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.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 25
- 试验地点
- 16
- 主要终点
- Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Appearance, including packaging and labelling, of the IMP (capsules, packaging) will not allow to recognize actual treatment (either ladarixin or placebo).
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients aged 18-45 years, inclusive;
- •New-onset T1D (1st IMP dose 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 therapy through multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII);
- •Fasting C peptide ≥0.205nmol/L on two occasions;
- •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.
排除标准
- •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 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);
- •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;
- •A history of significant cardiovascular disease/abnormality
- •Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks;
- •Known hypersensitivity to non-steroidal anti-inflammatory drugs;
- •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)];
- •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.);
- •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;
- •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);
- •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;
- •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).
研究组 & 干预措施
Ladarixin
The treatment group received 400 mg b.i.d. for 13 cycles of 14 days on/14 days off)
干预措施: Ladarixin (Drug)
Placebo
The control group received matched placebo
干预措施: Placebo (Other)
结局指标
主要结局
Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12
时间窗: Month 12 (52±2 weeks)
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). The time frame for the primary endpoint has been set at Month 12 (Week 52) in order to evaluate the potential of ladarixin effects on a long-term projection. Please note that "proportion" is expressed as "count" (number + % of participants)
次要结局
- Overall Number of Self-reported Episodes of Severe Hypoglycemia(From baseline to study termination (month 18, week 78))
- Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18(Months 6 (week 26±2), 12 (week 52±2) and 18 (week 78±2))
- Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks))
- Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks))
- Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious(Throughout the study up to 18 months)
- Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18(Month 6 (26±2 weeks) and Month 18 (78±2 weeks))
- 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(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks ))
- Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks))
- Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks))
- Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18(Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks))