A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04628481
• Collaborator: (none)
• Enrollment: 327
• Locations: 61
• Arms: 2
• Anticipated Duration (Months): 41.3
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of this clinical trial is to assess whether ladarixin treatment is effective in preserving beta-cell function and delaying the progression of type 1 diabetes (T1D) in adolescent and adult patients. The safety of ladarixin in the specific clinical setting will be also evaluated.

Condition or Disease	Intervention/Treatment	Phase
New-onset type1 Diabetes	Drug: Ladarixin; Drug: Placebo	Phase 3

Detailed Description

This is a phase 3, multicenter, double-blind, placebo-controlled study. It has been designed to further evaluate whether ladarixin is effective in preserving beta-cell function and slowing-down the progression of T1D) in patients with a more severe disease presentation.

The study is planned to be performed at about 40 study centers in EU, US and in other countries, if appropriated. At each study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.

The study is planned to involve -327 patients with new-onset T1D, to include about 200 adolescents (14-17 years). Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 327 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The study will proceed under double-blind condition up to month 18 visit of the last patient randomized. Thereafter, the blind will be broken and remaining follow-up will proceed in an open fashion. This approach will allow to anticipate access to efficacy data without significantly affecting data integrity.
• Primary Purpose: Treatment
• Official Title: Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess Efficacy - Safety of 400 mg Twice a Day Oral Ladarixin in Pts With Recent Onset Type 1 Diabetes and Low Residual β-cell Function at Baseline (GLADIATOR STUDY)
• Actual Study Start Date: Dec 21, 2020
• Anticipated Primary Completion Date: Jun 1, 2023
• Anticipated Study Completion Date: Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ladarixin 400 mg b.i.d. for 13 cycles of 14 days on/14 days off	Drug: Ladarixin; Oral ladarixin twice a day for 13 cycles; Other Names: allosteric inhibitor of CXCL8 (IL-8), CXCR1 and CXCR2 receptors
Placebo Comparator: Placebo matching placebo b.i.d. for 13 cycles of 14 days on/14 days off	Drug: Placebo; Oral placebo twice a day for 13 cycles

Outcome Measures

Primary Outcome Measures

1. Change from baseline in 2-hour AUC of C-peptide response to the Mixed Model Tolerance Test (MMTT) [Month 12]

   C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline

2. Change from baseline in HbA1c [Month 12]

   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.

Secondary Outcome Measures

1. Change from baseline in 2-hour AUC of C-peptide response to the MMTT [Months 6, 18 and 24]

   C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline

2. Change in HbA1c from baseline [Months 6, 18 and 24]

   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.

3. Time in range (TIR) by Continuous Glucose Monitoring (CGM) [Months 6, 12, 18, 24]

   Continuous glucose monitors (CGM) continually monitors glucose plasma levels through an external device that's attached to the body, and gives real-time updates.Time in range is the amount of time the patient spends in the target blood sugar (blood glucose) range-between 70 and 180 mg/dL for most people. The time in range method works with the individual CGM's data by looking at the amount of time blood sugar has been in target range and the times it has been high (hyperglycemia) or low (hypoglycemia). This data is helpful in finding out which types of foods and what activity level causes patient's blood sugar to rise and fall.

4. Proportion of patients with HbA1c <7% who did not experience severe hypoglycemic events during treatment [Months 6, 12, 18, 24]

   For the purpose of this study, a severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.e. glucose, or glucagon administration.

5. Average (previous 3 days) daily insulin requirement (IU/kg/day) [Months 6, 12, 18, 24]

   For the purpose of this study, daily insulin is averaged over the previous 3 days.Insulin requirement (IU/kg/day averaged over the previous 3 days) was to be recorded to Months 6, 12, 18 and 24. 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

6. Proportion of patients with HbA1c <7% and daily insulin requirement <0.5 (IU/kg/day) [Months 6, 12, 18, 24]

   The sample size of the study is calculated on the "proportion of patients with a HbA1c < 7% and daily insulin requirement <0.50 IU/Kg/day", a post-hoc composite endpoint derived from data of the phase 2 trial (MEX0114), considering a larger effect size expected from the longer treatment length (one year versus 3 months). Follow-up is extended up to 24 months to evaluate the potential persistency of any glycemic benefit.

