New-onset Type 1 Diabetes
Conditions
Keywords
Type 1 diabetes
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.
Interventions
DRUGLadarixin
400 mg b.i.d. for 13 cycles of 14 days on/14 days off
OTHERPlacebo
Placebo was administered orally with the same scheme of administration of LDX to preserve blinding
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Appearance, including packaging and labelling, of the IMP (capsules, packaging) will not allow to recognize actual treatment (either ladarixin or placebo).
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 ) | The number of patients with a reduction in HbA1c% \> 0.5% from baseline and daily insulin requirement \<0.50 IU/Kg/day was calculated at the hereunder specified timepoints. |
| 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) | C-peptide level is a widely used measure of pancreatic beta-cell function and the MMTT is one of the methods for its estimation. AUC stands for Area Under the Curve. AUC calculation was based on actual rather scheduled timings and it was calculated using the trapezoidal rule. C-peptide 0-120 min AUC (nmol/L) values were calculated based on all Basal-120min C-peptide values. Unscheduled assessments were excluded from the analysis. |
| 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) | 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. An A1C test measures the percentage of red blood cells that have glucose-coated hemoglobin. |
| 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) | For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. |
| 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) | 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 18 months to evaluate the potential persistency of any glycemic benefit. Please note that proportion is expressed as count (number + % of participants) |
| 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) | A severe hypoglycemic event was defined as an event with 1 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. Summary statistics of blood glucose level (mg/dL) are provided by treatment group at each time point for patients reporting severe hypoglycemia. |
| 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) | 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 and 18. 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 |
| 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) | 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. |
| Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | Throughout the study up to 18 months | An AE is any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with the trial intervention. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. |
| Overall Number of Self-reported Episodes of Severe Hypoglycemia | From baseline to study termination (month 18, week 78) | For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. Data reported refer to the overall number of episodes recorded by all analyzed patients in the two arms/groups (Ladarixin and placebo). |
Countries
Belgium, Georgia, Germany, Italy, Serbia, United States
Participant flow
Recruitment details
The number of patients randomized and treated was lower than planned in the study protocol. The Sponsor decided to stop patient enrolment on 28 March 2022, due to the recruitment rate being lower than expected. At the time of recruitment closure, 25 patients had been randomized compared with the 75 planned.
Pre-assignment details
Overall, 80 participants were screened, having signed the informed consent form. Out of these, 52 participants (65.0%) did not meet eligibility criteria (screen failure) and 3 participants (3.8%) withdrew their consent, making a total of 55 participants (68.8%) not enrolled and thus not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Ladarixin The treatment group received 400 mg b.i.d. for 13 cycles of 14 days on/14 days off)
Ladarixin: 400 mg b.i.d. for 13 cycles of 14 days on/14 days off | 18 |
| Placebo The control group received matched placebo
Placebo: Placebo was administered orally with the same scheme of administration of LDX to preserve blinding | 7 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Subject request/consent withdrawal | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Ladarixin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 18 Participants | 25 Participants |
| Age, Continuous | 27.3 years STANDARD_DEVIATION 7.7 | 25.5 years STANDARD_DEVIATION 7.6 | 26.0 years STANDARD_DEVIATION 7.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 18 Participants | 25 Participants |
| Region of Enrollment Germany | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Italy | 3 participants | 8 participants | 11 participants |
| Region of Enrollment Serbia | 1 participants | 5 participants | 6 participants |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 7 |
| other Total, other adverse events | 12 / 18 | 5 / 7 |
| serious Total, serious adverse events | 1 / 18 | 0 / 7 |
Outcome results
Primary
Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12
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)
Time frame: Month 12 (52±2 weeks)
Population: FAS: The Full Analysis Set consisted of all randomized patients who received at least one dose of the IMP (either ladarixin or placebo). The FAS was analyzed according to the ITT principle, i.e., by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The FAS was used for the primary analyses of the study and to present results on efficacy data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ladarixin | Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12 | 11 Participants |
| Placebo | Number of Patients With HbA1c <7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Month 12 | 5 Participants |
p-value: 0.807Chi-squared
Secondary
Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18
A severe hypoglycemic event was defined as an event with 1 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. Summary statistics of blood glucose level (mg/dL) are provided by treatment group at each time point for patients reporting severe hypoglycemia.
