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Trial record 1 of 3 for:    MEX0114
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A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02814838
Recruitment Status : Completed
First Posted : June 28, 2016
Results First Posted : January 12, 2021
Last Update Posted : January 12, 2021
Sponsor:
Information provided by (Responsible Party):
Dompé Farmaceutici S.p.A

Tracking Information
First Submitted Date  ICMJE June 13, 2016
First Posted Date  ICMJE June 28, 2016
Results First Submitted Date  ICMJE November 16, 2020
Results First Posted Date  ICMJE January 12, 2021
Last Update Posted Date January 12, 2021
Actual Study Start Date  ICMJE August 2016
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 8, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2016)
AUC of C-peptide [ Time Frame: week 13±1 ]
2-hour AUC of C-peptide response to the MMTT
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2021)
  • 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 ]
    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.
  • 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 ]
    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.
  • Change From Screening in Average (Previous 3 Days) Insulin Requirement [ Time Frame: Follow-ups at Weeks 13±1, 26±2 and 52±2 ]
    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.
  • Change From Screening in Glycated Haemoglobin (HbA1c) Levels [ Time Frame: Follow-ups at Weeks 13±1, 26±2 and 52±2 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit [ Time Frame: Follow-ups at Weeks 13±1, 26±2 and 52±2 ]
    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 of Patients Maintaining a Residual β-cell Function [ Time Frame: Follow-ups at Weeks 13±1, 26±2 and 52±2 ]
    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.
  • 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 ]
    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.
  • C-peptide AUC(15 to 120 Mins) Above Fasting Value [ Time Frame: Follow-ups at Weeks 13±1 26±2 and 52±2 ]
    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
  • 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. ]
    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.
  • 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. ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2016)
  • AUC of C-peptide [ Time Frame: Baseline ]
    2-hour AUC of C-peptide response to the MMTT
  • AUC of C-peptide [ Time Frame: week 26±2 ]
    2-hour AUC of C-peptide response to the MMTT
  • AUC of C-peptide [ Time Frame: week 52±2 ]
    2-hour AUC of C-peptide response to the MMTT
  • Insulin requirement [ Time Frame: baseline ]
    Average (previous 3 days) insulin requirement
  • Insulin requirement [ Time Frame: week 13±1 ]
    Average (previous 3 days) insulin requirement
  • Insulin requirement [ Time Frame: week 26±2 ]
    Average (previous 3 days) insulin requirement
  • Insulin requirement [ Time Frame: week 52±2 ]
    Average (previous 3 days) insulin requirement
  • HbA1c [ Time Frame: baseline ]
    HbA1c levels
  • HbA1c [ Time Frame: week 13±1 ]
    HbA1c levels
  • HbA1c [ Time Frame: week 26±2 ]
    HbA1c levels
  • HbA1c [ Time Frame: week 52±2 ]
    HbA1c levels
  • Cumulative severe hypoglycaemic events [ Time Frame: week 13±1 ]
    Cumulative severe hypoglycaemic events occurring from randomization
  • Cumulative severe hypoglycaemic events [ Time Frame: week 26±2 ]
    Cumulative severe hypoglycaemic events occurring from randomization
  • Cumulative severe hypoglycaemic events [ Time Frame: week 52±2 ]
    Cumulative severe hypoglycaemic events occurring from randomization
  • Adverse Events [ Time Frame: week 52±2 ]
    Adverse Events during the study period
  • Serious Adverse Events [ Time Frame: week 52±2 ]
    Adverse Events during the study period
  • Vital signs [ Time Frame: week 4 ]
    Changes in Blood Pressure and Heart Rate from screening
  • Vital signs [ Time Frame: week 13 ]
    Change in Blood Pressure and Heart Rate from screening
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Insulin-Dependent
Intervention  ICMJE
  • Drug: Ladarixin
    Ladarixin oral capsule
    Other Name: Active treatment
  • Drug: Placebo
    Placebo oral capsule
    Other Name: Placebo treatment
Study Arms  ICMJE
  • Experimental: Ladarixin
    Ladarixin oral capsule
    Intervention: Drug: Ladarixin
  • Placebo Comparator: Placebo
    Placebo oral capsule
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2019)
76
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2016)
72
Actual Study Completion Date  ICMJE May 15, 2019
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Germany,   Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02814838
Other Study ID Numbers  ICMJE MEX0114
2014-003968-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dompé Farmaceutici S.p.A
Study Sponsor  ICMJE Dompé Farmaceutici S.p.A
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Emanuele Bosi, MD Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan
PRS Account Dompé Farmaceutici S.p.A
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP