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Trial record 71 of 339 for:    C-peptide | "Diabetes Mellitus, Insulin-Dependent"

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

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ClinicalTrials.gov Identifier: NCT03182426
Recruitment Status : Recruiting
First Posted : June 9, 2017
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
Alberta Innovates Health Solutions
Information provided by (Responsible Party):
University of Alberta

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.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Drug: Plerixafor Drug: Alemtuzumab Drug: Anakinra Drug: Etanercept Drug: Liraglutide Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus
Actual Study Start Date : August 15, 2017
Estimated Primary Completion Date : August 30, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1
Drug Information available for: Plerixafor

Arm Intervention/treatment
Experimental: Treated arm

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
Systemic CD34+ stem cell mobilization for beta-cell repair
Other Name: Mozobil

Drug: Alemtuzumab
T-cell depletion
Other Name: Lemtrada

Drug: Anakinra
Anti-inflammatory
Other Name: Kineret

Drug: Etanercept
Anti-inflammatory
Other Name: Enbrel

Drug: Liraglutide
Beta-cell regeneration
Other Name: Victoza

Experimental: Control arm

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
Systemic CD34+ stem cell mobilization for beta-cell repair
Other Name: Mozobil

Drug: Alemtuzumab
T-cell depletion
Other Name: Lemtrada

Drug: Anakinra
Anti-inflammatory
Other Name: Kineret

Drug: Etanercept
Anti-inflammatory
Other Name: Enbrel

Drug: Liraglutide
Beta-cell regeneration
Other Name: Victoza




Primary Outcome Measures :
  1. Change of 2-hour mixed meal stimulated C-peptide AUC [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
    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.

  2. Rate of Serious Adverse Event/Medical Event of Special Interest [ Time Frame: Within 24 months ]

Secondary Outcome Measures :
  1. "Responder" status [ Time Frame: Month 3, 6, 9, 12, 18 and 24 ]
    A subject is considered a responder if at the given time point, the subject has: a) HbA1c ≤6.5% and b) mean daily insulin use < 0.5 IU/kg/day over 7 consecutive days during the 2 weeks preceding the visit.

  2. Exogenous insulin usage [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
    Mean total daily insulin dose assessed over 7 consecutive days during 2 weeks preceding clinic visits

  3. Proportion of subjects with HbA1c ≤6.5% [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
  4. Proportion of subjects with HbA1c ≤7.0% [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
  5. Proportion of subjects free from severe hypoglycaemia [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
    Proportion of subjects free from severe hypoglycemia reported frequency of hypoglycemia by Hypo Score and Lability Index and CGMS

  6. Proportion of subjects progressing to complete beta cell loss [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
    Proportion of subjects who become C-peptide negative

  7. Autoantibodies associated with T1DM [ Time Frame: Baseline, Month 24 or the study withdrawal visit ]
    Including GAD, ICA512, IA2A, ZnT8 and mIAA

  8. T1DM T-cell autoreactivity [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]
  9. T-cell phenotyping [ Time Frame: Baseline, Month 3, 6, 9, 12, 18 and 24 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03182426


Contacts
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Contact: Andrew Malcolm, PhD 780-492-8751 amalcolm@ualberta.ca

Locations
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Canada, Alberta
University of Alberta Recruiting
Edmonton, Alberta, Canada, T6G 2C8
Contact: Andrew Malcolm, PhD    (780) 492-8751    andrew.malcolm@ualberta.ca   
Contact: Parastoo Dinyari, BSc    (780) 492-1636    parastoo@islet.ca   
Principal Investigator: James Shapiro, MD PhD         
Sponsors and Collaborators
University of Alberta
Alberta Innovates Health Solutions
Investigators
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Principal Investigator: James Shapiro, MD, PhD University of Alberta

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Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT03182426     History of Changes
Other Study ID Numbers: Pro00053082
First Posted: June 9, 2017    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Liraglutide
Plerixafor octahydrochloride
Etanercept
Alemtuzumab
Interleukin 1 Receptor Antagonist Protein
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors
Antineoplastic Agents, Immunological
Antineoplastic Agents
Anti-HIV Agents