Time frame: Months 6 (week 26±2), 12 (week 52±2) and 18 (week 78±2)
Population: FAS: The Full Analysis Set consisted of all randomized patients who received at least one dose of the IMP. The FAS was analyzed according to the ITT principle, i.e., by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The FAS was used for the primary analyses of the study and to present results on efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ladarixin | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 6 | 48.11 mg/dL | Standard Deviation 4.73 |
| Ladarixin | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 12 | 48.71 mg/dL | Standard Deviation 4.75 |
| Ladarixin | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 18 | 48.27 mg/dL | Standard Deviation 4.9 |
| Placebo | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 6 | 51.00 mg/dL | Standard Deviation 3.94 |
| Placebo | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 12 | 49.57 mg/dL | Standard Deviation 5.71 |
| Placebo | Blood Glucose Levels for Patients Reporting Severe Hypoglycemia at Months 6, 12 and 18 | Month 18 | 50.13 mg/dL | Standard Deviation 5.51 |
Secondary
Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18
C-peptide level is a widely used measure of pancreatic beta-cell function and the MMTT is one of the methods for its estimation. AUC stands for Area Under the Curve. AUC calculation was based on actual rather scheduled timings and it was calculated using the trapezoidal rule. C-peptide 0-120 min AUC (nmol/L) values were calculated based on all Basal-120min C-peptide values. Unscheduled assessments were excluded from the analysis.
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Population: FAS (Full Analysis Set): all randomized patients who received at least one dose of the IMP (either ladarixin or placebo), analyzed according to the ITT principle. Discrepancies between Overall Number of Participants Analyzed and Number Analyzed for Ladarixin group due to: at Month 6: 2 participants withdrew their consent; at Month 12: 1 additional participant was lost at follow-up (who remained lost at follow-up even for Month 18 visit).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ladarixin | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 6 | -7.17 nmol/L | Standard Deviation 19.33 |
| Ladarixin | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 12 | 0.25 nmol/L | Standard Deviation 23.77 |
| Ladarixin | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 18 | -2.07 nmol/L | Standard Deviation 20.79 |
| Placebo | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 6 | -12.70 nmol/L | Standard Deviation 16.87 |
| Placebo | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 12 | -0.88 nmol/L | Standard Deviation 53.61 |
| Placebo | Change From Baseline in 2-hour AUC of C-peptide Response to the MMTT at Months 6, 12 and 18 | Month 18 | -5.41 nmol/L | Standard Deviation 32.52 |
Comparison: Comparison at month 6 for change from baselinep-value: 0.521t-test, 2 sided
Comparison: Comparison at month 12 for change from baselinep-value: 0.959t-test, 2 sided
Comparison: Comparison at month 18 for change from baselinep-value: 0.773t-test, 2 sided
Secondary
Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18
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 and 18. 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
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Population: FAS (Full Analysis Set): all randomized patients who received at least one dose of the IMP (either ladarixin or placebo), analyzed according to the ITT principle. Discrepancies between Overall Number of Participants Analyzed and Number Analyzed in both arms are due to participants withdrawing consent or with blood samples not collected at timepoints or lost at follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ladarixin | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 6 | -0.209 IU/kg/day | Standard Deviation 0.644 |
| Ladarixin | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 12 | -0.183 IU/kg/day | Standard Deviation 0.661 |
| Ladarixin | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 18 | -0.183 IU/kg/day | Standard Deviation 0.639 |
| Placebo | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 6 | -0.028 IU/kg/day | Standard Deviation 0.228 |
| Placebo | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 12 | 0.024 IU/kg/day | Standard Deviation 0.271 |
| Placebo | Change From Baseline in Average (Previous 3 Days) Daily Insulin Requirements (IU/kg/Day) at Months 6,12 and 18 | Month 18 | -0.005 IU/kg/day | Standard Deviation 0.342 |
Comparison: Comparison at month 6 for change from baselinep-value: 0.32Wilcoxon (Mann-Whitney)
Comparison: Comparison at month 12 for change from baselinep-value: 0.398Wilcoxon (Mann-Whitney)
Comparison: Comparison at month 18 for change from baselinep-value: 1Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18
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.
