Diabetes Mellitus, Insulin-DependentPhase 2NCT02814838
A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
A Phase 2 study testing Ladarixin in people with Diabetes Mellitus, Insulin-Dependent, run by Dompé Farmaceutici S.p.A at 8 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Diabetes Mellitus, Insulin-Dependent
- What is being tested?
- Ladarixin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 76 participants
- Where
- 8 sitesin 3 countries
- Study dates
- Aug 2016to 15 May 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Male and female patients aged 18-45 years, inclusive;
- New-onset T1D (randomization within 100 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, with the exclusion of patients taking twice daily pre-mixed insulin or on insulin pump;
- 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;
- 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.
Who cannot join
- Patients taking twice daily pre-mixed insulin or on insulin pump;
- 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;
- Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976);
- 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;
Show all 14Show fewer
- Complete Left Bundle Branch Block (LBBB), atrio-ventricular block (mobitz II 2nd degree or 2:1 atrio-ventricular block), complete heart block;
- Electronic pacemaker positioned or implanted defibrillator;
- History of significant cardiovascular disease;
- Known hypersensitivity to non-steroidal antiinflammatory drugs;
- Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day);
- 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.);
- 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;
- 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).
Trial locations and contacts
8 sites in 3 countries.
8 sites in 3 countries
Italy4 sites
Università Aldo Moro-Ospedale Policlinico
Bari, 70124
Presidio Policlinico di Monserrato
Cagliari, 88554
Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
Milan, 20132
Unità Operativa Complessa di Endocrinologia e Dialettologia. Università Campus Bio-Medico di Roma
Rome, 00128
Belgium2 sites
Universitair Ziekenhuis Brussel Diabetes Clinic
Brussels, 1090
Universitair Ziekenhuis Leuven Campus Gasthuisberg Endocrinology
Leuven, 3000
Germany2 sites
Med. Klinik und Poliklinik 3, Universitätsklinikum Giessen und Marburg GmbH
Giessen, 32392
Zentrum für Diabetes und Gefäßerkrankungen
Münster, 48145
About this study
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
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.
Read the 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.
- Conditions
- Diabetes Mellitus, Insulin-Dependent
- Being tested
- Ladarixin, Placebo
- Keywords
- Diabetes mellitus Type 1, Beta cells function
- Medical subject headings
- Diabetes Mellitus, Type 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LadarixinDrug
Also called Active treatment
Ladarixin oral capsule
PlaceboDrug
Also called Placebo treatment
Placebo oral capsule
| Study group | Role | What they receive |
|---|---|---|
| Ladarixin | Experimental | Ladarixin oral capsule Receives: Drug: Ladarixin |
| Placebo | Placebo comparator | Placebo oral capsule Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13
C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2.
Prior to the test, patients withheld long-acting insulin on the morning of the test. Rapid-acting and short-acting insulin were allowed up to 6hrs and 2 hrs, respectively, before the test. The test was rescheduled if the patient had a capillary glucose value of >200mg/dL or <70mg/dL.
After 2 pre-meal basal samples had been drawn between -20 to 0 min (basal 1 and basal 2), patients were given 6mL/kg of Boost® High Protein Nutritional Drink up to a maximum of 360mL, to be drunk within 5 min. Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at week 13+/-1 The 2-hour C-peptide AUC after the MMTT at Week 13±1 was transformed as log(x+1) values.
Measured: week 13±1
Secondary outcomes (13)
Area Under the Curve (AUC) (0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Weeks 26 and 52
C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2.
Prior to the test, patients withheld long-acting insulin on the morning of the test. Rapid-acting and short-acting insulin were allowed up to 6hrs and 2 hrs, respectively, before the test. The test was rescheduled if the patient had a capillary glucose value of >200mg/dL or <70mg/dL. After 2 pre-meal basal samples had been drawn between -20 to 0 min (basal 1 and basal 2), patients were given 6mL/kg of Boost® High Protein Nutritional Drink up to a maximum of 360mL, to be drunk within 5 min. Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at week 13+/-1.
The 2-hour C-peptide AUC after the MMTT at Week 13±1 was transformed as log(x+1) values.
Measured: Follow-ups at Weeks 26±2 and 52±2
Percent Change From Baseline of 2-hour AUC of C-peptide Response to the MMTT
C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2.
Prior to the test, patients withheld long-acting insulin on the morning of the test. Rapid-acting and short-acting insulin were allowed up to 6hrs and 2 hrs, respectively, before the test. The test was rescheduled if the patient had a capillary glucose value of >200mg/dL or <70mg/dL.
The test was initiated before 10 a.m. After 2 pre-meal basal samples had been drawn between -20 to 0 min (basal 1 and basal 2), patients were given 6mL/kg of Boost® High Protein Nutritional Drink (Nestlé Nutrition) up to a maximum of 360mL, to be drunk within 5 min. Post-meal samples were drawn at 15±5, 30±5, 60±10, 90±10, 120±15, 180±15 min after the meal.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
Change From Screening in Average (Previous 3 Days) Insulin Requirement
Insulin requirement (IU/kg/day averaged over the previous 3 days) was to be recorded in the interval from randomization to Week 13±1, Week 13±1 to Week 26±2, and Week 26±2 to Week 52±2.
From enrolment, 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 Telephone calls (outside scheduled visits) were scheduled on a regular basis to ensure optimization of metabolic control.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
Change From Screening in Glycated Haemoglobin (HbA1c) Levels
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.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
Basal to 180 Minutes Time Course of C-peptide Concentration Derived From the MMTT
Time points at each visit are Basal 1 and Basal 2 (samples collected at -20 and 0 min, respectively; Here are reported the following timepoints: Basal average (which is the average of Basal 1 and Basal 2), 15, 30, 60, 90, 120, and 180 minutes after the meal. For values at each time point see below.
Measured: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
Basal to 180 Minutes Time Course of Glucose Concentration Derived From the MMTT
Time points at each visit are Basal 1 and Basal 2 (samples collected at -20 and 0 min, respectively). Here are reported the following timepoints: Basal average (which is the average of Basal 1 and Basal 2), 15, 30, 60, 90, 120, and 180 minutes after the meal. For values at each time point see below.
Measured: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit
A severe hypoglycaemic event was defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behaviour, irrational behaviour, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the patient was unable to treat him/herself and which was associated with either a blood glucose level <54 mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
Proportion of Patients Maintaining a Residual β-cell Function
Maintenance of a residual ß-cell function is defined as at least one MMTT C-peptide value > 0.2 nmol/L.
Proportion is reported as Percentage of patients.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit
A severe hypoglycaemic event was defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the patient was unable to treat him/herself and which was associated with either a blood glucose level <54 mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Proportion is reported as percentage of patients. Events per patient are calculated from the date of randomisation.
Measured: Follow-ups at Weeks 13±1, 26±2 and 52±2
C-peptide AUC(15 to 120 Mins) Above Fasting Value
The means are all "adjusted means". The MMTT over the study: logAUC(15-120 min) of C-peptide above fasting value at Weeks 13±1, 26±2, and 52±2 is reported.
Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at weeks 13+/-1, 26±2 and 52±2
Measured: Follow-ups at Weeks 13±1 26±2 and 52±2
Area Under the Curve (AUC) (0-2 h) of C-peptide MMTT in Patients With Screening C-peptide < Median Value
A subgroup analysis of efficacy endpoints by fasting C-peptide at Screening was performed. The reported data specifically refers to fasting C-peptide at Screening <median value. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead. Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal.
The 2-hour C-peptide AUC after the MMTT was transformed as log(x+1) values.
Measured: Follow-up at Weeks 13±1, 26±2, and 52±2.
Area Under the Curve (AUC) (15-120 Min) of C-peptide MMTT Above Fasting Value in Patients With Screening C-peptide < Median Value
A subgroup analysis of efficacy endpoints by fasting C-peptide at Screening was performed. The reported data specifically refers to fasting C-peptide at Screening <median value. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at Weeks 13±1, 26±2, and 52±2.
Measured: Follow-up at Weeks 13±1, 26±2, and 52±2.
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
A severe hypoglycaemic event was defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the patient was unable to treat him/herself and which was associated with either a blood glucose level <54 mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Proportion is reported as percentage of patients, despite the measure type indicated is "number".
Events per patient are calculated from the date of randomisation.
Measured: Follow-up at Weeks 13±1, 26±2, and 52±2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jun 2016 (estimated)
- Study startAug 2016
- Primary completion15 May 2019
- Study completion15 May 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Insulin-DependentStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 76 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dompé Farmaceutici S.p.A
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Emanuele Bosi, MD, Principal investigator, Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02814838
- Sponsor's protocol ID
- MEX0114
- Other IDs
- 2014-003968-20, 2014
- Status last verified
- Dec 2023
- First submitted
- 13 Jun 2016
- Last updated
- 19 Apr 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Sordi V, Monti P, Lampasona V, Melzi R, Pellegrini S, Keymeulen B, Gillard P, Linn T, Bosi E, Rose L, Pozzilli P, Giorgino F, Cossu E, Piemonti L. Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders. Front Endocrinol (Lausanne). 2023 Jun 20;14:1175640. doi: 10.3389/fendo.2023.1175640. eCollection 2023.
PubMed 37409229
Study at a glance
From the registry record, last updated by the sponsor on 19 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02814838
- Acronym / sponsor ID
- MEX0114
- Conditions
- Diabetes Mellitus, Insulin-Dependent
- Keywords
- Diabetes mellitus Type 1, Beta cells function
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 76 participants (actual)
- Lead sponsor
- Dompé Farmaceutici S.p.AIndustry (pharma, biotech, devices)
- Study start
- Aug 2016 (actual)
- Primary completion
- 15 May 2019 (actual)
- Study completion
- 15 May 2019 (actual)
- First posted
- 28 Jun 2016 (estimated)
- Results
- Posted 12 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ladarixin | Experimental | Drug: LadarixinLadarixin oral capsule |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo oral capsule |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Male and female patients aged 18-45 years, inclusive;
- New-onset T1D (randomization within 100 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, with the exclusion of patients taking twice daily pre-mixed insulin or on insulin pump;
- 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;
Key exclusion criteria (14 listed)
- Patients taking twice daily pre-mixed insulin or on insulin pump;
- 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;
- Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976);
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LadarixinAlso: Active treatmentLadarixin oral capsule | Drug | Ladarixin |
| PlaceboAlso: Placebo treatmentPlacebo oral capsule | Drug | Placebo |
Primary outcome
Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13
Time frame: week 13±1
C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2. Prior to the test, patients withheld long-acting insulin on the morning of the test. Rapid-acting and short-acting insulin were allowed up to 6hrs and 2 hrs, respectively, before the test. The test was rescheduled if the patient had a capillary glucose value of >200mg/dL or <70mg/dL. After 2 pre-meal basal samples had been drawn between -20 to 0 min (basal 1 and basal 2), patients were given 6mL/kg of Boost® High Protein Nutritional Drink up to a maximum of 360mL, to be drunk within 5 min. Post-meal samples were drawn at 15, 30, 60, 90, 120 min after the meal at week 13+/-1 The 2-hour C-peptide AUC after the MMTT at Week 13±1 was transformed as log(x+1) values.
13 secondary outcomes
Area Under the Curve (AUC) (0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Weeks 26 and 52
Time frame: Follow-ups at Weeks 26±2 and 52±2
Percent Change From Baseline of 2-hour AUC of C-peptide Response to the MMTT
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
Change From Screening in Average (Previous 3 Days) Insulin Requirement
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
Change From Screening in Glycated Haemoglobin (HbA1c) Levels
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
Basal to 180 Minutes Time Course of C-peptide Concentration Derived From the MMTT
Time frame: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
Basal to 180 Minutes Time Course of Glucose Concentration Derived From the MMTT
Time frame: Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2
Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
Proportion of Patients Maintaining a Residual β-cell Function
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit
Time frame: Follow-ups at Weeks 13±1, 26±2 and 52±2
C-peptide AUC(15 to 120 Mins) Above Fasting Value
Time frame: Follow-ups at Weeks 13±1 26±2 and 52±2
Area Under the Curve (AUC) (0-2 h) of C-peptide MMTT in Patients With Screening C-peptide < Median Value
Time frame: Follow-up at Weeks 13±1, 26±2, and 52±2.
Area Under the Curve (AUC) (15-120 Min) of C-peptide MMTT Above Fasting Value in Patients With Screening C-peptide < Median Value
Time frame: Follow-up at Weeks 13±1, 26±2, and 52±2.
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
Time frame: Follow-up at Weeks 13±1, 26±2, and 52±2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Apr 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37409229Sordi V, Monti P, Lampasona V, Melzi R, Pellegrini S, Keymeulen B, Gillard P, Linn T, Bosi E, Rose L, Pozzilli P, Giorgino F, Cossu E, Piemonti L. Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders. Front Endocrinol (Lausanne). 2023 Jun 20;14:1175640. doi: 10.3389/fendo.2023.1175640. eCollection 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Emanuele Bosi, MD principal investigator
Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
8 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ladarixin in people with Diabetes Mellitus, Insulin-Dependent, run by Dompé Farmaceutici S.p.A at 8 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Italy, Belgium, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13 (time frame: week 13±1). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02814838, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Apr 2024.