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New-onset Type 1 Diabetes MellitusPhase 2STARTNCT00515099

Study of Antithymocyte Globulin for Treatment of New-onset T1DM

A Phase 2 study testing Antithymocyte globulin in people with New-onset Type 1 Diabetes Mellitus, run by National Institute of Allergy and Infectious Diseases (NIAID) at 9 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Antithymocyte globulin (e.g., Thymoglobulin®) is an antibody preparation that is commonly used to treat and prevent organ transplant rejection. The START trial aims to determine whether antithymocyte globulin (ATG) treatment can halt the progression of newly diagnosed type 1 diabetes when given within 12 weeks of… Read more about this study

Who is it for?
Ages 12 to 35 years
Conditions the study is for
New-onset Type 1 Diabetes Mellitus
What is being tested?
Antithymocyte globulin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
58 participants
Where
9 sitesUnited States
Study dates
Aug 2007to Jul 2013
Phase
Phase 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 35 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Diagnosis of type 1 diabetes (according to American Diabetes Association [ADA] criteria) within100 days of enrollment
  • Positive for one or more autoantibodies (anti-glutamic acid decarboxylase [GAD], anti-insulin, or IA-2 autoantibodies)
  • Peak stimulated C-peptide level >0.4 pmol/mL or >1.2ng/mL following an MMTT
  • Serologic evidence of prior Epstein-Barr virus (EBV) infection (EBV seropositive)
  • Willing to use acceptable forms of contraception

Who cannot join

  • Any sign of active infection (e.g., hepatitis, tuberculosis, EBV, cytomegalovirus (CMV), or toxoplasmosis) at screening
  • Positive for human immunodeficiency virus (HIV), tuberculosis, or hepatitis B surface antigen (HBsAg) at screening
  • Prior history of any significant cardiac disease, such as congestive heart failure, arrhythmia, or structural defects, or suspicion thereof
  • Use of glucocorticoids in the 28 days prior to study entry; or topical use of glucocorticoids
  • Use of diabetes medications (other than insulin) that may affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, or amylin
  • Evidence of liver dysfunction
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  • Evidence of kidney disease
  • Pregnancy or plan to become pregnant
  • Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500neutrophils/µL), lymphopenia (<800 lymphocytes/µL), or thrombocytopenia (<125,000 platelets/µL).
  • Prior treatment with rabbit ATG or known hypersensitivity or exposure to rabbit sera-derived products
  • Vaccination with a live virus within the last 6 weeks before enrollment
  • Prior or current therapy that is known to cause a significant, ongoing change in the course of T1DM or immunologic status
  • Any condition that may compromise study participation or may confound the interpretation of the study results

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

United States9 sites

  • Emory Children's Center

    Atlanta, Georgia, 30322

  • Barbara Davis Center for Childhood Diabetes, University of Colorado

    Aurora, Colorado, 80010

  • Children's Mercy Hospital

    Kansas City, Missouri, 64108

  • Children's Hospital/USC School of Medicine

    Los Angeles, California, 90027

  • University of Minnesota

    Minneapolis, Minnesota, 55455

  • Children's Hospital and Research Center

    Oakland, California, 92609

  • University of Pennsylvania/Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • UCSD/San Diego Children's Hospital

    San Diego, California, 92123

  • Diabetes Center at UCSF

    San Francisco, California, 94143

Other trials in United States

About this study

Official title: Effect of Antithymocyte Globulin on Preserving Beta Cell Function in New Onset Type 1 Diabetes Mellitus

Antithymocyte globulin (e.g., Thymoglobulin®) is an antibody preparation that is commonly used to treat and prevent organ transplant rejection. The START trial aims to determine whether antithymocyte globulin (ATG) treatment can halt the progression of newly diagnosed type 1 diabetes when given within 12 weeks of disease diagnosis.

Read the detailed description

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these cells, the body cannot maintain proper blood glucose levels in response to daily activities, such as eating or exercise. Generally, at the time someone is diagnosed with T1DM, not all of a person's beta cells have been destroyed - between 15-40% remain healthy and are still able to produce insulin. Importantly, even small amounts of naturally produced insulin can improve blood sugar control, make daily management of diabetes less complicated, and reduce the risk of long term complications. Preserving the remaining precious beta cells is therefore the goal of the START trial.

The medication being tested in the START trial is antithymocyte globulin (e.g., Thymoglobulin®), a mixture of specialized proteins called antibodies. ATG attaches itself to white blood cells known as T cells, some of which are responsible for the immune system's attack on beta cells that occurs in T1DM. ATG can change how T cells work, and can eliminate a large proportion of the T cells from the bloodstream temporarily. Treatment of new onset T1DM with ATG is therefore expected to alter the behavior of the T cells to halt their attack, and also reduce T cell numbers, so that new T cells that grow in their place will learn to accept the beta cells, rather than attacking them.

Following an initial screening appointment, eligible participants will be randomly assigned to one of two groups: the Experimental Group will receive the study treatment while the Control Group that will receive placebo. Each participant has a 2 in 3 chance of being assigned to the treatment group, and a 1 in 3 chance of being assigned to the placebo. The START trial is a blinded study, so neither participants nor study physicians will know to which group an individual has been assigned. All participants will receive intensive diabetes management. Participants in both groups will be admitted to the hospital for 5-8 days to receive infusions of either the study drug or placebo.