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Population: FAS (Full Analysis Set): all randomized patients who received at least one dose of the IMP (either ladarixin or placebo), analyzed according to the ITT principle. Discrepancies between Overall Number of Participants Analyzed and Number Analyzed in both arms are due to participants withdrawing consent or with blood samples not collected at timepoints or lost at follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ladarixin | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 6 | 0.418 mg/kg/min | Standard Deviation 0.815 |
| Ladarixin | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 12 | 0.067 mg/kg/min | Standard Deviation 1.504 |
| Ladarixin | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 18 | 0.242 mg/kg/min | Standard Deviation 1.142 |
| Placebo | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 6 | 0.367 mg/kg/min | Standard Deviation 0.816 |
| Placebo | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 12 | 0.623 mg/kg/min | Standard Deviation 0.862 |
| Placebo | Change From Baseline in Estimated Glucose Disposal Rate (eGDR) at Months 6, 12 and 18 | Month 18 | -0.238 mg/kg/min | Standard Deviation 1.255 |
Comparison: Comparison at month 6 for change from baselinep-value: 0.892t-test, 2 sided
Comparison: Comparison at month 12 for change from baselinep-value: 0.412t-test, 2 sided
Comparison: Comparison at month 18 for change from baselinep-value: 0.371Wilcoxon (Mann-Whitney)
Secondary
Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18
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. An A1C test measures the percentage of red blood cells that have glucose-coated hemoglobin.
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Population: FAS (Full Analysis Set): all randomized patients who received at least one dose of the IMP (either ladarixin or placebo), analyzed according to the ITT principle. Discrepancies between Overall Number of Participants Analyzed and Number Analyzed in both arms are due to participants withdrawing consent or with blood samples not collected at timepoints or lost at follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ladarixin | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 6 | -0.67 percentage HbA1c | Standard Deviation 0.88 |
| Ladarixin | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 12 | -0.51 percentage HbA1c | Standard Deviation 1.24 |
| Ladarixin | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 18 | -0.30 percentage HbA1c | Standard Deviation 1.55 |
| Placebo | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 6 | -0.84 percentage HbA1c | Standard Deviation 1.11 |
| Placebo | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 12 | -0.77 percentage HbA1c | Standard Deviation 1.28 |
| Placebo | Changes From Baseline in Percentage Glycated Hemoglobin (HbA1c) Levels at Months 6, 12 and 18 | Month 18 | -0.33 percentage HbA1c | Standard Deviation 0.67 |
Comparison: Comparison at month 6 for change from baselinep-value: 0.691t-test, 2 sided
Comparison: Comparison at month 12 for change from baselinep-value: 0.685t-test, 2 sided
Comparison: Comparison at month 18 for change from baselinep-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
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
The number of patients with a reduction in HbA1c% \> 0.5% from baseline and daily insulin requirement \<0.50 IU/Kg/day was calculated at the hereunder specified timepoints.
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks )
Population: FAS: The Full Analysis Set consisted of all randomized patients who received at least one dose of the IMP (either ladarixin or placebo). The FAS was analyzed according to the ITT principle, i.e., by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The FAS was used for the primary analyses of the study and to present results on efficacy data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ladarixin | 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 | Month 6 | 8 Participants |
| Ladarixin | 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 | Month 12 | 8 Participants |
| Ladarixin | 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 | Month 18 | 6 Participants |
| Placebo | 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 | Month 6 | 4 Participants |
| Placebo | 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 | Month 12 | 3 Participants |
| Placebo | 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 | Month 18 | 2 Participants |
Comparison: Comparison at month 6p-value: 0.867Chi-squared
Comparison: Comparison at month 12p-value: 0.769Chi-squared
Comparison: Comparison at month 18p-value: 0.776Chi-squared
Secondary
Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious
An AE is any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with the trial intervention. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.
