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

NCT04509791 | Completed Phase 2 DMC

• 2 other identifiers: S634662019-003265-17
• Study Type: interventional
• Target: 114
• Locations: 8 countries
• Sites: 14

Brief Summary

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

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• 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

  over 12 months

Study Arms (5)

placebo

PLACEBO COMPARATOR

placebo arm

Drug: Anti-Human Thymocyte Immunoglobulin, Rabbit

2.5 mg ATG/kg

ACTIVE COMPARATOR

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

1.5 mg ATG/kg

ACTIVE COMPARATOR

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

0.5 mg ATG/kg

ACTIVE COMPARATOR

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

0.1 mg ATG/kg

ACTIVE COMPARATOR

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

Interventions

Anti-Human Thymocyte Immunoglobulin, Rabbit DRUG

MELD - ATG : Minimum effective low dose ant-human thymocyte globulin (rabbit)

Also known as: ATG

0.1 mg ATG/kg; 0.5 mg ATG/kg; 1.5 mg ATG/kg; 2.5 mg ATG/kg; placebo

Eligibility Criteria

• Age: 5 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Universitaire Ziekenhuizen KU Leuven: lead

Study Sites (14)

Medical University of Graz

Graz, Austria

Location

Medical University of Vienna

Vienna, Austria

Location

Universitair Ziekenhuis Antwerpen

Antwerp, Belgium

Location

Universitair ziekenhuis Brussel

Brussels, Belgium

Location

Universite Libre de Bruxelles

Brussels, Belgium

Location

Universitaire Ziekenhuizen Leuven

Leuven, Belgium

Location

Herlev University Hospital

Herlev, Denmark

Location

Helsinki University Hospital Children and Adolescents

Helsinki, Finland

Location

Hannoversche Kinderheilanstalt Auf der Bult

Hannover, Germany

Location

IRCCS Ospedale San Raffaele

Milan, Italy

Location

University Medical Centre Ljubljana

Ljubljana, Slovenia

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, Oxon, OX3 9DU, United Kingdom

Location

Cambridge University Hospitals NHS Trust

Cambridge, United Kingdom

Location

The Royal London Hospital - Barts Health NHS Trust

London, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 34876434 BACKGROUND

• Mathieu C, Wych J, Hendriks AEJ, Van Ryckeghem L, Tree T, Chmura P, Moller C, Casteels K, Danne T, Reschke F, Smigoc Schweiger D, Battelino T, Johannesen J, Rami-Merhar B, Pieber T, De Block C, Evans M, Hilbrands R, Bosi E, Willemsen RH, Basu S, Pulkkinen MA, Knip M, Cnop M, Nitsche A, Schulte AM, Niemoller E, Peakman M, Wilhelm-Benartzi C, Gillespie D, Overbergh L, Mander AP, Marcovecchio ML; INNODIA. Minimum effective low dose of antithymocyte globulin in people aged 5-25 years with recent-onset stage 3 type 1 diabetes (MELD-ATG): a phase 2, multicentre, double-blind, randomised, placebo-controlled, adaptive dose-ranging trial. Lancet. 2025 Sep 27;406(10510):1375-1388. doi: 10.1016/S0140-6736(25)01674-5. Epub 2025 Sep 18.

  PMID: 40976248 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Antilymphocyte Serum

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)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures

Study Officials

• chantal Mathieu, MD,pHD

  Universitaire Ziekenhuizen KU Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: the trial design consists of 7 cohorts, each recruited sequentially, with between 3 and 5 treatment arms ( there will be fewer arms for later cohorts)

Study Record Dates

• First Submitted: August 7, 2020
• First Posted: August 12, 2020
• Study Start: November 24, 2020
• Primary Completion: December 16, 2024
• Study Completion: December 16, 2024
• Last Updated: January 10, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1); IT (1); SL (1); DK (1); GB (3); AU (2); DE (1); BE (4)