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

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Diabetes Mellitus, Insulin-Dependent
Interventions	Drug: Ladarixin Drug: Placebo
Enrollment	76

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Ladarixin	Placebo
Arm/Group Description	Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description	Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Period Title: Overall Study
Started	50	26
Completed	48	25
Not Completed	2	1
Reason Not Completed
3 agreed dates for the final visit missed	1	0
Consent withdrawal	1	1

Baseline Characteristics

Arm/Group Title		Ladarixin	Placebo	Total
Arm/Group Description		Ladarixin oral capsule ...	Placebo oral capsule ...	Total of all reporting groups
Arm/Group Description		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule	Total of all reporting groups
Overall Number of Baseline Participants		50	26	76
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	50 participants	26 participants	76 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	50 100.0%	26 100.0%	76 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	50 participants	26 participants	76 participants
	Female	21 42.0%	10 38.5%	31 40.8%
	Male	29 58.0%	16 61.5%	45 59.2%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	50 participants	26 participants	76 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 2.0%	0 0.0%	1 1.3%
	White	49 98.0%	26 100.0%	75 98.7%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	50 participants	26 participants	76 participants
Belgium		20	11	31
Italy		17	10	27
Germany		13	5	18

Outcome Measures

1.Primary Outcome


Title	Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13
Description	C-peptide level is a wid...
Description	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.
Time Frame	week 13±1

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo)


Arm/Group Title	Ladarixin	Placebo
Arm/Group Description:	Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:	Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed	49	26
Mean (Standard Deviation) Unit of Measure: log(ng*hr/ml [0-2 h]+1)
	4.026 (0.4852)	3.886 (0.7446)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3303
	Comments	[Not Specified]
	Method	Student's t test for unpaired samples
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95% -0.14 to 0.42
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Area Under the Curve (AUC) (0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Weeks 26 and 52
Description	C-peptide level is a wid...
Description	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.
Time Frame	Follow-ups at Weeks 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		47	25
Mean (Standard Deviation) Unit of Measure: log(ng*hr/ml [0-2 h]+1)
FU week 26	Number Analyzed	47 participants	25 participants
FU week 26		3.9351 (0.51710)	3.8076 (0.76473)
FU week 52	Number Analyzed	46 participants	25 participants
FU week 52		3.6371 (0.75222)	3.6380 (0.81268)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at FUP week 26
	Type of Statistical Test	Superiority
	Comments	The comparisons between groups on 2-hour AUC C-peptide efficacy endpoint was carried-out using a mixed linear model where the log(x+1) transformed 2-hour AUC C-peptide was the dependent variable, while treatment group, visit, treatment by visit interaction were the fixed factors of the model and patient will be the random effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.

Statistical Test of Hypothesis	P-Value	0.517
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0984
	Confidence Interval	(2-Sided) 95% -0.2028 to 0.3995
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At FUP week 52
	Type of Statistical Test	Superiority
	Comments	The comparisons between groups on 2-hour AUC C-peptide efficacy endpoint was carried-out using a mixed linear model where the log(x+1) transformed 2-hour AUC C-peptide was the dependent variable, while treatment group, visit, treatment by visit interaction were the fixed factors of the model and patient will be the random effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.

