Diabetes Mellitus, Type 1Phase 1/2NCT01106157
Reversing Type 1 Diabetes After it is Established
A Phase 1/2 study testing Anti-Thymocyte Globin (ATG) and Pegylated GCSF in people with Diabetes Mellitus, Type 1, run by University of Florida at 3 sites in United States.
Trial summary
The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production. Read more about this study
- Who is it for?
- Ages 12 to 45 years
- Conditions the study is for
- Diabetes Mellitus, Type 1
- What is being tested?
- Anti-Thymocyte Globin (ATG) and Pegylated GCSF
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 3 sitesUnited States
- Study dates
- Apr 2010to 16 Jul 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 45 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Must be > 12 years < 45
- Must have a diagnosis of T1D of greater than 4 months duration, with an upper limit of 2 years, Now only recruiting for those diagnosed greater than 1 year but less than 2 years.
- Must have at least one diabetes-related autoantibody present (e.g., islet cell autoantigen (ICA), GAD, ZnT8, or islet antigen 2 (IA2) autoantibodies)
- Must have stimulated C-peptide levels ≥ 0.1 pmol/ml (0.3ng/mL) when measured during a mixed meal tolerance test (MMTT), conducted at least 4 months from diagnosis of diabetes, and within 8 weeks of randomization
- Must be EBV PCR negative within two weeks of randomization if EBV seronegative at screening
- Be at least 6 weeks from last live immunization
Show all 9Show fewer
- Be willing to forgo live vaccines for 3 months following last dose of study drug
- Be willing to comply with intensive diabetes management
- Normal screening values for complete blood count (CBC), renal function and electrolytes (CMP).
Who cannot join
- Be immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (< 3,000 leukocytes /μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), or thrombocytopenia (<125,000 platelets/μL).
- Have a chronic infection at time of randomization
- Have a positive PPD
- Be currently pregnant or lactating, or anticipate getting pregnant within the next two years
- Require use of other immunosuppressive agents
- Have serologic evidence of current or past HIV, Tuberculosis, Hepatitis B or Hepatitis C infection
Show all 16Show fewer
- Have any complicating medical issues or abnormal clinical laboratory results that interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities (e.g., lymphopenia, leukopenia, or thrombocytopenia)
- Have a history of malignancies
- Evidence of liver dysfunction with angiotensin sensitivity test (AST) or ALT greater than 3 times the upper limits of normal
- Evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal
- Vaccination with a live virus within the last 6 weeks
- Current use of non-insulin pharmaceuticals that affect glycemic control
- Active participation in another T1D treatment study in the previous 30 days
- Known allergy to G-CSF or ATG
- Prior treatment with ATG or known allergy to rabbit derived products
- Any condition that in the investigator's opinion, may adversely affect study participation or may compromise the study results
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Barbara Davis Center for Childhood Diabetes
Aurora, Colorado, 80045-6511
University of Florida
Gainesville, Florida, 32610-0296
University of California, San Francisco
San Francisco, California, 94143-0748
About this study
Official title: Reversing Type 1 Diabetes After it is Established: A Pilot Safety and Feasibility Study of Anti-Thymocyte Globulin (Thymoglobulin®)and Pegylated GCSF (Neulasta®) in Established Type 1 Diabetes
The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production.
Read the detailed description
This is a randomized, placebo controlled, phase I/II trial. Potential subjects will be screened via a 4 hour mixed meal tolerance test to assess residual beta cell (C-peptide) function. If the C-peptide level at any time is ≥ 0.1 pmol/ml, and the subject meets the additional inclusion and exclusion criteria, they will be eligible for randomization and enrollment. The study will be randomized 2:1 such that 17 subjects will receive active therapy and 8 will receive placebo. Subjects must receive Thymoglobulin®/ Neulasta® or placebo within 8 weeks of randomization. Thymoglobulin® (2.5mg/kg)/placebo will be given as 0.5 mg/kg IV on day 1 and 2 mg/kg on day 2. Six doses of Neulasta® (6mg/dose)/placebo will be given as standard of care every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and complete blood count (CBC) will be done at the screening visit, just prior to study drug initiation, daily during the Thymoglobulin® infusion admission, and at follow up visits. Following discharge, daily phone calls will be made to the subjects during the first 5 days of therapy and weekly thereafter. In addition, weekly phone calls for the month following completion of therapy will be used to document adverse reactions. Thereafter calls will be made every two weeks.
