Recent Onset type1 Diabetes
Conditions
Keywords
type1 diabetes
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.
Interventions
DRUGLadarixin
Oral ladarixin twice a day for 13 cycles
DRUGPlacebo
Oral placebo twice a day for 13 cycles
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study proceeded under double-blind condition up to month 18 visit of the last patient randomized. Thereafter, the blind was broken and remaining follow-up will proceeded in an open fashion. This approach allowed to anticipate access to efficacy data without significantly affecting data integrity.
Intervention model description
Patients were 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 were balanced within centers.
Eligibility
Sex/Gender
ALL
Age
14 Years to 45 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Area Under the Concentration-time Curve (AUC) of C-peptide Response to the Mixed Model Tolerance Test (MMTT) | Baseline and at Month 6 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 12, 18, and 24 | Baseline and 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. |
| Change in Glycated Hemoglobin (HbA1c) From Baseline | Baseline and at Months 6, 12, 18 and 24 | 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. |
| Percentage of Participants With HbA1c <7% Who Did Not Experience Severe Hypoglycemic Events During Treatment | At Months 6, 12, 18, and 24 | 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. |
| Average (Previous 3 Days) Daily Insulin Requirement International Units Per Kilogram Per Day (IU/kg/Day) | At Months 6, 12, 18, and 24 | The average daily insulin requirement at each visit was calculated from the daily insulin requirement measured at the 3 days prior to the visit. |
| Percentage of Participants With HbA1c <7% and Daily Insulin Requirement <0.5 IU/kg/Day | At Months 6, 12, 18, and 24 | 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. |
| Number of Self-reported Episodes of Severe Hypoglycemia | Post-baseline up to Month 24 | This outcome assessed the total number of self-reported episodes of severe hypoglycemia occurring across all participants. |
| Percentage of Patients Not Requiring Insulin Therapy | Months 6, 12, 18 and 24 | This outcome assessed the percentage of participants who did not require an insulin therapy at the timepoint of interest. |
| Estimated Glucose Disposal Rate (eGDR) | Months 6, 12, 18, and 24 | 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). |
Countries
Belgium, Georgia, Germany, Israel, Italy, Serbia, Slovenia, United States
Participant flow
Recruitment details
A total of 141 participants were randomized in the study and 140 participants received treatment.
Pre-assignment details
There was a run-in period to allow the start of ladarixin dosing within 180 days from the first insulin injection, followed by randomization. Of the 141 participants randomized, one participant did not receive the study treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 26.4 years STANDARD_DEVIATION 8.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 134 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 94 | 0 / 46 | 0 / 289 |
| other Total, other adverse events | 71 / 94 | 33 / 46 | 10 / 289 |
| serious Total, serious adverse events | 1 / 94 | 1 / 46 | 0 / 289 |
Outcome results
None listed