Statistical Test of Hypothesis	P-Value	0.7999
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0486
	Confidence Interval	(2-Sided) 95% -0.4294 to 0.3322
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Percent Change From Baseline of 2-hour AUC of C-peptide Response to the MMTT
Description	C-peptide level is a wid...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		49	25
Mean (Standard Deviation) Unit of Measure: percentage of change
FU week 13	Number Analyzed	49 participants	25 participants
FU week 13		5.7818 (36.74477)	-6.0734 (38.22179)
FU week 26	Number Analyzed	47 participants	24 participants
FU week 26		-0.8701 (42.93044)	-13.7347 (37.41900)
FU week 52	Number Analyzed	46 participants	24 participants
FU week 52		-22.2532 (38.84672)	-24.2215 (42.67277)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2224
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	12.0411
	Confidence Interval	(2-Sided) 95% -7.3823 to 31.4644
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3931
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	8.4803
	Confidence Interval	(2-Sided) 95% -11.0935 to 28.0541
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7664
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-2.9502
	Confidence Interval	(2-Sided) 95% -22.5476 to 16.6473
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Change From Screening in Average (Previous 3 Days) Insulin Requirement
Description	Insulin requirement (IU/...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		47	26
Mean (Standard Deviation) Unit of Measure: IU/kg/day
FU week 13	Number Analyzed	47 participants	26 participants
FU week 13		-0.067 (0.1774)	-0.018 (0.1314)
FU week 26	Number Analyzed	47 participants	25 participants
FU week 26		-0.011 (0.2625)	0.032 (0.1699)
FU week 52	Number Analyzed	46 participants	25 participants
FU week 52		0.025 (0.2507)	0.101 (0.2411)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.2225
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.048
	Confidence Interval	(2-Sided) 95% -0.1257 to 0.0298
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 26
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.551
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0369
	Confidence Interval	(2-Sided) 95% -0.1596 to 0.0858
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 52
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.2501
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.063
	Confidence Interval	(2-Sided) 95% -0.1712 to 0.0453
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Change From Screening in Glycated Haemoglobin (HbA1c) Levels
Description	HbA1c measurement can be...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation) Unit of Measure: percentage of glycated haemoglobin
FU week 13	Number Analyzed	48 participants	25 participants
FU week 13		-1.40 (1.674)	-1.18 (1.352)
FU week 26	Number Analyzed	47 participants	24 participants
FU week 26		-1.19 (2.003)	-0.63 (1.141)
FU week 52	Number Analyzed	46 participants	25 participants
FU week 52		-0.69 (2.225)	-0.76 (1.333)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at FU week 13
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.6252
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.1494
	Confidence Interval	(2-Sided) 95% -0.7514 to 0.4526
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At FU week 26
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.366
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.2804
	Confidence Interval	(2-Sided) 95% -0.8904 to 0.3297
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At FU week 52
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.5026
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.2063
	Confidence Interval	(2-Sided) 95% -0.3992 to 0.8118
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Basal to 180 Minutes Time Course of C-peptide Concentration Derived From the MMTT
Description	Time points at each visit are Basal 1 and Basal 2 (samples collected a...
Description	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.
Time Frame	Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		50	26
Mean (Standard Deviation) Unit of Measure: nmol/L
Screening - Basal average	Number Analyzed	50 participants	26 participants
Screening - Basal average		0.218 (0.1087)	0.225 (0.1416)
Screening - 15 min	Number Analyzed	50 participants	26 participants
Screening - 15 min		0.294 (0.1621)	0.299 (0.1779)
Screening - 30 min	Number Analyzed	50 participants	26 participants
Screening - 30 min		0.422 (0.2126)	0.452 (0.3036)
Screening - 60 min	Number Analyzed	50 participants	25 participants
Screening - 60 min		0.545 (0.2631)	0.537 (0.2354)
Screening - 90 min	Number Analyzed	50 participants	25 participants
Screening - 90 min		0.613 (0.2467)	0.581 (0.2486)
Screening - 120 min	Number Analyzed	49 participants	26 participants
Screening - 120 min		0.620 (0.2559)	0.656 (0.2923)
Screening - 180 min	Number Analyzed	49 participants	25 participants
Screening - 180 min		0.527 (0.2252)	0.550 (0.2277)
week 13 - Basal average	Number Analyzed	49 participants	26 participants
week 13 - Basal average		0.231 (0.1136)	0.210 (0.1315)
week 13 - 15 min	Number Analyzed	49 participants	26 participants
week 13 - 15 min		0.300 (0.1385)	0.285 (0.1956)
week 13 - 30 min	Number Analyzed	49 participants	26 participants
week 13 - 30 min		0.427 (0.2048)	0.392 (0.2418)
week 13 - 60 min	Number Analyzed	49 participants	26 participants
week 13 - 60 min		0.571 (0.2660)	0.523 (0.2729)
week 13 - 90 min	Number Analyzed	49 participants	26 participants
week 13 - 90 min		0.620 (0.2859)	0.594 (0.3176)
week 13 - 120 min	Number Analyzed	49 participants	26 participants
week 13 - 120 min		0.637 (0.2869)	0.601 (0.3050)
week 13 - 180 min	Number Analyzed	48 participants	26 participants
week 13 - 180 min		0.518 (0.2302)	0.527 (0.2778)
week 26 - Basal average	Number Analyzed	47 participants	25 participants
week 26 - Basal average		0.212 (0.0941)	0.207 (0.1192)
week 26 - 15 min	Number Analyzed	47 participants	25 participants
week 26 - 15 min		0.278 (0.1294)	0.260 (0.1426)
week 26 - 30 min	Number Analyzed	47 participants	25 participants
week 26 - 30 min		0.391 (0.1857)	0.368 (0.2150)
week 26 - 60 min	Number Analyzed	47 participants	25 participants
week 26 - 60 min		0.534 (0.2463)	0.511 (0.2967)
week 26 - 90 min	Number Analyzed	47 participants	25 participants
week 26 - 90 min		0.569 (0.2606)	0.552 (0.3101)
week 26 - 120 min	Number Analyzed	46 participants	25 participants
week 26 - 120 min		0.592 (0.2703)	0.552 (0.2907)
week 26 - 180 min	Number Analyzed	47 participants	25 participants
week 26 - 180 min		0.504 (0.2189)	0.466 (0.2362)
week 52 - Basal average	Number Analyzed	46 participants	25 participants
week 52 - Basal average		0.168 (0.1070)	0.178 (0.1068)
week 52 - 15 min	Number Analyzed	46 participants	25 participants
week 52 - 15 min		0.228 (0.1606)	0.249 (0.1616)
week 52 - 30 min	Number Analyzed	46 participants	25 participants
week 52 - 30 min		0.321 (0.2231)	0.314 (0.1826)
week 52 - 60 min	Number Analyzed	46 participants	25 participants
week 52 - 60 min		0.430 (0.2693)	0.440 (0.2671)
week 52 - 90 min	Number Analyzed	46 participants	25 participants
week 52 - 90 min		0.463 (0.2806)	0.465 (0.2881)
week 52 - 120 min	Number Analyzed	46 participants	25 participants
week 52 - 120 min		0.503 (0.3085)	0.492 (0.2717)
week 52 - 180 min	Number Analyzed	46 participants	25 participants
week 52 - 180 min		0.426 (0.2341)	0.443 (0.2441)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with C-peptide (nmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.2527
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0242
	Confidence Interval	(2-Sided) 95% -0.0174 to 0.0658
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 26
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with C-peptide (nmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.2743
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0236
	Confidence Interval	(2-Sided) 95% -0.0188 to 0.066
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 52
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with C-peptide (nmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.7856
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0059
	Confidence Interval	(2-Sided) 95% -0.0485 to 0.0367
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Basal to 180 Minutes Time Course of Glucose Concentration Derived From the MMTT
Description	Time points at each visit are Basal 1 and Basal 2 (samples collected a...
Description	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.
