Clinical Trial on Ladarixin Adjunctive Therapy to Improve Glycemic Control in Type 1 Diabetes.

Study Overview
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Brief Summary
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Primary objective: To determine whether oral ladarixin versus placebo adjunctive therapy improves glycemic control in overweight, insulin resistant (IR) adult subjects with type 1 diabetes (T1D). Secondary objectives: To ascertain the effect of ladarixin on glycemic variability as per CGM derived parameters. To determine the safety of oral ladarixin versus placebo adjunctive therapy in overweight, IR adult subjects with T1D. Exploratory objectives (if site is able and deems appropriate to accommodate and conduct these objectives): To determine the effects on insulin sensitivity and circulating markers of inflammation (leukocytes and inflammatory cytokines). Glycemic variability by additional CGM parameters. eGDR and BMI assessments.

Detailed Description
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This study will be a randomized, placebo-controlled, double-blinded, 2- parallel arm, phase II trial. It will enroll up to 86 patients across all genders, 21-65 years, inclusive, with established insulin-requiring T1D and IR, assigned (1:1) to receive either oral ladarixin 400 mg b.i.d. for 7 cycles (26 weeks) of 14 days on/14 days off (treatment group) or matched placebo (control group). Patients will be involved in the trial for 5 study visits, for a total of 28 weeks. Recruitment will be competitive among the study sites, until the planned number of patients is randomized.

Official Title
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Randomized, Placebo-controlled, Double-blinded, 2-parallel Arm, Clinical Trial Evaluating Ladarixin 400 mg Bid as Adjunctive Therapy to Improve Glycemic Control in Overweight Insulin-resistant Patients With Type 1 Diabetes.

Conditions
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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: clinical diagnosis of autoimmune T1D as documented by positive T1D-related autoantibodies [the presence of at least one or more of Insulin autoantibodies (IAA), Anti-GAD (GAD65), Anti-IA2 (IA2), Zinc Transporter 8 (ZnT8)]; age 21-65 years, inclusive, at the time of consent; T1D duration > 1 year; detectable fasting C-peptide as per the result of screening laboratory measurement; current insulin standard of care (ISOC), either established use of an insulin pump (closed loop system excluded) or a stable dose level and dose frequency for the last two months prior to screening, with no plans to switch the modality of insulin administration during the trial; routine use of a self-owned (if applicable) Continuous Glucose Monitoring (CGM) system that can record glucose concentrations continuously for at least 7 days; HbA1c value >7.5% as per the result of screening laboratory measurement; evidence of IR based on a total daily insulin dose >0.8 U/kg/day; subject is overweight or obese as per body mass index (BMI) of between 24-33 kg/m2, inclusive; ability to comply with all protocol procedures for the duration of the study, including scheduled follow-up visits and examinations, and willing to be contacted by clinical trial staff; provision of signed informed consent prior of any study-related procedure not part of standard medical care. Exclusion Criteria: use of a closed loop system for integrated glucose reading/insulin infusion; known or suspected hypersensitivity to the active pharmaceutical ingredient, non-steroidal anti-inflammatory drugs or any excipient of the investigational medicinal products (e.g. lactose and croscarmellose) as well as patients with congenital lactase deficiency, galactosaemia or glucose-galactose intolerance will have to be excluded; use of non-insulin medications for adjunctive blood glucose control (e.g: antidiabetic agents such as metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, SGLT-2 inhibitors or amylin) within one month of randomization as well as required in the participant's standard of care; use of medications for weight reduction such as: Belviq (lorcaserin), Qsymia (Phentermine + topiramate), Orlistat (xenical) within one month of randomization as well as required in the participant's standard of care; use of a medication such as stimulants, antidepressants and/or psychotropic agents that could affect weight gain or glycemic control of T1D; treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index [i.e., phenytoin, warfarin, and high dose of amitriptyline (>50 mg/day)]; use of angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin; evidence of QTcF >470 msec and a history of significant cardiovascular disease/abnormality; any condition, including unstable diet and disordered eating behaviour, that in the judgment of the investigator will adversely affect patient's safety or the completion of the protocol or otherwise confound study outcome; pregnancy (subjects of child-bearing potential) based on serum test (quantitative beta hCG) at screening; unwillingness to use effective contraceptive measures up to 2 months following trial discharge (all participants); clinical diagnosis of celiac disease that is in poor control as defined by most recent tissue transglutaminase (tTG) that is in the abnormal range; history of ≥1 Diabetic Ketoacidosis (DKA) events in the past 6 months; hypoalbuminemia (serum albumin <3 g/dL); 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]; moderate to severe renal impairment calculated by estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 as determined using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; past (within 1 month prior to screening) or current administration of any immunosuppressive medications (including oral or systemically injected steroids) and use of any investigational agents, including any agents that impact the immune response; a condition already known which interferes with the ability to accurately determine glycated HbA1c; significant systemic infection during the 4 weeks before the 1st dose of study drug (e.g., infection requiring hospitalization, major surgery, or i.v. 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).

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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 across all genders, 21-65 years, inclusive, with established insulin-requiring T1D and IR, will be assigned (1:1) to receive either oral ladarixin 400 mg b.i.d. for 7 cycles (26 weeks) of 14 days on/14 days off (treatment group) or matched placebo (control group) for a total of 28 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ladarixin<br>Ladarixin will be administered orally at the dose of 400 mg b.i.d. for 7 cycles of 14 days with an interval of 14 days off, for a total duration of 26 weeks. | Drug: Ladarixin<br>* The two daily oral doses of ladarixin (400 mg each dose) will be administered at about a 12-hour interval (morning and evening; ideally between 6:30/11:30 and 18:30/23:30). At each administration, 2 capsules will be swallowed with a glass of water, at least 2 hours apart from breakfast or dinner<br>* Other names: LDX;|
| Placebo Comparator: Placebo<br>Matching placebo will be administered with the same treatment schedule of the IMP. | Other: Placebo<br>* Placebo will be administered with the same ladarixin schedule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of responders at week 27/28 (visit 4), with responders defined as patients with an HbA1c reduction from baseline of ≥0.50% (absolute difference) without episodes of severe hypoglycemia |  | at week 27/28 (visit 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of responders at week 11/12 (visit 3) |  | at week 11/12 (visit 3) | 
| The mean difference from baseline in HbA1c [Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)] |  | week 11/12 (visit 3) and 27/28 (visit 4)] | 
| Average (previous 3 days) daily insulin requirements (IU/kg/day) assessed at week 11/12 (visit 3) and 27/28 (visit 4) |  | at week 11/12 (visit 3) and 27/28 (visit 4) | 
| Glycemic Variability by CGM (previous 7 days): time in range (TIR), time above range (TAR) time below range (TBR), standard deviation and coefficient of variation assessed at week 11/12 (visit 3) and 27/28 (visit 4) |  | at week 11/12 (visit 3) and 27/28 (visit 4) | 
| Incidence of Treatment Emergent Adverse Events (TEAEs) recorded from the beginning of study treatment to up to the end of study participation |  | Throughout the study, up to week 26 (day 182) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glycemic control, insulin-resistant type 1 diabetes.