MELD-ATG: Phase II, Dose Ranging, Efficacy Study of Anti-thymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 Diabetes (T1D) (Meld-ATG)

This study has been set up within the framework of the INNODIA network. INNODIA is a global partnership between 31 academic institutions, 6 industrial partners, a small sized enterprise and 2 patient organizations, bringing their knowledge and experience together with one common goal: "To fight type 1 diabetes". (www.innodia.eu) The overall aim of INNODIA is to advance in a decisive way how to predict, stage, evaluate and prevent the onset and progression of type 1 diabetes (T1D).

For this, INNODIA has established a comprehensive and interdisciplinary network of clinical and basic scientists, who are leading experts in the field of T1D research in Europe and UK (United Kingdom), with complementary expertise from the areas of immunology, Beta-cell biology, biomarker research and T1D therapy, joining forces in a coordinated fashion with industry partners and two foundations, as well as with all major stakeholders in the process, including regulatory bodies and patients with T1D and their families.

The MELD-ATG trial is a phase II, Multi-centre, randomised, double-blind, placebo-controlled, Multi-arm parallel cohort trial.

• to investigate the effect of 2.5 mg/kg og ATG on the preservation of stimulated C-peptide at 12 months compared to placebo
• to identify the minimally effective dose of ATG that shows an effect on C-peptide when compared to placebo at 12 months

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit

Detailed Description

A phase II, Multi-centre, randomised, double-blind, placebo-controlled, Multi-arm parallel cohort trial.

Randomisation wil be stratified by age. The trial consist of seven cohorts. The first cohort of 30 participants will be randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg.

ATG total dose in a 1:1:1:1 allocation ratio. There will be an initial age step down selection of this cohort with recruitment starting with dose aged 12-25 years and, providing no new safety concerns are raised in the first 10 participants to receive active dose, progressing to all ages (5-25 years) The next two cohorts of 12 participants will be randomised to placebo, 2.5 mg/kg, and 2 specified middle ATG total doses in a 1:1:1:1 allocation ratio.

The next four cohorts of 15 participants will be randomised to placebo, 2.5 mg/kg, and a single selected middle ATG total doses in a 1:1:1 allocation ratio.

This design allows sequential adjustment of the middle doses to be explored following review of all safety and early efficacy data by the Independent Data Monitoring Committee ( IDMC) and Dose Determine Committee (DDC) to seek the minimum effective dose

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Medical University of Graz
  • Vienna, Austria
    • Medical University of Vienna
• Belgium
  • Antwerp, Belgium
    • Universitair Ziekenhuis Antwerpen
  • Brussels, Belgium
    • Universitair Ziekenhuis Brussel
  • Brussels, Belgium
    • Université libre de Bruxelles
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven
• Denmark
  • Herlev, Denmark
    • Herlev University Hospital
• Finland
  • Helsinki, Finland
    • Helsinki University Hospital Children and Adolescents
• Germany
  • Hannöver, Germany
    • Hannoversche Kinderheilanstalt Auf der Bult
• Italy
  • Milano, Italy
    • Irccs Ospedale San Raffaele
• Slovenia
  • Ljubljana, Slovenia
    • University Medical Centre Ljubljana
• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NHS Trust
  • London, United Kingdom
    • The Royal London Hospital - Barts Health NHS Trust
  • Oxon
    • Oxford, Oxon, United Kingdom, OX3 9DU
      • Oxford University Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• has given written informed consent to participate; or have a parent or legal guardian provide written informed consent. Individual under the age of consent will be asked to assent to trial participation
• be aged > 5 years to < 25 years at written informed consent/assent
• have been diagnosed with T1d within 3-9 weeks of planned treatment day 1
• have random C-peptide levels > 200 pmol/L measured at screening, as tested centrally
• have 1 or more diabetes-related autoantibody (GADA, IA-2A or ZnT8A) present at screening, as tested centrally
• will be > 6 weeks form last live immunisation at planned treatment day 1 and be willing to forgo live vaccines during the trial until 6 months post treatment
• be willing to comply with intensive diabetes management

Exclusion Criteria:

• Type 2 diabetes
• Evidence of prior or current tuberculosis (TB) infection
• Clinically significant abnormal full blood count (FBC), renal function or liver function at screening
• Requiring use of other immunosuppressive or immunomodulation agents, including chronic use of systemic steroids
• any active chronic infections at screening, or any active acute or chronic infections at baseline or on treatment day, which would contraindicate any additional immunosuppression
• seropositive for human immunodeficiency virus (HIV),hepatitis B of hepatitis C infection at screening
• positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) based on local testing regimen
• unwilling to use appropriate contraception if sexually active during the trial, from date of written informed consent until completion of the 12-month follow-up visit
• any history of malignancies, other than skin
• current or ongoing use of non-insulin pharmaceuticals that effect glycaemic control
• active participation in another T1D treatment interventional trial in the previous 30 days prior to screening ( excluding treatment with insulin)
• any prior treatment with ATG, Abatacept or Anti-CD3 monoclonal antibody (Anti-CD3)
• known allergy to ATG or to similar products
• any condition, complicating medical issues, or abnormal clinical laboratory results that the investigator judges may adversely affect trial conduct, cause increased risk to the participant, or compromise the trial results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; placebo arm	Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit; MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit); Other Names: ATG
Active Comparator: 2.5 mg ATG/kg; the trial consists of 7 cohorts. The first cohort of 30 participants will be randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg en 0.1 mg/kg in a 1:1:1:1:1 allocation ratio	Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit; MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit); Other Names: ATG
Active Comparator: 1.5 mg ATG/kg; the next two cohorts of 12 participants will be randomised to placebo, 2.5 mg/Kg, and 2 specified middle ATG total doses in a 1:1:1:1 allocation ratio	Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit; MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit); Other Names: ATG
Active Comparator: 0.5 mg ATG/kg; The next four cohorts of 15 participants will be randomised to placebo, 2.5 mg/kg and a single selected middle ATG total dose in a 1:1:1 allocation ratio	Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit; MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit); Other Names: ATG
Active Comparator: 0.1 mg ATG/kg; the trial consists of 7 cohorts. The first cohort of 30 participants will be randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg en 0.1 mg/kg in a 1:1:1:1:1 allocation ratio	Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit; MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit); Other Names: ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
the area under the stimulated C-peptide response curve	over the first 2 hours of a mixed meal tolerance test (MMTT) at 12 months post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the area under the stimulated C-peptide response curve		over the first 2 hours of a MMTT at baseline, 3, 6 and 12 months
dry blood spot (DBS) C-peptide measurements		at all observation times
Cluster of differentiation 4 (CD4) positive T cells and Cluster of differentiation 8 (CD8) positive T cells		over 12 months
HbA1c		over 12 months
insulin requirements	The need for insulin (units) on a daily basis	over 12 months
T1D-associated autoantibodies (glutamic acid decarboxylase antibodies (GADA), insulin auto-antibodies (IAA), IA-2 antibodies (IA-2A) and Zinc transporter 8 antibodies (ZnT8A))	The presence of T1D-associated autoantibodies	over 12 months
continuous glucose monitoring (CGM) measurements ( time in range, time above time below)		over 12 months

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Chantal Mathieu, MD,pHD, Universitaire Ziekenhuizen KU Leuven

Publications and helpful links

General Publications

• Wilhelm-Benartzi CS, Miller SE, Bruggraber S, Picton D, Wilson M, Gatley K, Chhabra A, Marcovecchio ML, Hendriks AEJ, Morobe H, Chmura PJ, Bond S, Aschemeier-Fuchs B, Knip M, Tree T, Overbergh L, Pall J, Arnaud O, Haller MJ, Nitsche A, Schulte AM, Mathieu C, Mander A, Dunger D. Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes. BMJ Open. 2021 Dec 7;11(12):e053669. doi: 10.1136/bmjopen-2021-053669.

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2020
• Primary Completion (Actual): December 16, 2024
• Study Completion (Actual): December 16, 2024

Study Registration Dates

• First Submitted: August 7, 2020
• First Submitted That Met QC Criteria: August 10, 2020
• First Posted (Actual): August 12, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 8, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; Thymoglobulin
• Other Study ID Numbers: S63466; 2019-003265-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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