Time frame: Throughout the study up to 18 months
Population: SAF population: The Safety (SAF) population consisted of all randomized patients who received at least one dose of the IMP. The SAF population was analyzed according to the actual treatment received and was used to present results on safety data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ladarixin | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | serious TEAE | 1 Participants |
| Ladarixin | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | TEAEs leading to IMP discontinuation | 1 Participants |
| Ladarixin | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | non-serious TEAE | 12 Participants |
| Ladarixin | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | TEAEs leading to death | 0 Participants |
| Ladarixin | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | any TEAE | 12 Participants |
| Placebo | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | TEAEs leading to death | 0 Participants |
| Placebo | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | any TEAE | 5 Participants |
| Placebo | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | serious TEAE | 0 Participants |
| Placebo | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | non-serious TEAE | 5 Participants |
| Placebo | Number of Patients With at Least One Adverse Events (AEs), Serious or Not Serious | TEAEs leading to IMP discontinuation | 1 Participants |
Secondary
Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18
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 18 months to evaluate the potential persistency of any glycemic benefit. Please note that proportion is expressed as count (number + % of participants)
Time frame: Month 6 (26±2 weeks) and Month 18 (78±2 weeks)
Population: FAS: The Full Analysis Set consisted of all randomized patients who received at least one dose of the IMP (either ladarixin or placebo). The FAS was analyzed according to the ITT principle, i.e., by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The FAS was used for the primary analyses of the study and to present results on efficacy data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ladarixin | Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18 | Month 6 | 12 Participants |
| Ladarixin | Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18 | Month 18 | 8 Participants |
| Placebo | Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18 | Month 6 | 6 Participants |
| Placebo | Number of Patients With HbA1c < 7% and Daily Insulin Requirement <0.50 IU/Kg/Day at Months 6 and 18 | Month 18 | 5 Participants |
Comparison: Comparison at month 6p-value: 0.746Chi-squared
Comparison: Comparison at month 18p-value: 0.201Chi-squared
Secondary
Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18
For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time frame: Months 6 (26±2 weeks), 12 (52±2 weeks) and 18 (78±2 weeks)
Population: FAS (Full Analysis Set): all randomized patients who received at least one dose of the IMP (either ladarixin or placebo), analyzed according to the ITT principle. Discrepancies between Overall Number of Participants Analyzed and Number Analyzed in both arms are due to participants withdrawing consent or with blood samples not collected at timepoints or lost at follow-up.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ladarixin | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 6 | 7 Participants |
| Ladarixin | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 12 | 8 Participants |
| Ladarixin | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 18 | 7 Participants |
| Placebo | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 6 | 3 Participants |
| Placebo | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 12 | 3 Participants |
| Placebo | Number of Patients With HbA1c < 7% Who Did Not Experience Severe Hypoglycemic Events During Treatment at Months 6,12 and 18 | Month 18 | 2 Participants |
Comparison: Comparison at month 6p-value: 0.867Chi-squared
Comparison: Comparison at month 12p-value: 0.769Chi-squared
Comparison: Comparison at month 18p-value: 0.577Chi-squared
Secondary
Overall Number of Self-reported Episodes of Severe Hypoglycemia
For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. Data reported refer to the overall number of episodes recorded by all analyzed patients in the two arms/groups (Ladarixin and placebo).
Time frame: From baseline to study termination (month 18, week 78)
Population: FAS: The Full Analysis Set consisted of all randomized patients who received at least one dose of the IMP. The FAS was analyzed according to the ITT principle, i.e., by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The FAS was used for the primary analyses of the study and to present results on efficacy data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ladarixin | Overall Number of Self-reported Episodes of Severe Hypoglycemia | 28 total number of severe hypoglyc episodes |
| Placebo | Overall Number of Self-reported Episodes of Severe Hypoglycemia | 8 total number of severe hypoglyc episodes |
p-value: 0.55495% CI: [0.573, 2.819]Cox proportional hazards model