- Conditions
- Diabetes Mellitus, Type 1
- Being tested
- Anti-Thymocyte Globin (ATG), Placebo, Pegylated GCSF
- Keywords
- Autoimmune, Diabetes Mellitus, Glucose Metabolism
- Medical subject headings
- Diabetes Mellitus, Type 1, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-Thymocyte Globin (ATG)Drug
Also called Thymoglobulin
Anti-Thymocyte Globin (ATG) will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2.
PlaceboDrug
Also called Saline infusion
Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes
Pegylated GCSFDrug
Also called Neulasta
6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion.
| Study group | Role | What they receive |
|---|---|---|
| Anti-Thymocyte Globin plus pegylated GCSF | Experimental | Subjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks. Receives: Drug: Anti-Thymocyte Globin (ATG); Drug: Pegylated GCSF |
| Placebo | Placebo comparator | Saline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Metabolic Function Baseline to 12 Months.
Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo
Measured: Baseline and 12 months
Secondary outcomes (9)
Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months
Change in regulatory T cells (Treg) baseline to 12 months
Measured: Change in Baseline to 12 months
A1c
Change in A1c baseline to 12 months
Measured: Change in baseline to 12 months
Change in Insulin Requirements, Baseline to 12 Months
Change in Insulin Requirements, baseline to 12 months
Measured: Change from baseline to 12 months
Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months
Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months
Measured: Change from baseline to 12 months
Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months
Change in Insulin Autoantibodies (IAA) over 12 months
Measured: Change from baseline to 12 months
Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months
Change in Insulinoma Associated 2 Autoantibodies (IA-2A)
Measured: Change from baseline to 12 months
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months
Measured: Change from baseline to 12 months
Percentage of Neutrophils
Change in Neutrophil Count over 12 months
Measured: Change from baseline to 12 months
Change in White Blood Count (WBC) From Baseline to 12 Months
Change in WBC over 12 months
Measured: Change from baseline to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2010 (estimated)
- Study startApr 2010
- Primary completionJan 2015
- Study completion16 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- The Leona M. and Harry B. Helmsley Charitable Trust, Genzyme, a Sanofi Company
- Responsible party
- Sponsor
- Investigators
- Michael J. Haller, MD, Principal investigator, University of Florida Pediatric Endocrinology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01106157
- Sponsor's protocol ID
- UF-ATG-GCSF001
- Other IDs
- IRB201702525, 041-2010, OCR16038
- Status last verified
- Jul 2019
- First submitted
- 15 Apr 2010
- Last updated
- 5 Aug 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Parker MJ, Xue S, Alexander JJ, Wasserfall CH, Campbell-Thompson ML, Battaglia M, Gregori S, Mathews CE, Song S, Troutt M, Eisenbeis S, Williams J, Schatz DA, Haller MJ, Atkinson MA. Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes. 2009 Oct;58(10):2277-84. doi: 10.2337/db09-0557. Epub 2009 Jul 23.
PubMed 19628781Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, Zou B, Brusko TM, Hulme MA, Wasserfall CH, Mathews CE, Atkinson MA, Schatz DA. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015 Jan;125(1):448-55. doi: 10.1172/JCI78492. Epub 2014 Dec 15.
PubMed 25500887
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reversing Type 1 Diabetes After it is Established: A Pilot Safety and Feasibility Study of Anti-Thymocyte Globulin (Thymoglobulin®)and Pegylated GCSF (Neulasta®) in Established Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT01106157
- Acronym / sponsor ID
- UF-ATG-GCSF001
- Conditions
- Diabetes Mellitus, Type 1
- Keywords
- Autoimmune, Diabetes Mellitus, Glucose Metabolism
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- The Leona M. and Harry B. Helmsley Charitable Trust, Genzyme, a Sanofi Company
- Study start
- Apr 2010 (actual)
- Primary completion
- Jan 2015 (actual)
- Study completion
- 16 Jul 2019 (actual)
- First posted
- 19 Apr 2010 (estimated)
- Results
- Posted 20 Jan 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production.
Detailed description
This is a randomized, placebo controlled, phase I/II trial. Potential subjects will be screened via a 4 hour mixed meal tolerance test to assess residual beta cell (C-peptide) function. If the C-peptide level at any time is ≥ 0.1 pmol/ml, and the subject meets the additional inclusion and exclusion criteria, they will be eligible for randomization and enrollment. The study will be randomized 2:1 such that 17 subjects will receive active therapy and 8 will receive placebo. Subjects must receive Thymoglobulin®/ Neulasta® or placebo within 8 weeks of randomization. Thymoglobulin® (2.5mg/kg)/placebo will be given as 0.5 mg/kg IV on day 1 and 2 mg/kg on day 2. Six doses of Neulasta® (6mg/dose)/placebo will be given as standard of care every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and complete blood count (CBC) will be done at the screening visit, just prior to study drug initiation, daily during the Thymoglobulin® infusion admission, and at follow up visits. Following discharge, daily phone calls will be made to the subjects during the first 5 days of therapy and weekly thereafter. In addition, weekly phone calls for the month following completion of therapy will be used to document adverse reactions. Thereafter calls will be made every two weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Anti-Thymocyte Globin plus pegylated GCSF | Experimental | Drug: Anti-Thymocyte Globin (ATG), Drug: Pegylated GCSFSubjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks. |
| Placebo | Placebo comparator | Drug: PlaceboSaline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner |
Who may qualify
- Ages
- 12 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (9 listed)
- Must be > 12 years < 45
- Must have a diagnosis of T1D of greater than 4 months duration, with an upper limit of 2 years, Now only recruiting for those diagnosed greater than 1 year but less than 2 years.
- Must have at least one diabetes-related autoantibody present (e.g., islet cell autoantigen (ICA), GAD, ZnT8, or islet antigen 2 (IA2) autoantibodies)
- Must have stimulated C-peptide levels ≥ 0.1 pmol/ml (0.3ng/mL) when measured during a mixed meal tolerance test (MMTT), conducted at least 4 months from diagnosis of diabetes, and within 8 weeks of randomization
- Must be EBV PCR negative within two weeks of randomization if EBV seronegative at screening
Key exclusion criteria (16 listed)
- Be immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (< 3,000 leukocytes /μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), or thrombocytopenia (<125,000 platelets/μL).
- Have a chronic infection at time of randomization
- Have a positive PPD
- Be currently pregnant or lactating, or anticipate getting pregnant within the next two years
- Require use of other immunosuppressive agents
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anti-Thymocyte Globin (ATG)Also: ThymoglobulinAnti-Thymocyte Globin (ATG) will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2. | Drug | Anti-Thymocyte Globin plus pegylated GCSF |
| PlaceboAlso: Saline infusionSaline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes | Drug | Placebo |
| Pegylated GCSFAlso: Neulasta6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion. | Drug | Anti-Thymocyte Globin plus pegylated GCSF |
Primary outcome
Change in Metabolic Function Baseline to 12 Months.
Time frame: Baseline and 12 months
Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo
9 secondary outcomes
Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months
Time frame: Change in Baseline to 12 months
A1c
Time frame: Change in baseline to 12 months
Change in Insulin Requirements, Baseline to 12 Months
Time frame: Change from baseline to 12 months
Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months
Time frame: Change from baseline to 12 months
Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months
Time frame: Change from baseline to 12 months
Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months
Time frame: Change from baseline to 12 months
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months
Time frame: Change from baseline to 12 months
Percentage of Neutrophils
Time frame: Change from baseline to 12 months
Change in White Blood Count (WBC) From Baseline to 12 Months
Time frame: Change from baseline to 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19628781Parker MJ, Xue S, Alexander JJ, Wasserfall CH, Campbell-Thompson ML, Battaglia M, Gregori S, Mathews CE, Song S, Troutt M, Eisenbeis S, Williams J, Schatz DA, Haller MJ, Atkinson MA. Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes. 2009 Oct;58(10):2277-84. doi: 10.2337/db09-0557. Epub 2009 Jul 23.
- Derived from this study: PubMed 25500887Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, Zou B, Brusko TM, Hulme MA, Wasserfall CH, Mathews CE, Atkinson MA, Schatz DA. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015 Jan;125(1):448-55. doi: 10.1172/JCI78492. Epub 2014 Dec 15.
- University of Florida Diabetes Center of ExcellenceLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael J. Haller, MD principal investigator
University of Florida Pediatric Endocrinology
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Anti-Thymocyte Globin (ATG) and Pegylated GCSF in people with Diabetes Mellitus, Type 1, run by University of Florida at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Jan 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Metabolic Function Baseline to 12 Months. (time frame: Baseline and 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01106157, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2019.