A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02814838
• Collaborator: (none)
• Enrollment: 76
• Locations: 8
• Arms: 2
• Actual Duration (Months): 33.4
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.

The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Insulin-Dependent	Drug: Ladarixin; Drug: Placebo	Phase 2

Detailed Description

T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.

T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.

Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.

Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.

As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.

Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of 400 mg Twice a Day Oral Ladarixin in Patients With New-onset Type 1 Diabetes
• Actual Study Start Date: Aug 1, 2016
• Actual Primary Completion Date: May 15, 2019
• Actual Study Completion Date: May 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ladarixin Ladarixin oral capsule	Drug: Ladarixin; Ladarixin oral capsule; Other Names: Active treatment
Placebo Comparator: Placebo Placebo oral capsule	Drug: Placebo; Placebo oral capsule; Other Names: Placebo treatment

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve (AUC)(0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Week 13 [week 13±1]

   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.

Secondary Outcome Measures

1. Area Under the Curve (AUC) (0-2 h) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at Weeks 26 and 52 [Follow-ups at Weeks 26±2 and 52±2]

   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.

2. Percent Change From Baseline of 2-hour AUC of C-peptide Response to the MMTT [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

3. Change From Screening in Average (Previous 3 Days) Insulin Requirement [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

4. Change From Screening in Glycated Haemoglobin (HbA1c) Levels [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

5. Basal to 180 Minutes Time Course of C-peptide Concentration Derived From the MMTT [Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2]

   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.

6. Basal to 180 Minutes Time Course of Glucose Concentration Derived From the MMTT [Baseline, follow-ups at Weeks 13±1, 26±2, and 52±2]

   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.

7. Cumulative Severe Hypoglycaemic Events Occurring From Randomisation by Visit [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

8. Proportion of Patients Maintaining a Residual β-cell Function [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

9. Proportion of Patients With HbA1c <7% and Absence of Episodes of Severe Hypoglycaemia From the Previous Visit [Follow-ups at Weeks 13±1, 26±2 and 52±2]

   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.

10. C-peptide AUC(15 to 120 Mins) Above Fasting Value [Follow-ups at Weeks 13±1 26±2 and 52±2]

    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

11. Area Under the Curve (AUC) (0-2 h) of C-peptide MMTT in Patients With Screening C-peptide < Median Value [Follow-up at Weeks 13±1, 26±2, and 52±2.]

    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.

12. Area Under the Curve (AUC) (15-120 Min) of C-peptide MMTT Above Fasting Value in Patients With Screening C-peptide < Median Value [Follow-up at Weeks 13±1, 26±2, and 52±2.]

    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.

13. 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 [Follow-up at Weeks 13±1, 26±2, and 52±2]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female patients aged 18-45 years, inclusive;

2. New-onset T1D (randomization 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, with the exclusion of patients taking twice daily pre-mixed insulin or on insulin pump;

5. Residual β-cell function as per peak stimulated (MMTT) C-peptide level >0.6ng/mL (0.2nmol/L); MMTT should not be performed within one week of resolution of a diabetic ketoacidosis event;

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. Patients taking twice daily pre-mixed insulin or on insulin pump;

2. 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;

3. Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976);

4. 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];

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

6. QTcF > 470 msec;

7. Complete Left Bundle Branch Block (LBBB), atrio-ventricular block (mobitz II 2nd degree or 2:1 atrio-ventricular block), complete heart block;

8. Electronic pacemaker positioned or implanted defibrillator;

9. History of significant cardiovascular disease;

10. Known hypersensitivity to non-steroidal antiinflammatory drugs;

11. Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day);

12. Previous (within 2 weeks prior to randomization) and concomitant treatment with metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. β-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.);

13. 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;

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 an 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitair Ziekenhuis Brussel Diabetes Clinic	Brussels		Belgium	1090
2	Universitair Ziekenhuis Leuven Campus Gasthuisberg Endocrinology	Leuven		Belgium	3000
3	Med. Klinik und Poliklinik 3, Universitätsklinikum Giessen und Marburg GmbH	Giessen		Germany	32392
4	Zentrum für Diabetes und Gefäßerkrankungen	Münster		Germany	48145
5	Università Aldo Moro-Ospedale Policlinico	Bari		Italy	70124
6	Presidio Policlinico di Monserrato	Cagliari		Italy	88554
7	Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan	Milan		Italy	20132
8	Unità Operativa Complessa di Endocrinologia e Dialettologia. Università Campus Bio-Medico di Roma	Rome		Italy	00128

