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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
289
Change From Baseline in 2-hour Area Under the Concentration-time Curve (AUC) of C-peptide Response to the Mixed Model Tolerance Test (MMTT)
Change from baseline in the 2-hour C-peptide Area Under the Curve (AUC) following a Mixed-Meal Tolerance Test (MMTT) at Month 6. The analysis used an adjusted ANCOVA model with the change from baseline in log(AUC + 1) as the dependent variable. Qualitative independent variables included treatment group, age group, sex, and BMI group, with the baseline value as a quantitative covariate. Missing data at Month 6 were handled via multiple imputation using a retrieved dropout approach. Missing values were imputed using a regression model based on the participant's allocated treatment arm and baseline value, utilizing data from participants who discontinued treatment but completed the Month 6 measurement. Baseline is defined as the last visit prior to randomization. Change from Baseline is defined as post-baseline visit value minus baseline visit value. The adjusted mean along with its the corresponding 95% confidence interval (CI) has been presented.
Time frame: Baseline and at Month 6
Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 12, 18, and 24
Change from baseline in the 2-hour C-peptide AUC following a MMTT at Months 6, 12, and 18. The analysis used an adjusted ANCOVA model with the change from baseline in log(AUC + 1) as the dependent variable. Qualitative independent variables included treatment group, age group, sex, and BMI group, with the baseline value as a quantitative covariate. Missing data at Months 12, 18 and 24 were handled via multiple imputation using a retrieved dropout approach. Missing values were imputed using a regression model based on the participant's allocated treatment arm and baseline value, utilizing data from participants who discontinued treatment but completed the measurement at the timepoint of interest. Intermediate timepoints were included as covariates in the model. Baseline is defined as the last visit prior to randomization. Change from Baseline is defined as post-baseline visit value minus baseline visit value.
Time frame: Baseline and at Months 12, 18, and 24
Change in Glycated Hemoglobin (HbA1c) From Baseline
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University of Alabama at Birmingham (UAB) - The Kirklin Clinic (TKC) - Multidisciplinary Comprehensive Diabetes Clinic (MCDC)
Birmingham, Alabama, United States
Phoenician Centers for Research and Innovation
Phoenix, Arizona, United States
University of California San Diego
La Jolla, California, United States
Center of Excellence in Diabetes & Endocrinology (CEDE)
Sacramento, California, United States
University of Colorado School of Medicine - Barbara Davis Center for Childhood Diabetes (BDC) - Specialty Clinic
Aurora, Colorado, United States
Christiana Care Endocrinology Specialists
Newark, Delaware, United States
Diabetes Care Center - Hudson
Hudson, Florida, United States
Global Life Research Network
Miami, Florida, United States
AdventHealth (Florida Hospital) - Diabetes Institute - Orlando
Orlando, Florida, United States
Atlanta Diabetes Associates (ADA)
Atlanta, Georgia, United States
...and 47 more locations
The change from baseline in HbA1c was analyzed using an adjusted ANCOVA model. The dependent variable is the change from baseline in HbA1c at each respective time point, with treatment, age group, sex, and BMI group as qualitative independent variables and the baseline value as a quantitative covariate. . Missing data are addressed via Multiple Imputation (MI) using a retrieved dropout approach, where values are imputed based on a regression model incorporating treatment arm, baseline value, and intermediate assessments as covariates. Baseline is defined as the last visit prior to randomization. Change from Baseline is defined as post-baseline visit value minus baseline visit value. The adjusted mean along with its the corresponding 95% confidence interval (CI) has been presented.
Time frame: Baseline and at Months 6, 12, 18 and 24
Percentage of Participants With HbA1c <7% Who Did Not Experience Severe Hypoglycemic Events During Treatment
The proportion of participants with HbA1c \< 7% was calculated by timepoint: the numerator was the number of participants with events occurring at a specific timepoint (month X visit), without cumulating participants with events up to that timepoint. Participants with severe hypoglycemic events were considered cumulatively and only events up to month 12 were considered (condition was evaluated by considering treatment period only). If HbA1c ≥ 7% or the participant had experienced a severe hypoglycemic event, then the endpoint was equal to "No" even in the case of one missing component. If either the HbA1c or severe hypoglycemic event data was missing, but the other satisfied the criteria for the endpoint, then the response to the endpoint was missing.
Time frame: At Months 6, 12, 18, and 24
Average (Previous 3 Days) Daily Insulin Requirement International Units Per Kilogram Per Day (IU/kg/Day)
The average daily insulin requirement at each visit was calculated from the daily insulin requirement measured at the 3 days prior to the visit.
Time frame: At Months 6, 12, 18, and 24
Percentage of Participants With HbA1c <7% and Daily Insulin Requirement <0.5 IU/kg/Day
Percentage of participants with HbA1c \<7% and daily insulin requirement \<0.5 (IU/Kg/day) was calculated for each time point, the numerator is the number of participants in each treatment group with events occurring at a specific timepoint, and the denominator is the number of participants in each treatment group reaching the specific visit.
Time frame: At Months 6, 12, 18, and 24
Number of Self-reported Episodes of Severe Hypoglycemia
This outcome assessed the total number of self-reported episodes of severe hypoglycemia occurring across all participants.
Time frame: Post-baseline up to Month 24
Percentage of Patients Not Requiring Insulin Therapy
This outcome assessed the percentage of participants who did not require an insulin therapy at the timepoint of interest.
Time frame: Months 6, 12, 18 and 24
Estimated Glucose Disposal Rate (eGDR)
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. The eGDR was calculated using a formula incorporating Glycated Hemoglobin (HbA1c), hypertension status (blood pressure), and the Waist-to-Hip Ratio (WHR), with results expressed in milligrams per kilogram per minute (mg/kg/min).
Time frame: Months 6, 12, 18, and 24