Clinical trial NCT02814838: A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Insulin-Dependent
Keywords: Diabetes mellitus Type 1
Beta cells function
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2016-06-28
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, 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 was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.

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 showed 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, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.

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).

Primary outcomes:
measure: Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13
timeFrame: week 13±1
Secondary outcomes:
measure: Area Under the Curve (AUC) (0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Weeks 26 and 52
timeFrame: Follow-ups at Weeks 26±2 and 52±2
measure: Percent Change From Baseline of 2-hour AUC of C-peptide Response to the MMTT
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: Change From Screening in Average (Previous 3 Days) Insulin Requirement
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: Change From Screening in Glycated Haemoglobin (HbA1c) Levels
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: Basal to 180 Minutes Time Course of C-peptide Concentration Derived From the MMTT
timeFrame: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
measure: Basal to 180 Minutes Time Course of Glucose Concentration Derived From the MMTT
timeFrame: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
measure: Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: Proportion of Patients Maintaining a Residual β-cell Function
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit
timeFrame: Follow-ups at Weeks 13±1, 26±2 and 52±2
measure: C-peptide AUC(15 to 120 Mins) Above Fasting Value
timeFrame: Follow-ups at Weeks 13±1 26±2 and 52±2
measure: Area Under the Curve (AUC) (0-2 h) of C-peptide MMTT in Patients With Screening C-peptide < Median Value
timeFrame: Follow-up at Weeks 13±1, 26±2, and 52±2.
measure: Area Under the Curve (AUC) (15-120 Min) of C-peptide MMTT Above Fasting Value in Patients With Screening C-peptide < Median Value
timeFrame: Follow-up at Weeks 13±1, 26±2, and 52±2.
measure: Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit in Patients With Screening C-peptide < Median Value
timeFrame: Follow-up at Weeks 13±1, 26±2, and 52±2
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel Diabetes Clinic
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven Campus Gasthuisberg Endocrinology
city: Giessen
country: Germany
facility: Med. Klinik und Poliklinik 3, Universitätsklinikum Giessen und Marburg GmbH
city: Münster
country: Germany
facility: Zentrum für Diabetes und Gefäßerkrankungen
city: Bari
country: Italy
facility: Università Aldo Moro-Ospedale Policlinico
city: Cagliari
country: Italy
facility: Presidio Policlinico di Monserrato
city: Milan
country: Italy
facility: Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
city: Rome
country: Italy
facility: Unità Operativa Complessa di Endocrinologia e Dialettologia. Università Campus Bio-Medico di Roma
Study officials:
affiliation: Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
name: Emanuele Bosi, MD
role: PRINCIPAL_INVESTIGATOR
References: