Clinical trial NCT04509791: MELD-ATG: Phase II, Dose Ranging, Efficacy Study of Anti-thymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 Diabetes (T1D)
Official title: MELD-ATG: Phase II, Dose Ranging, Efficacy Study of Anti-thymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 Diabetes (T1D)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2020-08-12
Enrollment: 114
Sex: ALL
Minimum age (years): 5
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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)
Primary purpose: TREATMENT

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

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

Eligibility criteria: 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

Primary outcomes:
measure: the area under the stimulated C-peptide response curve
timeFrame: over the first 2 hours of a mixed meal tolerance test (MMTT) at 12 months post treatment
Secondary outcomes:
measure: the area under the stimulated C-peptide response curve
timeFrame: over the first 2 hours of a MMTT at baseline, 3, 6 and 12 months
measure: dry blood spot (DBS) C-peptide measurements
timeFrame: at all observation times
measure: Cluster of differentiation 4 (CD4) positive T cells and Cluster of differentiation 8 (CD8) positive T cells
timeFrame: over 12 months
measure: HbA1c
timeFrame: over 12 months
measure: insulin requirements
timeFrame: over 12 months
measure: T1D-associated autoantibodies (glutamic acid decarboxylase antibodies (GADA), insulin auto-antibodies (IAA), IA-2 antibodies (IA-2A) and Zinc transporter 8 antibodies (ZnT8A))
timeFrame: over 12 months
measure: continuous glucose monitoring (CGM) measurements ( time in range, time above time below)
timeFrame: over 12 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Antwerp
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Brussels
country: Belgium
facility: Universitair ziekenhuis Brussel
city: Brussels
country: Belgium
facility: Universite Libre de Bruxelles
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Herlev
country: Denmark
facility: Herlev University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital Children and Adolescents
city: Hannöver
country: Germany
facility: Hannoversche Kinderheilanstalt Auf der Bult
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
state: Oxon
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust
city: London
country: United Kingdom
facility: The Royal London Hospital - Barts Health NHS Trust
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: chantal Mathieu, MD,pHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.