Ladarixin as Adjunctive Therapy to Improve Insulin Sensitivity and Glucometabolic Outcomes in Type 1 Diabetes

NCT05035368 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: LDX0121
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Objectives Primary study objective: To determine whether orally-administered ladarixin versus placebo adjunctive therapy improves insulin sensitivity in overweight, insulin-resistant (IR) type 1 Diabetic (T1D) adult subjects. Secondary study objectives: To determine whether orally-administered ladarixin versus placebo adjunctive therapy is safe and well-tolerated in overweight, IR T1D adult subjects.

Conditions

Type I Diabetes

Keywords

Type I diabetes; Insulin-resistance; Overweight

Outcome Measures

Primary Outcomes (1)

• The mean difference in glucose infusion rate (GIR) from baseline

  The glucose infusion rate (GIR) is a measure of the rate at which the patient receives intravenous administration of dextrose, which increases blood sugar levels. GIR is expressed in mg per kilogram body weight per minute (mg/Kg/min).

  Week 25 of each treatment period (visits 4 and 8)

Secondary Outcomes (2)

• Change from baseline of HbA1c levels

  Week 25/26 (no later than 10 days after the last IMP dose) of each treatment period (visits 5 and 9)

• Change in average (previous 3 days) daily insulin requirements

  Week 25/26 (no later than 10 days after the last IMP dose) of each treatment period (visits 5 and 9)

Study Arms (2)

Ladarixin - placebo

EXPERIMENTAL

In this arm the treatment sequence is ladarixin 400 mg twice-a-day, followed by placebo, as adjunctive therapy to insulin in overweight, IR, T1D patients. IMP will be administered for 24 weeks in each treatment period with a 21-day washout between the two periods. (Ladarixin 24 weeks, washout 21 days, Placebo 24 weeks).

Drug: Ladarixin; Other: Placebo

Placebo - Ladarixin

EXPERIMENTAL

In this arm the treatment sequence is placebo followed by ladarixin 400 mg twice-a-day, as adjunctive therapy to insulin in overweight, IR, T1D patients. IMP will be administered for 24 weeks in each treatment period with a 21-day washout between the two periods. (Placebo 24 weeks, washout 21 days, Ladarixin 24 weeks).

Drug: Ladarixin; Other: Placebo

Interventions

Ladarixin DRUG

Ladarixin will be administered orally at the dose of 400 mg twice a day at about 12-hour interval (morning and evening).

Also known as: LDX

Ladarixin - placebo; Placebo - Ladarixin

Placebo OTHER

Placebo is administered with the same schedule of Ladarixin.

Ladarixin - placebo; Placebo - Ladarixin

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• clinical diagnosis of autoimmune T1D as documented by positive T1D diabetes-related autoantibodies \[the presence at diagnosis of at least one or more of - Insulin autoantibodies (IAA), Anti-GAD (GAD65), Anti-IA2 (IA2), Zinc Transporter 8 (ZnT8) must be documented from medical records or new laboratory measurement (not including IAA)\];
• age 21-65 years at the time of consent;
• T1D duration =\>5 years;
• current insulin standard of care (ISOC), either use of an insulin pump or a stable dose level and dose frequency (i.e. established dose range that does not fluctuate beyond 1SD of the median over a period of the last two months prior to enrollment), multiple daily injections of insulin (at least 3 injections per day) for the last two months prior to enrollment, with no plans to switch the modality of insulin administration during the 4 months following screening (e.g., injection user switching to a pump, pump user switching to injections);
• HbA1c between 7.5%-10.0%, inclusive, as per results of screening laboratory measurement;
• evidence of IR based on a total daily insulin dose \>0.8 U/kg/ day and/or a screening estimated glucose disposal rate (eGDR) \< 9 mg/kg/min 1-3 value strongly indicative of IR, sex- and ageadjusted;
• subject is overweight or obese with a BMI of between 25-40 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 written informed consent prior of any study-related procedure not part of standard medical care.

You may not qualify if:

• patients with known or suspected hypersensitivity to 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);
• use of medications for weight reduction (such as: Belviq (lorcaserin), Qsymia (Phentermine + topiramate), Orlistat (xenical));
• use of a medication such as stimulants, antidepressants and/or psychotropic agents that could affect weight gain or glycemic control of T1D;
• subject is on treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index \[i.e., phenytoin, warfarin, and high dose of amitriptyline (\>50 mg/day)\];
• any medications known to influence glucose tolerance (e.g. beta-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.);
• evidence of cardiac QTcF \> 470 msec and/or any history of significant cardiovascular disease/abnormality;
• any condition, including unstable dietary approach and disordered eating behaviour patterns, 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 (females) based on serum test (quantitative beta hCG) at screening; unwillingness to use effective contraceptive measures up to 2 months following trial discharge (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).
• 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;
• history of ≥1 severe hypoglycemic events (cognitive impairment that required assistance to treat) in the past 6 months;
• hypoalbuminemia defined as 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 (CKDEPI) creatinine equation;

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (1)

Institute of Cellular Therapeutics Allegheny Health Network

Pittsburgh, Pennsylvania, 15212, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Insulin Resistance; Overweight

Interventions

2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Nick Giannoukakis, PhD

  Allegheny General Hospital and West-Penn Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The identity of the treatment will remain unknown to the patient, Investigator, site staff, CRO and Dompé's Development personnel until the study is unmasked.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study is a randomized, placebo-controlled, double-blinded, 2-arm, 2-period crossover phase II trial using the CXCR1/CXCR2 chemokine receptor antagonist ladarixin versus placebo as adjunctive therapy to insulin to improve insulin sensitivity as well as glucometabolic outcomes in adult, insulin-requiring, overweight, IR T1D patients. This trial will randomize 38 male and female patients 21-65 years of age, inclusive, with established insulin requiring T1D and IR. After a 2:1 randomization into a treatment sequence (either ladarixin followed by placebo, or placebo followed by ladarixin, respectively), patients will be followed up for a maximum of 53 weeks.

Study Record Dates

• First Submitted: August 30, 2021
• First Posted: September 5, 2021
• Study Start: September 30, 2021
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: December 22, 2023

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)