUG

T-cell depletion

Also known as: Lemtrada

Control arm; Treated arm

Anakinra DRUG

Anti-inflammatory

Also known as: Kineret

Control arm; Treated arm

Etanercept DRUG

Anti-inflammatory

Also known as: Enbrel

Control arm; Treated arm

Liraglutide DRUG

Beta-cell regeneration

Also known as: Victoza

Control arm; Treated arm

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Alberta: lead
• Alberta Innovates Health Solutions: collaborator

Study Sites (1)

University of Alberta

Edmonton, Alberta, T6G 2C8, Canada

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

plerixafor; Alemtuzumab; Interleukin 1 Receptor Antagonist Protein; Etanercept; Liraglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Immunoglobulin Constant Regions; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• James Shapiro, MD, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2017
• First Posted: June 9, 2017
• Study Start: August 15, 2017
• Primary Completion: July 15, 2024
• Study Completion: July 15, 2024
• Last Updated: July 19, 2024

Record last verified: 2024-07

Locations

CA (1)