7. Number of self-reported episodes of severe hypoglycemia [Months 6, 12, 18, 24]

   For the purpose of this study, a severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.e. glucose, or glucagon administration.

8. Percentage of patients not requiring insulin therapy [Months 6, 12, 18, 24]

   This outcome aims to assess the % of patients who do not require an insulin therapy

9. Estimated Glucose Disposal Rate (eGDR) [Months 6, 12, 18, 24]

   Estimated Glucose Disposal Rate (eGDR) is a marker for the Assessment of Insulin Resistance and a validated clinical tool for estimating insulin sensitivity in type 1 diabetes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female patients aged 14-45 years, inclusive;

2. Recent onset T1D (1st IMP dose within 180 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 therapy through one or more separate subcutaneous injections or Continuous Subcutaneous Insulin Infusion (CSII).

5. Fasting C peptide < 0.205nmol/L;

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

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

8. Patients who have given written informed consent prior of any study-related procedure not part of standard medical care (participants under the age of 18, shall provide an assent for the study as per country requirements). Specific consent must be given by adolescents to be selected for the full PK analysis.

Exclusion Criteria:

1. A type 2 diabetes diagnosis or any other unstable chronic disease for which dose adjustment of specific medication is anticipated during the trial;

2. Moderate to severe renal impairment as per estimated Glomerular Filtration Rate (eGFR) 60 mL/min/1.73m2, as determined using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (see Appendix 14.4.3);

3. 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];

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

5. QTcF > 470 msec;

6. Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks;

7. A history of significant cardiovascular disease/abnormality;

8. Known hypersensitivity to non-steroidal anti-inflammatory drugs;

9. Concomitant treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index [i.e. phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose amitriptyline (> 50 mg/day)];

10. Previous (past 2 weeks) and concomitant treatment with antidiabetic agents as metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, SGLT2-inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. beta-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.);

11. Past (past month) or current administration of any immunosuppressive medications (including oral or systemic corticosteroids) and use of any investigational agents, including any agents that impact the immune response or the cytokine system;

12. Significant systemic infection during the 4 weeks before the 1st dose of the study drug (e.g., infection requiring hospitalization, major surgery, or IV antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localized cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion);

13. History of positive status for hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C and HIV..

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 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); abstinence.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham (UAB) - The Kirklin Clinic (TKC) - Multidisciplinary Comprehensive Diabetes Clinic (MCDC)	Birmingham	Alabama	United States	35294
2	Phoenician Centers for Research and Innovation	Phoenix	Arizona	United States	85021
3	University of California San Diego	La Jolla	California	United States	92037-0990
4	University of California San Diego	La Jolla	California	United States	92093
5	Center of Excellence in Diabetes & Endocrinology (CEDE)	Sacramento	California	United States	95821-2123
6	University of Colorado School of Medicine - Barbara Davis Center for Childhood Diabetes (BDC) - Specialty Clinic	Aurora	Colorado	United States	80045
7	Christiana Care Endocrinology Specialists	Newark	Delaware	United States	19713
8	Diabetes Care Center - Hudson	Hudson	Florida	United States	34667-7151
9	Global Life Research Network	Miami	Florida	United States	33155
10	AdventHealth (Florida Hospital) - Diabetes Institute - Orlando	Orlando	Florida	United States	32804
11	AdventHealth (Florida Hospital) - Diabetes Institute - Orlando	Orlando	Florida	United States	32804
12	Atlanta Diabetes Associates (ADA)	Atlanta	Georgia	United States	30318
13	The University of Chicago	Chicago	Illinois	United States	60637
14	Prairie Education and Research Cooperative d/b/a Central Illinois Diabetes and Clinical	Springfield	Illinois	United States	62711
15	Indiana University - Riley Hospital for Children	Indianapolis	Indiana	United States	46202
16	The Cotton-O'Neil Diabetes and Endocrinology Center	Topeka	Kansas	United States	66606-28
17	University of Louisville	Louisville	Kentucky	United States	40292
18	Joslin Diabetes Center, Harvard Medical School	Boston	Massachusetts	United States	02215
19	UBMD Physicians Group - Pediatrics - Conventus	Buffalo	New York	United States	14203
20	"WakeMed Physician Practices - Pediatric Endocrinology - WakeMed Raleigh Medical Park Location"	Raleigh	North Carolina	United States	27610
21	University of Pennsylvania Perelman School of Medicine	Philadelphia	Pennsylvania	United States	19104
22	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
23	University of Pittsburgh - UPMC	Pittsburgh	Pennsylvania	United States	15261
24	Cook Children's Endocrinology and Diabetes Program	Fort Worth	Texas	United States	76104
25	Texas Children's Hospital	Houston	Texas	United States	77030
26	Eastern Virginia Medical School (EVMS) - Strelitz Diabetes Center	Norfolk	Virginia	United States	23510
27	Clinique du Sud Luxembourg - Vivialia-Arlon	Arlon		Belgium
28	Universitair Ziekenhuis Brussel (UZB)	Jette		Belgium
29	General Hospital AZ Nikolaas	Sint-Niklaas		Belgium
30	Aleksandre Aladashvili Clinic LLC	Tbilisi		Georgia	48102
31	National Center for Diabetes Research LTD	Tbilisi		Georgia	48159
32	National Institute of Endocrinology LTD	Tbilisi		Georgia	48159
33	Tbilisi Heart and Vascular Clinic LTD	Tbilisi		Georgia	48159
34	Medical Center - University of Freiburg	Freiburg	Baden-Wuerttemberg	Germany	79106
35	Medical Center - University of Freiburg	Freiburg		Germany
36	Universitaetsklinikum Gessen und Marburg GmbH - Medizinische Klinik und Poliklinik III	Glessen		Germany	35392
37	Diabestesinstitut Heidelberg	Heidelberg		Germany
38	Die Praxis am Ludwigsplatz	Ludwigshafen am Rhein		Germany
39	Institut fuer Diabetes forschung in Muenster (IDFM)	Münster		Germany
40	Schwerpunktpraxis fuer Diabetes & Ernaehrungsmedizin	Münster		Germany
41	Soroka Medical Center	Be'er Sheva		Israel
42	Schneider Children's Medical Center, Petah Tikva	Petah Tikva		Israel	4920235
43	Tel Aviv Sourasky Medical Center	Tel Aviv-Yafo		Israel
44	Ospedale Pediatrico G. Salesi - Centro Regionale di Diabetologia Clinica Pediatrica	Ancona		Italy	60123
45	Azienda Ospedaliero-Universitaria Conzorziale Policlinico di Bari	Bari		Italy	70124
46	Università degli Studi Magna Graecia di Catanzaro, Azienda Ospedaliero-Universitaria Mater Domini	Catanzaro		Italy
47	Universitá degli Studi di Milano - Ospedale Luigi Saco	Milan		Italy	20157
48	Centro regionale di Diabetologia Pediatrica "G. Stoppoloni", Azienda Ospedaliera Universitaria "Luigi Vanvitelli"	Napoli		Italy
49	Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"	Palermo		Italy	90127
50	Università Campus Bio-Medico di Roma (UCBM) - Policlinico Universitario	Roma		Italy	00128
51	Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale Pediatrico Bambino Gesu	Roma		Italy
52	Universita Cattolica del Sacro Cuore - Policlinico Universitario "Agostino Gemelli"	Roma		Italy
53	"Sapienza" Università di Roma- Azienda Ospedaliero Universitaria Policlinico Umberto I	Rome		Italy	00161
54	University Children's Hospital	Belgrade		Serbia	110000
55	Clinical Center of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases	Belgrade		Serbia	11000
56	Clinical Center of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases	Belgrade		Serbia	11000
57	University Children's Hospital	Belgrade		Serbia
58	Clinical center Kragujevac, Clinic for internal diseases, Center for endocrinology, diabetes and metabolic diseases	Kragujevac		Serbia	34000
59	Clinical Center Nis, Clinic for endocrinology	Niš		Serbia	18000
60	Clinical Center Nis, Clinic for endocrinology	Niš		Serbia
61	University Children's Hospital, University Medical Center Ljubljana	Lubiana		Slovenia

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Study Director: Annarita Maurizi, MD, Dompé Farmaceutici

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT04628481
• Other Study ID Numbers: LDX0319; 2020-001926-71
• First Posted: Nov 13, 2020
• Last Update Posted: Jul 11, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Dompé Farmaceutici S.p.A: type1 diabetes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1

Study Results

No Results Posted as of Jul 11, 2022