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

Study Overview
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Brief Summary
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The objectives of this clinical trial are: to evaluate whether a 12 month treatment with ladarixin is effective to improve glycemic control in newly diagnosed T1D adult patients with preserved beta-cell function. to evaluate the safety of ladarixin in the specific clinical setting

Detailed Description
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The study is a phase 2, multicenter, double-blind, placebo-controlled study. It will randomize approximately 75 adult patients with new-onset type 1 diabetes (T1D) and preserved beta-cell function (fasting C-peptide >0.205 nmol/l) at baseline. Patients will be 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 18 months from the 1st administration of the study medication. The study database will be locked and data analyzed when the last patient randomized has completed month 12 follow-up visit. After this time point, the follow-up will continue under open-label conditions up to month 18,

Official Title
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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.

Conditions
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New-onset Type 1 Diabetes

Intervention / Treatment
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* Drug: Ladarixin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 18-45 years, inclusive; New-onset T1D (1st IMP dose within 100 days from 1st insulin administration); 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); Require, or has required at some time, insulin therapy through multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII); Fasting C peptide ≥0.205nmol/L on two occasions; Patient able to comply with all protocol procedures for the duration of the study, including scheduled follow-up visits and examinations; Patients who have given written informed consent prior of any study-related procedure not part of standard medical care. Exclusion Criteria: 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; 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); 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]; Hypoalbuminemia defined as serum albumin < 3 g/dL; QTcF > 470 msec; A history of significant cardiovascular disease/abnormality Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks; Known hypersensitivity to non-steroidal anti-inflammatory drugs; 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)]; 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.); 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; 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); 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 ant hepatitis A virus (immunoglobulin M), hepatitis B surface antigen, or ant hepatitis C virus and HIV; 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ladarixin<br>The treatment group will receive 400 mg b.i.d. for 13 cycles of 14 days on/14 days off) | Drug: Ladarixin<br>* 400 mg b.i.d. for 13 cycles of 14 days on/14 days off<br>* Other names: LDX;|
| Placebo Comparator: Placebo<br>The control group will receive matched placebo | Other: Placebo<br>* Placebo will be administered orally with the same scheme of administration of LDX to preserve blinding<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HbA1c <7% and daily insulin requirement <0.50 IU/Kg/day | 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. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HbA1c < 7% and daily insulin requirement <0.50 IU/Kg/day | 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. | Months 6 and 18 | 
| Proportion of patients with a reduction in HbA1c% > 0.5% from baseline and daily insulin requirement <0.50 IU/Kg | Proportion of patients with a reduction in HbA1c% > 0.5% from baseline and daily insulin requirement <0.50 IU/Kg/day was calculated | Months 6, 12 and 18 | 
| 2-hour AUC of C-peptide response to the MMTT | C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2. Prior to the test, patients withheld long-acting insulin on the morning of the test. Rapid-acting and short-acting insulin were allowed up to 6hrs and 2 hrs, respectively, before the test. The test was rescheduled if the patient had a capillary glucose value of >200mg/dL or <70mg/dL. After 2 pre-meal basal samples had been drawn between -20 to 0 min (basal 1 and basal 2), patients were given 6mL/kg of a high protein nutritional drink up to a maximum of 360mL, to be drunk within 5 min. Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at Months 6, 12 and 18. | Months 6, 12 and 18 | 
| Time in range (TIR) by Continuous Glucose Monitoring (CGM) | Continuous glucose monitors (CGM) continually monitors glucose plasma levels through an external device that's attached to the body, and gives real-time updates.Time in range is the amount of time the patient spends in the target blood sugar (blood glucose) range-between 70 and 180 mg/dL for most people. The time in range method works with the individual CGM's data by looking at the amount of time blood sugar has been in target range and the times it has been high (hyperglycemia) or low (hypoglycemia). This data is helpful in finding out which types of foods and what activity level causes patient's blood sugar to rise and fall. | Months 6, 12 and 18 | 
| HbA1c levels | 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. | Months 6, 12 and 18 | 
| Proportion of patients with HbA1c < 7% who did not experience severe hypoglycemic events during treatment | 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, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: PPG | PPG=2-hour postprandial glucose. All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System | Months 6, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: MAGE | MAGE=Mean Amplitude Glycemic Excursions. All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System. | Months 6, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: CONGA-n | CONGA-n=continuous overall net glycemic action. All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System. | Months 6, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: MODD | MODD=Mean Of the Daily Differences. All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System. | Months 6, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: mean daily blood glucose | All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System. | Months 6, 12 and 18 | 
| Additional Glucose Variability Indices derived from CGM: Standard Deviation (SD) | All these glycemic variability indices refer to the intra-day or inter-day values and differences derived from the glucose values (these latter expressed in mg/dL) collected index by index using continuous glucose monitoring (CGM) System. | Months 6, 12 and 18 | 
| 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. | Months 6, 12 and 18 | 
| Average (previous 3 days) daily insulin requirements (IU/kg/day) | 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, 12 and 18 | 
| 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. | Months 6, 12 and 18 | 
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes