A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline.

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of 400 mg Twice a Day Oral Ladarixin in Patients With New-onset Type 1 Diabetes and Preserved Beta-cell Function at Baseline.

The objective of this clinical trial was to assess whether ladarixin treatment is effective to improve glycemic control in newly diagnosed Type 1 Diabetes (T1D) adult patients with preserved β-cell function.

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

Study Overview

• Status: Terminated
• Conditions: New-onset Type 1 Diabetes
• Intervention / Treatment: Drug: Ladarixin; Other: Placebo

Detailed Description

This was a phase II clinical trial designed as a randomized, double-blind, placebo-controlled, multicenter study to evaluate whether ladarixin is effective in preserving β-cell function and slowing-down the progression of T1D in adult patients with new-onset T1D and preserved β- cell function (fasting C-peptide ≥0.205 nmol/L) at baseline.

Seventy-five (75) patients were to be randomized based on an unbalanced randomization allocation ratio (2:1) to ladarixin hard gelatine capsules for oral administration (2 x 200 mg two times a day [b.i.d.] for 13 cycles of 14 days on/14 days off) or matched placebo. Assuming a 10% drop-out rate, approximately 84 patients were expected to be enrolled and to be treated for 1 year.

Each patient was to be involved in the study for a run-in period (screening and baseline assessments) followed by a randomization visit, a treatment period of 12 months, and a post-randomization period up to 18 months from the 1st treatment dose.

The study enrolment was stopped, though, on 28 March 2022, due to low enrolment rate, at the randomization of the 25th patient. The study terminated early, on 11 October 2023 (LPLV).

Due to the early termination of the study, efficacy analyses were reduced in scope given the limited sample size of the study compared with the one expected.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Jette, Belgium
    • Universitair Ziekenhuis Brussel (UZB)
• Georgia
  • Tbilisi, Georgia, 48159
    • National Center for Diabetes Research LTD
  • Tbilisi, Georgia, 48159
    • National Institute of Endocrinology LTD
• Germany
  • Glessen, Germany, 35392
    • Universitaetsklinikum Gessen und Marburg GmbH - Medizinische Klinik und Poliklinik III
  • Heidelberg, Germany, 69115
    • St. Josefskrankenhaus Diabestesinstitut Heidelberg
  • Muenster, Germany, 48145
    • Institut fuer Diabetes forschung in Muenster (IDFM)
• Italy
  • Bari, Italy, 70124
    • Azienda Ospedaliero-Universitaria Conzorziale Policlinico di Bari
  • Catanzaro, Italy, 88100
    • Università degli Studi Magna Graecia di Catanzaro, Azienda Ospedaliero-Universitaria Mater Domini
  • Milan, Italy, 20157
    • Universitá degli Studi di Milano - Ospedale Luigi Sacco
  • Palermo, Italy, 90127
    • Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"
  • Roma, Italy, 00128
    • Università Campus Bio-Medico di Roma (UCBM)
  • Rome, Italy, 00161
    • "Sapienza" Università di Roma- Azienda Ospedaliero Universitaria Policlinico Umberto I
• Serbia
  • Belgrade, Serbia, 11000
    • University of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases
  • Kragujevac, Serbia, 34000
    • University of Kragujevac, Clinic for internal diseases, Center for endocrinology, diabetes and metabolic diseases
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado School of Medicine - Barbara Davis Center for Childhood Diabetes (BDC) - Specialty Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Atlanta Diabetes Associates (ADA)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female patients aged 18-45 years, inclusive;
2. New-onset T1D (1st IMP dose within 100 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 multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII);
5. Fasting C peptide ≥0.205nmol/L on two occasions;
6. Patient able to comply with all protocol procedures for the duration of the study, including scheduled follow-up visits and examinations;
7. Patients who have given written informed consent prior of any study-related procedure not part of standard medical care.

Exclusion Criteria:

1. Any other chronic disease, including type 2 diabetes, apart from autoimmune hypothyroidism requiring thyroid hormone replacement only; patients with severe (myxedema) disease potentially requiring immunosuppressive therapy will be excluded;
2. Moderate to severe renal impairment as per estimated Glomerular Filtration Rate (eGFR) 60 mL/min/1.73 m2, as determined using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (see Appendix 14.4.3);
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. A history of significant cardiovascular disease/abnormality
7. Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks;
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, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (>50 mg/day)];
10. Previous (within 2 weeks prior to randomization) 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 (within 1 month prior to randomization) or current administration of any immunosuppressive medications (including oral, inhaled or systemically injected steroids) 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 first 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. Hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C and HIV positive serologic status Serologic evidence of current infectious liver disease (hepatitis A, B, or C), including anti hepatitis A virus (immunoglobulin M), hepatitis B surface antigen, or anti hepatitis C virus 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ladarixin; The treatment group received 400 mg b.i.d. for 13 cycles of 14 days on/14 days off)	Drug: Ladarixin; 400 mg b.i.d. for 13 cycles of 14 days on/14 days off; Other Names: LDX
Placebo Comparator: Placebo; The control group received matched placebo	Other: Placebo; Placebo was administered orally with the same scheme of administration of LDX to preserve blinding

