Clinical trial NCT04899271: A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline.
Official title: A Phase 2, Multicenter, 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 and Preserved Beta-cell Function at Baseline.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: New-onset Type 1 Diabetes
Keywords: Type 1 diabetes
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2021-05-24
Enrollment: 25
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 was to assess whether ladarixin treatment is effective to improve glycemic control in newly diagnosed Type 1 Diabetes (T1D) adult patients with preserved β-cell function.

The safety of ladarixin in the specific clinical setting was also evaluated.

Detailed description: This was a phase II clinical trial designed as a randomized, double-blind, placebo-controlled, multicenter study to evaluate whether ladarixin is effective in preserving β-cell function and slowing-down the progression of T1D in adult patients with new-onset T1D and preserved β- cell function (fasting C-peptide ≥0.205 nmol/L) at baseline.

Seventy-five (75) patients were to be randomized based on an unbalanced randomization allocation ratio (2:1) to ladarixin hard gelatine capsules for oral administration (2 x 200 mg two times a day \[b.i.d.\] for 13 cycles of 14 days on/14 days off) or matched placebo. Assuming a 10% drop-out rate, approximately 84 patients were expected to be enrolled and to be treated for 1 year.

Each patient was to be involved in the study for a run-in period (screening and baseline assessments) followed by a randomization visit, a treatment period of 12 months, and a post-randomization period up to 18 months from the 1st treatment dose.

The study enrolment was stopped, though, on 28 March 2022, due to low enrolment rate, at the randomization of the 25th patient. The study terminated early, on 11 October 2023 (LPLV).

Due to the early termination of the study, efficacy analyses were reduced in scope given the limited sample size of the study compared with the one expected.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients aged 18-45 years, inclusive;
2. New-onset T1D (1st IMP dose 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 therapy through multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII);
5. Fasting C peptide ≥0.205nmol/L on two occasions;
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. 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;
2. Moderate to severe renal impairment as per estimated Glomerular Filtration Rate (eGFR) 60 mL/min/1.73 m2, 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. A history of significant cardiovascular disease/abnormality
7. Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks;
8. Known hypersensitivity to non-steroidal anti-inflammatory drugs;
9. Concomitant treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index \[i.e., phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (\>50 mg/day)\];
10. Previous (within 2 weeks prior to randomization) 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 (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;
12. Significant systemic infection during the 4 weeks before the first 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. Hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C and HIV positive serologic status Serologic evidence of current infectious liver disease (hepatitis A, B, or C), including anti hepatitis A virus (immunoglobulin M), hepatitis B surface antigen, or anti hepatitis C virus 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).

Primary outcomes:
measure: Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12
timeFrame: Month 12 (52±2 weeks)
Secondary outcomes:
measure: Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18
timeFrame: Month 6 (26±2 weeks) and Month 18 (78±2 weeks)
measure: Number of Patients With a Reduction in HbA1c% > 0.5% From Baseline and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6, 12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks )
measure: Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
measure: Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
measure: Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
measure: Overall Number of Self-reported Episodes of Severe Hypoglycemia
timeFrame: From baseline to study termination (month 18, week 78)
measure: Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18
timeFrame: Months 6 (week 26±2), 12 (week 52±2) and 18 (week 78±2)
measure: Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
measure: Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18
timeFrame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
measure: Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious
timeFrame: Throughout the study up to 18 months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado School of Medicine - Barbara Davis Center for Childhood Diabetes (BDC) - Specialty Clinic
state: Colorado
city: Atlanta
country: United States
facility: Atlanta Diabetes Associates (ADA)
state: Georgia
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel (UZB)
city: Tbilisi
country: Georgia
facility: National Center for Diabetes Research LTD
city: Tbilisi
country: Georgia
facility: National Institute of Endocrinology LTD
city: Glessen
country: Germany
facility: Universitaetsklinikum Gessen und Marburg GmbH - Medizinische Klinik und Poliklinik III
city: Heidelberg
country: Germany
facility: St. Josefskrankenhaus Diabestesinstitut Heidelberg
city: Muenster
country: Germany
facility: Institut fuer Diabetes forschung in Muenster (IDFM)
city: Bari
country: Italy
facility: Azienda Ospedaliero-Universitaria Conzorziale Policlinico di Bari
city: Catanzaro
country: Italy
facility: Università degli Studi Magna Graecia di Catanzaro, Azienda Ospedaliero-Universitaria Mater Domini
city: Milan
country: Italy
facility: Universitá degli Studi di Milano - Ospedale Luigi Sacco
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"
city: Roma
country: Italy
facility: Università Campus Bio-Medico di Roma (UCBM)
city: Rome
country: Italy
facility: "Sapienza" Università di Roma- Azienda Ospedaliero Universitaria Policlinico Umberto I
city: Belgrade
country: Serbia
facility: University of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases
city: Kragujevac
country: Serbia
facility: University of Kragujevac, Clinic for internal diseases, Center for endocrinology, diabetes and metabolic diseases
Study officials:
affiliation: Dompé Farmaceutici
name: Enrico M Minnella, MD
role: STUDY_DIRECTOR
References: