A Phase 2, Multicentre, 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

A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

Sponsors

Lead sponsor: Dompé Farmaceutici S.p.A

Source Dompé Farmaceutici S.p.A
Brief Summary

The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.

The study will be a phase 2, multicentre, double-blind study. It will involve 72 patients with new-onset type 1 diabetes (T1D), randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 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 enrolled.

Detailed Description

T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.

T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.

Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.

Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.

As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.

Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly shows the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provide a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supports the conduct of the present study.

Overall Status Completed
Start Date August 2016
Completion Date October 20, 2019
Primary Completion Date May 15, 2019
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
AUC of C-peptide week 13±1
Secondary Outcome
Measure Time Frame
AUC of C-peptide Baseline
AUC of C-peptide week 26±2
AUC of C-peptide week 52±2
Insulin requirement baseline
Insulin requirement week 13±1
Insulin requirement week 26±2
Insulin requirement week 52±2
HbA1c baseline
HbA1c week 13±1
HbA1c week 26±2
HbA1c week 52±2
Cumulative severe hypoglycaemic events week 13±1
Cumulative severe hypoglycaemic events week 26±2
Cumulative severe hypoglycaemic events week 52±2
Adverse Events week 52±2
Serious Adverse Events week 52±2
Vital signs week 4
Vital signs week 13
Enrollment 76
Condition
Intervention

Intervention type: Drug

Intervention name: Ladarixin

Description: Ladarixin oral capsule

Arm group label: Ladarixin

Other name: Active treatment

Intervention type: Drug

Intervention name: Placebo

Description: Placebo oral capsule

Arm group label: Placebo

Other name: Placebo treatment

Eligibility

Criteria:

Inclusion Criteria:

1. Male and female patients aged 18-45 years, inclusive;

2. New-onset T1D (randomization within 100 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, with the exclusion of patients taking twice daily pre-mixed insulin or on insulin pump;

5. Residual β-cell function as per peak stimulated (MMTT) C-peptide level >0.6ng/mL (0.2nmol/L); MMTT should not be performed within one week of resolution of a diabetic ketoacidosis event;

6. Patient able to comply with all protocol procedures for the duration of the study, including scheduled follow-up visits and examinations;

7. Patients who have given written informed consent prior of any study-related procedure not part of standard medical care.

Exclusion Criteria:

1. Patients taking twice daily pre-mixed insulin or on insulin pump;

2. 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;

3. Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976);

4. 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];

5. Hypoalbuminemia defined as serum albumin < 3 g/dL;

6. QTcF > 470 msec;

7. Complete Left Bundle Branch Block (LBBB), atrio-ventricular block (mobitz II 2nd degree or 2:1 atrio-ventricular block), complete heart block;

8. Electronic pacemaker positioned or implanted defibrillator;

9. History of significant cardiovascular disease;

10. Known hypersensitivity to non-steroidal antiinflammatory drugs;

11. Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day);

12. Previous (within 2 weeks prior to randomization) and concomitant treatment with metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. β-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.);

13. 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;

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 an 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).

Gender: All

Minimum age: 18 Years

Maximum age: 45 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Emanuele Bosi, MD Principal Investigator Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
Location
facility
Universitair Ziekenhuis Brussel Diabetes Clinic | Brussels, 1090, Belgium
Universitair Ziekenhuis Leuven Campus Gasthuisberg Endocrinology | Leuven, 3000, Belgium
Med. Klinik und Poliklinik 3, Universitätsklinikum Giessen und Marburg GmbH | Giessen, 32392, Germany
Zentrum für Diabetes und Gefäßerkrankungen | Münster, 48145, Germany
Università Aldo Moro-Ospedale Policlinico | Bari, 70124, Italy
Presidio Policlinico di Monserrato | Cagliari, 88554, Italy
Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan | Milan, 20132, Italy
Unità Operativa Complessa di Endocrinologia e Dialettologia. Università Campus Bio-Medico di Roma | Rome, 00128, Italy
Location Countries

Belgium

Germany

Italy

Verification Date

November 2019

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Ladarixin

Arm group type: Experimental

Description: Ladarixin oral capsule

Arm group label: Placebo

Arm group type: Placebo Comparator

Description: Placebo oral capsule

Patient Data Undecided
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov