Clinical trial NCT04628481: A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function
Official title: Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess Effect and Safety of 400 mg Twice a Day Oral Ladarixin in Patients With Recent Onset Type 1 Diabetes and Low Residual β-cell Function at Baseline (GLADIATOR)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Recent Onset type1 Diabetes
Keywords: type1 diabetes
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2020-11-13
Enrollment: 140
Sex: ALL
Minimum age (years): 14
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.
Primary purpose: TREATMENT

Brief summary: Objectives The objective of this clinical trial is to assess whether ladarixin treatment has an effect to preserve β-cell function and delay the progression of T1D in adolescent and adult patients.

The safety of ladarixin in the specific clinical setting will be also evaluated.

Detailed description: The study will be a phase 2, multicenter, double-blind, placebo-controlled study. It will randomize approximately 130-140 patients (with up to an estimated 15-20% adolescents), with recent onset (within 180 days from 1st insulin administration) type 1 diabetes (T1D), assigned (2:1) to receive either oral ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or placebo (control group). Recruitment will be competitive among the study sites, until the planned number of patients is randomized.

Ladarixin and placebo will be both administered for 1 year. All patients will be followed-up for 24 months from the 1st administration of the study medication. After the initial 12-m treatment period, all patients will enter into a 12-month follow-up (total period 24-month after first IMP administration). The study database (DB) will be locked when the last randomized patient has completed the month 12 visit (or being lost in follow-up), and relative data have been fully reconciled and cleaned; at that point, the DB will be unblinded and all endpoints, including the 6-month primary endpoint, will be analyzed, and the follow-up will continue under open-label conditions up to month 24.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients aged 14-45 years, inclusive;
2. Recent onset T1D (1st IMP dose within 180 days from 1st insulin administration);
3. Positive for at least one diabetes-related auto-antibody (anti-GAD; IAA, if obtained within 10 days of the onset of insulin therapy; IA-2 antibody; ZnT8);
4. Require, or has required at some time, insulin therapy through one or more separate subcutaneous injections or Continuous Subcutaneous Insulin Infusion (CSII).
5. Fasting C peptide \< 0.205nmol/L;
6. Residual beta-cell function as per peak stimulated (MMTT) C-peptide level \>0.2nmol/L; MMTT should not be performed within one week of resolution of a diabetic ketoacidosis event;
7. Patient able to comply with all protocol procedures for the duration of the study, including scheduled follow-up visits and examinations;
8. Patients who have given written informed consent prior of any study-related procedure not part of standard medical care (participants under the age of 18, shall provide an assent for the study as per country requirements). Specific consent must be given by adolescents to be selected for the full PK analysis.

Exclusion Criteria:

1. A type 2 diabetes diagnosis or any other unstable chronic disease for which dose adjustment of specific medication is anticipated during the trial;
2. Moderate to severe renal impairment as per estimated Glomerular Filtration Rate (eGFR) 60 mL/min/1.73m2, as determined using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation;
3. Hepatic dysfunction defined by increased ALT/AST \> 3 x upper limit of normal (ULN) and increased total bilirubin \> 3 mg/dL \[\>51.3 μmol/L\];
4. Hypoalbuminemia defined as serum albumin \< 3 g/dL;
5. QTcF \> 470 msec;
6. Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks;
7. A history of significant cardiovascular disease/abnormality;
8. Known hypersensitivity to non-steroidal anti-inflammatory drugs;
9. Concomitant treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index \[i.e. phenytoin, warfarin, sulphonylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose amitriptyline (\> 50 mg/day)\];
10. Previous (past 2 weeks) and concomitant treatment with antidiabetic agents as metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, SGLT2-inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. beta-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.);
11. Past (past month) or current administration of any immunosuppressive medications (including oral or systemic corticosteroids) and use of any investigational agents, including any agents that impact the immune response or the cytokine system;
12. Significant systemic infection during the 4 weeks before the 1st dose of the study drug (e.g., infection requiring hospitalization, major surgery, or IV antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localized cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion);
13. History of positive status for hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C and HIV..
14. Pregnant or breast-feeding women. Unwillingness to use effective contraceptive measures up to 2 months after the end of study drug administration (females and males). Effective contraceptive measures include a hormonal birth control (e.g. oral pills, long term injections, vaginal ring, patch); the intrauterine device (IUD); a double barrier method (e.g. condom or diaphragm plus spermicide foam); abstinence.

Primary outcomes:
measure: Change from baseline in 2-hour AUC of C-peptide response to the Mixed Model Tolerance Test (MMTT)
timeFrame: Month 6
Secondary outcomes:
measure: Change from baseline in 2-hour AUC of C-peptide response to the MMTT
timeFrame: Months 12, 18 and 24
measure: Change in HbA1c from baseline
timeFrame: Months 6, 12, 18 and 24
measure: Time in range (TIR) by Continuous Glucose Monitoring (CGM)
timeFrame: Months 6, 12, 18, 24
measure: Proportion of patients with HbA1c <7% who did not experience severe hypoglycemic events during treatment
timeFrame: Months 6, 12, 18, 24
measure: Average (previous 3 days) daily insulin requirement (IU/kg/day)
timeFrame: Months 6, 12, 18, 24
measure: Proportion of patients with HbA1c <7% and daily insulin requirement <0.5 (IU/kg/day)
timeFrame: Months 6, 12, 18, 24
measure: Additional Glucose Variability Indices derived from CGM
timeFrame: Months 6, 12, 18 and 24
measure: Additional Glucose Variability Indices derived from MAGE
timeFrame: Months 6, 12, 18 and 24
measure: Additional Glucose Variability Indices derived from CONGA-n
timeFrame: Months 6, 12, 18 and 24
measure: Additional Glucose Variability Indices derived from MODD
timeFrame: Months 6, 12, 18 and 24
measure: Additional Glucose Variability Indices derived from mean daily blood glucose, SD
timeFrame: Months 6, 12, 18 and 24
measure: Number of self-reported episodes of severe hypoglycemia
timeFrame: Months 6, 12, 18, 24
measure: Percentage of patients not requiring insulin therapy
timeFrame: Months 6, 12, 18, 24
measure: Estimated Glucose Disposal Rate (eGDR)
timeFrame: Months 6, 12, 18, 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (UAB) - The Kirklin Clinic (TKC) - Multidisciplinary Comprehensive Diabetes Clinic (MCDC)
state: Alabama
city: Phoenix
country: United States
facility: Phoenician Centers for Research and Innovation
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Sacramento
country: United States
facility: Center of Excellence in Diabetes & Endocrinology (CEDE)
state: California
city: Aurora
country: United States
facility: University of Colorado School of Medicine - Barbara Davis Center for Childhood Diabetes (BDC) - Specialty Clinic
state: Colorado
city: Newark
country: United States
facility: Christiana Care Endocrinology Specialists
state: Delaware
city: Hudson
country: United States
facility: Diabetes Care Center - Hudson
state: Florida
city: Miami
country: United States
facility: Global Life Research Network
state: Florida
city: Orlando
country: United States
facility: AdventHealth (Florida Hospital) - Diabetes Institute - Orlando
state: Florida
city: Atlanta
country: United States
facility: Atlanta Diabetes Associates (ADA)
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Springfield
country: United States
facility: Prairie Education and Research Cooperative d/b/a Central Illinois Diabetes and Clinical
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University - Riley Hospital for Children
state: Indiana
city: Topeka
country: United States
facility: The Cotton-O'Neil Diabetes and Endocrinology Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Boston
country: United States
facility: Joslin Diabetes Center, Harvard Medical School
state: Massachusetts
city: Buffalo
country: United States
facility: UBMD Physicians Group - Pediatrics - Conventus
state: New York
city: Raleigh
country: United States
facility: "WakeMed Physician Practices - Pediatric Endocrinology - WakeMed Raleigh Medical Park Location"
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania Perelman School of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh - UPMC
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Endocrinology and Diabetes Program
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Norfolk
country: United States
facility: Eastern Virginia Medical School (EVMS) - Strelitz Diabetes Center
state: Virginia
city: Arlon
country: Belgium
facility: Clinique du Sud Luxembourg - Vivialia-Arlon
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel (UZB)
city: Sint-Niklaas
country: Belgium
facility: General Hospital AZ Nikolaas
city: Tbilisi
country: Georgia
facility: Aleksandre Aladashvili Clinic LLC
city: Tbilisi
country: Georgia
facility: National Center for Diabetes Research LTD
city: Tbilisi
country: Georgia
facility: National Institute of Endocrinology LTD
city: Tbilisi
country: Georgia
facility: Tbilisi Heart and Vascular Clinic LTD
city: Freiburg
country: Germany
facility: Medical Center - University of Freiburg
city: Glessen
country: Germany
facility: Universitaetsklinikum Gessen und Marburg GmbH - Medizinische Klinik und Poliklinik III
city: Heidelberg
country: Germany
facility: Diabestesinstitut Heidelberg
city: Ludwigshafen am Rhein
country: Germany
facility: Die Praxis am Ludwigsplatz
city: Münster
country: Germany
facility: Institut fuer Diabetes forschung in Muenster (IDFM)
city: Münster
country: Germany
facility: Schwerpunktpraxis fuer Diabetes & Ernaehrungsmedizin
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center, Petah Tikva
city: Tel Aviv-Yafo
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Ancona
country: Italy
facility: Ospedale Pediatrico G. Salesi - Centro Regionale di Diabetologia Clinica Pediatrica
city: Bari
country: Italy
facility: Azienda Ospedaliero-Universitaria Conzorziale Policlinico di Bari
city: Catanzaro
country: Italy
facility: Università degli Studi Magna Graecia di Catanzaro, Azienda Ospedaliero-Universitaria Mater Domini
city: Milan
country: Italy
facility: Universitá degli Studi di Milano - Ospedale Luigi Saco
city: Napoli
country: Italy
facility: Centro regionale di Diabetologia Pediatrica "G. Stoppoloni", Azienda Ospedaliera Universitaria "Luigi Vanvitelli"
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"
city: Roma
country: Italy
facility: Università Campus Bio-Medico di Roma (UCBM) - Policlinico Universitario
city: Roma
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale Pediatrico Bambino Gesu
city: Roma
country: Italy
facility: Universita Cattolica del Sacro Cuore - Policlinico Universitario "Agostino Gemelli"
city: Rome
country: Italy
facility: "Sapienza" Università di Roma- Azienda Ospedaliero Universitaria Policlinico Umberto I
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases
city: Belgrade
country: Serbia
facility: University Children's Hospital
city: Kragujevac
country: Serbia
facility: Clinical center Kragujevac, Clinic for internal diseases, Center for endocrinology, diabetes and metabolic diseases
city: Niš
country: Serbia
facility: Clinical Center Nis, Clinic for endocrinology
city: Niš
country: Serbia
facility: Clinical Center Nis, Clinic for endocrinology
city: Lubiana
country: Slovenia
facility: University Children's Hospital, University Medical Center Ljubljana
Study officials:
References: