A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function

Study Overview
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Brief Summary
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The objective of this clinical trial is to assess whether ladarixin treatment is effective in preserving beta-cell function and delaying the progression of type 1 diabetes (T1D) in adolescent and adult patients. The safety of ladarixin in the specific clinical setting will be also evaluated.

Detailed Description
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This is a phase 3, multicenter, double-blind, placebo-controlled study. It has been designed to further evaluate whether ladarixin is effective in preserving beta-cell function and slowing-down the progression of T1D) in patients with a more severe disease presentation. The study is planned to be performed at about 40 study centers in EU, US and in other countries, if appropriated. At each study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations. The study is planned to involve -327 patients with new-onset T1D, to include about 200 adolescents (14-17 years). 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.

Official Title
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Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess Efficacy - Safety of 400 mg Twice a Day Oral Ladarixin in Pts With Recent Onset Type 1 Diabetes and Low Residual β-cell Function at Baseline (GLADIATOR STUDY)

Conditions
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New-onset type1 Diabetes

Intervention / Treatment
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* Drug: Ladarixin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 14-45 years, inclusive; Recent onset T1D (1st IMP dose within 180 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 one or more separate subcutaneous injections or Continuous Subcutaneous Insulin Infusion (CSII). Fasting C peptide < 0.205nmol/L; 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; 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 (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: A type 2 diabetes diagnosis or any other unstable chronic disease for which dose adjustment of specific medication is anticipated during the trial; 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 (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; Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks; A history of significant cardiovascular disease/abnormality; 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 amitriptyline (> 50 mg/day)]; 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.); 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; 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); History of positive status for hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C 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); abstinence.

Ages Eligible for Study
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Minimum Age: 14 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
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ladarixin<br>400 mg b.i.d. for 13 cycles of 14 days on/14 days off | Drug: Ladarixin<br>* Oral ladarixin twice a day for 13 cycles<br>* Other names: allosteric inhibitor of CXCL8 (IL-8), CXCR1 and CXCR2 receptors;|
| Placebo Comparator: Placebo<br>matching placebo b.i.d. for 13 cycles of 14 days on/14 days off | Drug: Placebo<br>* Oral placebo twice a day for 13 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 2-hour AUC of C-peptide response to the Mixed Model Tolerance Test (MMTT) | C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline | Month 12 | 
| Change from baseline in HbA1c | 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. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 2-hour AUC of C-peptide response to the MMTT | C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline | Months 6, 18 and 24 | 
| Change in HbA1c from baseline | 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, 18 and 24 | 
| 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, 18, 24 | 
| Proportion of patients with HbA1c <7% who did not experience severe hypoglycemic events during treatment | For the purpose of this study, a severe hypoglycemic 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 or prompt recovery after oral carbohydrate, i.e. glucose, or glucagon administration. | Months 6, 12, 18, 24 | 
| Average (previous 3 days) daily insulin requirement (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, 18 and 24. 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, 18, 24 | 
| Proportion of patients with HbA1c <7% and daily insulin requirement <0.5 (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 24 months to evaluate the potential persistency of any glycemic benefit. | Months 6, 12, 18, 24 | 
| Number of self-reported episodes of severe hypoglycemia | For the purpose of this study, a severe hypoglycemic 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 or prompt recovery after oral carbohydrate, i.e. glucose, or glucagon administration. | Months 6, 12, 18, 24 | 
| Percentage of patients not requiring insulin therapy | This outcome aims to assess the % of patients who do not require an insulin therapy | Months 6, 12, 18, 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. | Months 6, 12, 18, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type1 diabetes