The duration of the study is 2 years. Participants will have 8 follow-up appointments in the first year and 4 visits in the second year. Most of these visits will last 1- 2 hours. A review of interval health, a physical exam, an assessment of diabetes control including recent 5 day insulin use and blood sugar (e.g., glucose) testing, and blood collection for laboratory testing will occur at each visit. Four of the visits will last about 5 hours, during which participants will undergo mixed-meal tolerance testing (MMTT). This involves drinking a special drink, similar to a milkshake, and having blood specimens taken over a 4-hour period.

Subjects will be reimbursed for travel and parking expenses, and will receive compensation for their participation in the longer mixed meal tolerance test visits.

Being tested
Antithymocyte globulin, Placebo
Keywords
New-onset Type 1 Diabetes Mellitus, New-onset T1DM, New-onset Type 1 Diabetes, New-onset T1D, Newly Diagnosed Type 1 Diabetes Mellitus, Autoimmune diabetes, Thymoglobulin, ATG, Rabbit antithymocyte globulin
Medical subject headings
Diabetes Mellitus, Type 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Antithymocyte globulinDrug

    Also called ATG, Thymoglobulin®, Rabbit antithymocyte globulin, RATG

    Daily 4-day escalating dose

  • PlaceboDrug

    Also called Inactive drug (pharmacologically), Saline solution

    Daily 4-day saline solution

Study groups in NCT00515099
Study groupRoleWhat they receive
Antithymocyte globulinExperimentalThis group received a total of 6.5 mg/kg of antithymocyte globulin (e.g., Thymoglobulin®) divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Receives: Drug: Antithymocyte globulin
PlaceboPlacebo comparatorThis group received a saline solution to match the Thymoglobulin doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)

    C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint.

    Measured: Baseline (Pre-treatment initiation), Month 12

Secondary outcomes (6)

  1. 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)

    C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.

    Measured: Baseline (Pre-treatment initiation), Month 12

  2. Insulin Use in Units Per Kilogram Body Weight Per Day

    The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.

    Measured: Baseline (Pre-treatment), Months 12 and 24

  3. Number of Participants Who Are Exogenous-Insulin-Free

    The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.

    Measured: Baseline (Pre-treatment), Months 12 , 18, and 24

  4. Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation

    Major hypoglycemic events are defined as a glucose concentration <55 mg/dL (grades 2-5, NCI-CTCAE version 3.0), or clinically: involving seizure(s) or involving loss of consciousness (coma), or requiring assistance from another individual in order to recover.

    Measured: Baseline (Pre-treatment), Months 12 , and 24

  5. 2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT)

    C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) and 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the CDER at the FDA as a valid efficacy endpoint.

    Measured: Baseline (Pre-treatment), Month 24

  6. Hemoglobin A1c

    Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of <\=5.6% is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM).

    Measured: Baseline (Pre-treatment), Months 12 and 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Aug 2007 (estimated)
  2. Study startAug 2007
  3. Primary completionJun 2012
  4. Study completionJul 2013

Why it stopped: Slow accrual

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Care provider
Enrolment
58 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00515099
Sponsor's protocol ID
DAIT ITN028AI
Acronym
START
Status last verified
Apr 2017
First submitted
10 Aug 2007
Last updated
11 May 2017
Data monitoring committee
Yes
Individual data sharing
Yes: Participant level data and additional relevant materials are available to the public in TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal. ITN TrialShare makes data from the consortium's clinical trials publicly available.

Publications

  • Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. doi: 10.2337/diabetes.53.1.250.

    PubMed 14693724

  • Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.

    PubMed 18628574

  • Gitelman SE, Gottlieb PA, Rigby MR, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Aggarwal S, Phippard D, Sayre PH, Ding L, Bluestone JA, Ehlers MR; START Study Team. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2013 Dec;1(4):306-16. doi: 10.1016/S2213-8587(13)70065-2. Epub 2013 Aug 28.

    PubMed 24622416

  • Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Harris KM, Kanaparthi S, Phippard D, Ding L, Bluestone JA, Ehlers MR; ITN START Study Team. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016 Jun;59(6):1153-61. doi: 10.1007/s00125-016-3917-4. Epub 2016 Apr 6.

    PubMed 27053235

  • Salama A, Evanno G, Lim N, Rousse J, Le Berre L, Nicot A, Bach JM, Brouard S, Harris KM, Ehlers MR, Gitelman SE, Soulillou JP. Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Transplantation. 2017 Oct;101(10):2501-2507. doi: 10.1097/TP.0000000000001686.

    PubMed 28198767

  • Boyle KD, Keyes-Elstein L, Ehlers MR, McNamara J, Rigby MR, Gitelman SE, Weiner LJ, Much KL, Herold KC. Two- and Four-Hour Tests Differ in Capture of C-Peptide Responses to a Mixed Meal in Type 1 Diabetes. Diabetes Care. 2016 Jun;39(6):e76-8. doi: 10.2337/dc15-2077. Epub 2016 Apr 13. No abstract available.

    PubMed 27208317

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Antithymocyte globulin in people with New-onset Type 1 Diabetes Mellitus, run by National Institute of Allergy and Infectious Diseases (NIAID) at 9 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 5 inclusion and 13 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: stopped early, as of the sponsor's last update on 11 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 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 phase mean?

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 21 Apr 2014). 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?

2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) (time frame: Baseline (Pre-treatment initiation), Month 12). 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 NCT00515099, which also lists 6 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 11 May 2017.

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