Time Frame	Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		50	26
Mean (Standard Deviation) Unit of Measure: mmol/L
Screening - basal average	Number Analyzed	50 participants	26 participants
Screening - basal average		6.965 (1.6858)	6.855 (1.9507)
Screening - 15 min	Number Analyzed	50 participants	26 participants
Screening - 15 min		8.108 (1.8453)	8.013 (2.0941)
Screening - 30 min	Number Analyzed	50 participants	26 participants
Screening - 30 min		10.438 (2.2282)	10.096 (2.4694)
Screening - 60 min	Number Analyzed	50 participants	25 participants
Screening - 60 min		12.146 (2.9387)	12.068 (2.9204)
Screening - 90 min	Number Analyzed	50 participants	25 participants
Screening - 90 min		12.350 (3.4122)	12.076 (3.9156)
Screening - 120 min	Number Analyzed	50 participants	26 participants
Screening - 120 min		11.400 (3.4561)	11.827 (4.0204)
Screening - 180 min	Number Analyzed	49 participants	25 participants
Screening - 180 min		9.478 (3.6320)	9.652 (4.0549)
Week 13 - Basal average	Number Analyzed	49 participants	25 participants
Week 13 - Basal average		7.074 (1.9973)	6.644 (2.1145)
Week 13 - 15 min	Number Analyzed	49 participants	25 participants
Week 13 - 15 min		8.231 (2.1415)	7.836 (2.2409)
Week 13 - 30 min	Number Analyzed	49 participants	25 participants
Week 13 - 30 min		10.727 (2.5691)	10.224 (2.3600)
Week 13 - 60 min	Number Analyzed	49 participants	24 participants
Week 13 - 60 min		12.614 (3.1536)	12.871 (2.6908)
Week 13 - 90 min	Number Analyzed	49 participants	25 participants
Week 13 - 90 min		12.553 (3.7998)	13.092 (3.1608)
Week 13 - 120 min	Number Analyzed	49 participants	25 participants
Week 13 - 120 min		11.773 (4.0990)	12.260 (3.7590)
Week 13 - 180 min	Number Analyzed	49 participants	25 participants
Week 13 - 180 min		9.761 (3.9834)	9.984 (3.8597)
Week 26 - Basal average	Number Analyzed	48 participants	25 participants
Week 26 - Basal average		7.496 (2.0261)	7.600 (2.6387)
Week 26 - 15 min	Number Analyzed	48 participants	24 participants
Week 26 - 15 min		8.750 (2.0827)	9.058 (2.7026)
Week 26 - 30 min	Number Analyzed	48 participants	25 participants
Week 26 - 30 min		10.927 (2.3901)	11.240 (2.6187)
Week 26 - 60 min	Number Analyzed	48 participants	25 participants
Week 26 - 60 min		13.494 (2.8623)	14.222 (2.8795)
Week 26 - 90 min	Number Analyzed	48 participants	25 participants
Week 26 - 90 min		13.665 (3.8399)	15.020 (3.4469)
Week 26 - 120 min	Number Analyzed	48 participants	25 participants
Week 26 - 120 min		13.240 (4.1302)	14.424 (3.7761)
Week 26 - 180 min	Number Analyzed	48 participants	25 participants
Week 26 - 180 min		10.956 (4.2031)	12.028 (3.8832)
Week 52 - Basal average	Number Analyzed	46 participants	25 participants
Week 52 - Basal average		7.457 (2.3045)	8.163 (2.2251)
Week 52 - 15 min	Number Analyzed	46 participants	25 participants
Week 52 - 15 min		8.939 (2.7210)	9.544 (2.2230)
Week 52 - 30 min	Number Analyzed	46 participants	25 participants
Week 52 - 30 min		11.374 (2.6806)	11.688 (2.6411)
Week 52 - 60 min	Number Analyzed	46 participants	24 participants
Week 52 - 60 min		14.315 (3.1205)	14.725 (2.9631)
Week 52 - 90 min	Number Analyzed	46 participants	25 participants
Week 52 - 90 min		14.911 (3.5768)	15.276 (3.7144)
Week 52 - 120 min	Number Analyzed	46 participants	25 participants
Week 52 - 120 min		14.354 (3.9162)	15.140 (3.7514)
Week 52 - 180 min	Number Analyzed	46 participants	25 participants
Week 52 - 180 min		12.148 (4.0817)	13.148 (3.9136)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Glucose (mmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.9307
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0253
	Confidence Interval	(2-Sided) 95% -0.5986 to 0.548
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Glucose (mmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.0139
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.7236
	Confidence Interval	(2-Sided) 95% -1.2989 to -0.1483
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 52
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with Glucose (mmol/L) actual value as dependent variable, treatment, visit, time, treatment by visit interaction, time by visit interaction, treatment by visit by time interaction as fixed effects and time by visit interaction is specified in repeated statement.

Statistical Test of Hypothesis	P-Value	0.0432
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.5979
	Confidence Interval	(2-Sided) 95% -1.1775 to -0.0184
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit
Description	A severe hypoglycaemic event was defined as an event with one of the f...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		50	26
Mean (Standard Deviation) Unit of Measure: events
FU week 13	Number Analyzed	49 participants	26 participants
FU week 13		0.0 (0.0)	0.0 (0.0)
FU Week 26	Number Analyzed	48 participants	25 participants
FU Week 26		0.0 (0.14)	0.0 (0.20)
FU Week 52	Number Analyzed	49 participants	25 participants
FU Week 52		0.1 (0.32)	0.0 (0.20)

9.Secondary Outcome


Title	Proportion of Patients Maintaining a Residual β-cell Function
Description	Maintenance of a residua...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo)


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		49	26
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of patients
FU Week 13	Number Analyzed	49 participants	26 participants
FU Week 13		96.0 (86.29 to 99.51)	88.5 (69.85 to 97.55)
FU week 26	Number Analyzed	46 participants	25 participants
FU week 26		86.0 (73.26 to 94.18)	84.6 (65.13 to 95.64)
FU Week 52	Number Analyzed	45 participants	25 participants
FU Week 52		78.0 (64.04 to 88.47)	76.9 (56.35 to 91.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1171
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6586
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5056
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

10.Secondary Outcome


Title	Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit
Description	A severe hypoglycaemic e...
Description	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.
Time Frame	Follow-ups at Weeks 13±1, 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population = all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo)


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		49	25
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of patients
FU Week 13	Number Analyzed	49 participants	25 participants
FU Week 13		90.0 (78.19 to 96.67)	73.1 (52.21 to 88.43)
FU week 26	Number Analyzed	48 participants	24 participants
FU week 26		78.0 (64.04 to 88.47)	50.0 (29.93 to 70.07)
FU Week 52	Number Analyzed	47 participants	25 participants
FU Week 52		62.0 (47.17 to 75.35)	53.8 (33.37 to 73.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0779
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0248
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4504
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

11.Secondary Outcome


Title	C-peptide AUC(15 to 120 Mins) Above Fasting Value
Description	The means are all "...
Description	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
Time Frame	Follow-ups at Weeks 13±1 26±2 and 52±2

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title	Ladarixin	Placebo
Arm/Group Description:	Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:	Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed	50	26
Mean (95% Confidence Interval) Unit of Measure: log(ng*hr/ml [15-120 min]+1)
FU Week 13	3.3736 (3.1730 to 3.5742)	3.2334 (2.9568 to 3.5100)
FU week 26	3.2419 (3.0186 to 3.4652)	3.0649 (2.7562 to 3.3735)
FU week 52	2.9733 (2.7150 to 3.2316)	2.9282 (2.5720 to 3.2844)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 13
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.4163
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.1402
	Confidence Interval	(2-Sided) 95% -0.2015 to 0.4819
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.3575
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.177
	Confidence Interval	(2-Sided) 95% -0.2039 to 0.558
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments	Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

Statistical Test of Hypothesis	P-Value	0.8386
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0451
	Confidence Interval	(2-Sided) 95% -0.3948 to 0.4851
	Estimation Comments	[Not Specified]

12.Secondary Outcome


Title	Area Under the Curve (AUC) (0-2 h) of C-peptide MMTT in Patients With Screening C-peptide < Median Value
Description	A subgroup analysis of e...
Description	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.
Time Frame	Follow-up at Weeks 13±1, 26±2, and 52±2.

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		26	11
Mean (Standard Deviation) Unit of Measure: log(ng*hr/ml [0-2 h]+1)
FU Week 13	Number Analyzed	26 participants	11 participants
FU Week 13		3.8085 (0.45692)	3.4543 (0.86632)
FU Week 26	Number Analyzed	25 participants	10 participants
FU Week 26		3.8202 (0.48142)	3.3178 (0.91906)
FU Week 52	Number Analyzed	24 participants	10 participants
FU Week 52		3.3796 (0.68616)	3.1562 (0.97130)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 13
	Type of Statistical Test	Superiority
	Comments	Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.

Statistical Test of Hypothesis	P-Value	= 0.1114
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.354
	Confidence Interval	(2-Sided) 95% -0.09 to 0.75
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments	Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.

Statistical Test of Hypothesis	P-Value	= 0.0411
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.502
	Confidence Interval	(2-Sided) 95% 0.02 to 0.98
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments	Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.

Statistical Test of Hypothesis	P-Value	= 0.4506
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.223
	Confidence Interval	(2-Sided) 95% -0.37 to 0.82
	Estimation Comments	[Not Specified]

13.Secondary Outcome


Title	Area Under the Curve (AUC) (15-120 Min) of C-peptide MMTT Above Fasting Value in Patients With Screening C-peptide < Median Value
Description	A subgroup analysis of e...
Description	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.
Time Frame	Follow-up at Weeks 13±1, 26±2, and 52±2.