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12	The sample size of the study is calculated on the "proportion of patients with a HbA1c < 7% and daily insulin requirement <0.50 IU/Kg/day", a post-hoc composite endpoint derived from data of the phase 2 trial (MEX0114), considering a larger effect size expected from the longer treatment length (one year versus 3 months). The time frame for the primary endpoint has been set at Month 12 (Week 52) in order to evaluate the potential of ladarixin effects on a long-term projection. Please note that "proportion" is expressed as "count" (number + % of participants)	Month 12 (52±2 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18	The sample size of the study is calculated on the "proportion of patients with a HbA1c < 7% and daily insulin requirement <0.50 IU/Kg/day", a post-hoc composite endpoint derived from data of the phase 2 trial (MEX0114), considering a larger effect size expected from the longer treatment length (one year versus 3 months). Follow-up is extended up to 18 months to evaluate the potential persistency of any glycemic benefit. Please note that "proportion" is expressed as "count" (number + % of participants)	Month 6 (26±2 weeks) and Month 18 (78±2 weeks)
Number of Patients With a Reduction in HbA1c% > 0.5% From Baseline and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6, 12 and 18	The number of patients with a reduction in HbA1c% > 0.5% from baseline and daily insulin requirement <0.50 IU/Kg/day was calculated at the hereunder specified timepoints.	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks )
Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18	C-peptide level is a widely used measure of pancreatic beta-cell function and the MMTT is one of the methods for its estimation. AUC stands for Area Under the Curve. AUC calculation was based on actual rather scheduled timings and it was calculated using the trapezoidal rule. C-peptide 0-120 min AUC (nmol/L) values were calculated based on all Basal-120min C-peptide values. Unscheduled assessments were excluded from the analysis.	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18	HbA1c measurement can be used as a diagnostic test for diabetes providing that stringent quality assurance tests are in place and assays are standardised to criteria aligned to the international reference values, and there are no conditions present which preclude its accurate measurement. An HbA1c of 6.5% is recommended as the cut point for diagnosing diabetes. A value of less than 6.5% does not exclude diabetes diagnosed using glucose tests. An A1C test measures the percentage of red blood cells that have glucose-coated hemoglobin.	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18	For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Overall Number of Self-reported Episodes of Severe Hypoglycemia	For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. Data reported refer to the overall number of episodes recorded by all analyzed patients in the two arms/groups (Ladarixin and placebo).	From baseline to study termination (month 18, week 78)
Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18	A severe hypoglycemic event was defined as an event with 1 of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.e. glucose, or glucagon administration. Summary statistics of blood glucose level (mg/dL) are provided by treatment group at each time point for patients reporting severe hypoglycemia.	Months 6 (week 26±2), 12 (week 52±2) and 18 (week 78±2)
Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18	For the purpose of this study, daily insulin is averaged over the previous 3 days.Insulin requirement (IU/kg/day averaged over the previous 3 days) was to be recorded to Months 6, 12 and 18. Patients were admitted to intensive diabetes management, according to current ADA recommendation [2014]. Patients were instructed to self-monitor their glucose values at least 4 times a day and to report (glucose meter/log) outcome to the diabetes management team. Insulin intake was adjusted to target HbA1c levels of less than 7% and self-monitored (fingerstick): pre-prandial blood glucose of 70-130 mg/dL; post-prandial blood glucose < 180 mg/dL; bed-time blood glucose of 110-150 mg/dL	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18	Estimated Glucose Disposal Rate (eGDR) is a marker for the Assessment of Insulin Resistance and a validated clinical tool for estimating insulin sensitivity in type 1 diabetes.	Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious	An AE is any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with the trial intervention. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.	Throughout the study up to 18 months

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Study Director: Enrico M Minnella, MD, Dompé Farmaceutici

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2020
• Primary Completion (Actual): April 27, 2023
• Study Completion (Actual): October 11, 2023

Study Registration Dates

• First Submitted: May 10, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): May 24, 2021

Study Record Updates

• Last Update Posted (Actual): May 14, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Type 1 diabetes
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: LDX0419; 2020-002966-15 (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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No