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		26	11
Mean (Standard Deviation) Unit of Measure: log(ng*hr/ml [15-120 min] +1)
FU week 13	Number Analyzed	26 participants	11 participants
FU week 13		3.1590 (0.56135)	2.7959 (1.07745)
FU week 26	Number Analyzed	25 participants	10 participants
FU week 26		27.7841 (15.10337)	18.6842 (15.46837)
FU week 52	Number Analyzed	24 participants	10 participants
FU week 52		2.7993 (0.82214)	19.9415 (16.95597)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 13 Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1847
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.3631
	Confidence Interval	(2-Sided) 95% -0.1817 to 0.908
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 26 Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.031
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.6304
	Confidence Interval	(2-Sided) 95% 0.0609 to 1.1998
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 52 Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6299
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.1639
	Confidence Interval	(2-Sided) 95% -0.5202 to 0.8479
	Estimation Comments	[Not Specified]

14.Secondary Outcome


Title	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
Description	A severe hypoglycaemic e...
Description	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.
Time Frame	Follow-up at Weeks 13±1, 26±2, and 52±2

Outcome Measure Data

Analysis Population Description

ITT population: all patients who were randomised and received at least 1 dose of study treatment (either ladarixin or placebo).

Please note that the number of participants analysed represents the number of patients contributing to summary statistics.


Arm/Group Title		Ladarixin	Placebo
Arm/Group Description:		Ladarixin oral capsule ...	Placebo oral capsule ...
Arm/Group Description:		Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Overall Number of Participants Analyzed		26	11
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of patients
FU week 13	Number Analyzed	26 participants	11 participants
FU week 13		88.5 (69.85 to 97.55)	63.6 (30.79 to 89.07)
FU week 26	Number Analyzed	25 participants	9 participants
FU week 26		88.5 (69.85 to 97.55)	36.4 (10.93 to 69.21)
FU week 52	Number Analyzed	25 participants	10 participants
FU week 52		65.4 (44.33 to 82.79)	45.5 (16.75 to 76.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.163
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 26
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0074
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 52
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4437
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Adverse Events

Time Frame	AEs were recorded and reported in the CRF from enrollment throughout patient's participation in the study (last planned visit or early withdrawal date), an average of 3 years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Ladarixin		Placebo
Arm/Group Description	Ladarixin oral capsule ...		Placebo oral capsule ...
Arm/Group Description	Ladarixin oral capsule Ladarixin: Ladarixin oral capsule		Placebo oral capsule Placebo: Placebo oral capsule
All-Cause Mortality
	Ladarixin		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/50 (0.00%)		0/26 (0.00%)
Serious Adverse Events Serious Adverse Events
	Ladarixin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/50 (6.00%)		1/26 (3.85%)
Gastrointestinal disorders
Gastrointestinal disorder ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Injury, poisoning and procedural complications
Clavicle fracture ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Laceration ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Metabolism and nutrition disorders
Hyperglycaemia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Psychiatric disorders
mental disorder ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
1 Term from vocabulary, MedDRA 19.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Ladarixin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/50 (74.00%)		21/26 (80.77%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Eosinophilia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Iron deficiency anaemia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Lymphadenopathy ^† 1	1/50 (2.00%)	2	0/26 (0.00%)	0
Lymphocytosis ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	2
Neutropenia ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Polycythaemia ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Cardiac disorders
Palpitations ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Ear and labyrinth disorders
Ear discomfort ^† 1	1/50 (2.00%)	2	0/26 (0.00%)	0
Ear pain ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Gastrointestinal disorders
abdominal discomfort ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Abdominal pain ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Abdominal pain upper ^† 1	3/50 (6.00%)	4	2/26 (7.69%)	2
Constipation ^† 1	2/50 (4.00%)	3	0/26 (0.00%)	0
Dental caries ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Diarrhoea ^† 1	2/50 (4.00%)	2	2/26 (7.69%)	2
Dyspepsia ^† 1	6/50 (12.00%)	9	0/26 (0.00%)	0
Dysphagia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Faeces hard ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Gatroesophageal reflux disease ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Hyperchlorhydria ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Nausea ^† 1	3/50 (6.00%)	4	3/26 (11.54%)	4
Odynophagia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Pancreatitis chronic ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Toothache ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Vomiting ^† 1	2/50 (4.00%)	2	1/26 (3.85%)	1
General disorders
Asthenia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Fatigue ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Injection site reaction ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Malaise ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Pyrexia ^† 1	6/50 (12.00%)	7	2/26 (7.69%)	3
Sensation of foreign body ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Hepatobiliary disorders
Hyperbilirubinaemia ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Immune system disorders
Anaphylactic reaction ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Drug hypersensitivity ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Hypersensitivity ^† 1	0/50 (0.00%)	0	2/26 (7.69%)	3
Infections and infestations
Bronchitis ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Cystitis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Ear infection ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Eye infection ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Folliculitis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Gastroenteritis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Gastroeteritis viral ^† 1	1/50 (2.00%)	1	3/26 (11.54%)	3
Gingivitis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Infected bite ^† 1	1/50 (2.00%)	2	0/26 (0.00%)	0
Influenza ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Laryngitis ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	2
Oral herpes ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Pharyngitis ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Sinusitis ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	2
Tinea pedis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Tonsillitis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Tooth abscess ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Upper respiratory tract infection ^† 1	3/50 (6.00%)	3	1/26 (3.85%)	1
Urinary tract infection ^† 1	2/50 (4.00%)	2	1/26 (3.85%)	1
Viral infection ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Viral upper respiratory tract infection ^† 1	13/50 (26.00%)	19	4/26 (15.38%)	6
Injury, poisoning and procedural complications
Alcohol poisoning ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Contusion ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Fall ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Joint injury ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Ligament sprain ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Limb injury ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Muscle injury ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Skin wound ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Sunburn ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Investigations
Alanine aminotransferase increased ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Aspartate aminotransferase increased ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Blood bilirubin increased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Blood iron decreased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
C-reactive protein increased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Eosinophil count decreased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Glycosylated haemoglobin increased ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Haemoglobin increased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Vitamin D decreased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Weight increased ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Hyperglycaemia ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Hypoglycaemia ^† 1	4/50 (8.00%)	7	1/26 (3.85%)	2
Iron deficiency ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	3/50 (6.00%)	4	0/26 (0.00%)	0
Back pain ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	3
Muscle spasms ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Myalgia ^† 1	1/50 (2.00%)	3	0/26 (0.00%)	0
Osteoarthritis ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Pain in extremity ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Nervous system disorders
Dizziness ^† 1	3/50 (6.00%)	3	1/26 (3.85%)	1
Headache ^† 1	14/50 (28.00%)	20	6/26 (23.08%)	8
Migrane ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Syncope ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Psychiatric disorders
Depression ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Emotional distress ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Insomnia ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Renal and urinary disorders
Polyuria ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Reproductive system and breast disorders
Breast pain ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Dysmenorrhoea ^† 1	2/50 (4.00%)	4	0/26 (0.00%)	0
Nipple inflammation ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Cough ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Increased viscosity of upper respiratiory secretion ^† 1	1/50 (2.00%)	4	0/26 (0.00%)	0
Oropharyngeal pain ^† 1	4/50 (8.00%)	5	0/26 (0.00%)	0
Vocal cord inflammation ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Skin and subcutaneous tissue disorders
Acne ^† 1	1/50 (2.00%)	1	0/26 (0.00%)	0
Alopecia ^† 1	1/50 (2.00%)	1	1/26 (3.85%)	1
Rash ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Surgical and medical procedures
Diabetes mellitus management ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
Tooth extraction ^† 1	2/50 (4.00%)	2	0/26 (0.00%)	0
Vascular disorders
Hypertension ^† 1	0/50 (0.00%)	0	1/26 (3.85%)	1
1 Term from vocabulary, MedDRA 19.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Pier Adelchi Ruffini, MD
Organization:	Dompé Farmaceutici SpA
Phone:	+39 02583831
EMail:	pieradelchi.ruffini@dompe.com

Layout table for additonal information

Responsible Party:	Dompé Farmaceutici S.p.A
ClinicalTrials.gov Identifier:	NCT02814838
Other Study ID Numbers:	MEX0114 2014-003968-20 ( EudraCT Number )
First Submitted:	June 13, 2016
First Posted:	June 28, 2016
Results First Submitted:	November 16, 2020
Results First Posted:	January 12, 2021
Last Update Posted:	January 12, 2021

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