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Principal Investigator: Emanuele Bosi, MD, Internal Medicine - Diabetes & Endocrinology Unit, San Raffaele Hospital Milan

Study Documents (Full-Text)

• Study Protocol - Apr 3, 2020
• Statistical Analysis Plan - Sep 17, 2019

More Information

Publications

None provided.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT02814838
• Other Study ID Numbers: MEX0114; 2014-003968-20
• First Posted: Jun 28, 2016
• Last Update Posted: Sep 27, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Dompé Farmaceutici S.p.A: Diabetes mellitus Type 1; Beta cells function
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1

Study Results

Participant Flow

Arm/Group Title	Ladarixin	Placebo
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

Baseline Characteristics

Arm/Group Title	Ladarixin	Placebo	Total
Arm/Group Description	Ladarixin oral capsule Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule	Total of all reporting groups
Overall Participants	50	26	76
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	50 100%	26 100%	76 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	21 42%	10 38.5%	31 40.8%
Male	29 58%	16 61.5%	45 59.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2%	0 0%	1 1.3%
White	49 98%	26 100%	75 98.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Belgium	20 40%	11 42.3%	31 40.8%
Italy	17 34%	10 38.5%	27 35.5%
Germany	13 26%	5 19.2%	18 23.7%

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	49	26
Mean (Standard Deviation) [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
Statistical Test of Hypothesis	p-Value	0.3303
	Comments
	Method	Student's t test for unpaired samples
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	47	25
FU week 26	3.9351 (0.51710)	3.8076 (0.76473)
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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0984
	Confidence Interval	(2-Sided) 95%; -0.2028 to 0.3995
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0486
	Confidence Interval	(2-Sided) 95%; -0.4294 to 0.3322
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	49	25
FU week 13	5.7818 (36.74477)	-6.0734 (38.22179)
FU week 26	-0.8701 (42.93044)	-13.7347 (37.41900)
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
Statistical Test of Hypothesis	p-Value	0.2224
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	12.0411
	Confidence Interval	(2-Sided) 95%; -7.3823 to 31.4644
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3931
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	8.4803
	Confidence Interval	(2-Sided) 95%; -11.0935 to 28.0541
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7664
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-2.9502
	Confidence Interval	(2-Sided) 95%; -22.5476 to 16.6473
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Screening in Average (Previous 3 Days) Insulin Requirement
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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	47	26
FU week 13	-0.067 (0.1774)	-0.018 (0.1314)
FU week 26	-0.011 (0.2625)	0.032 (0.1699)
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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.048
	Confidence Interval	(2-Sided) 95%; -0.1257 to 0.0298
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0369
	Confidence Interval	(2-Sided) 95%; -0.1596 to 0.0858
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.063
	Confidence Interval	(2-Sided) 95%; -0.1712 to 0.0453
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Screening in Glycated Haemoglobin (HbA1c) Levels
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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	48	25
FU week 13	-1.40 (1.674)	-1.18 (1.352)
FU week 26	-1.19 (2.003)	-0.63 (1.141)
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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.1494
	Confidence Interval	(2-Sided) 95%; -0.7514 to 0.4526
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.2804
	Confidence Interval	(2-Sided) 95%; -0.8904 to 0.3297
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.2063
	Confidence Interval	(2-Sided) 95%; -0.3992 to 0.8118
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	50	26
Screening - Basal average	0.218 (0.1087)	0.225 (0.1416)
Screening - 15 min	0.294 (0.1621)	0.299 (0.1779)
Screening - 30 min	0.422 (0.2126)	0.452 (0.3036)
Screening - 60 min	0.545 (0.2631)	0.537 (0.2354)
Screening - 90 min	0.613 (0.2467)	0.581 (0.2486)
Screening - 120 min	0.620 (0.2559)	0.656 (0.2923)
Screening - 180 min	0.527 (0.2252)	0.550 (0.2277)
week 13 - Basal average	0.231 (0.1136)	0.210 (0.1315)
week 13 - 15 min	0.300 (0.1385)	0.285 (0.1956)
week 13 - 30 min	0.427 (0.2048)	0.392 (0.2418)
week 13 - 60 min	0.571 (0.2660)	0.523 (0.2729)
week 13 - 90 min	0.620 (0.2859)	0.594 (0.3176)
week 13 - 120 min	0.637 (0.2869)	0.601 (0.3050)
week 13 - 180 min	0.518 (0.2302)	0.527 (0.2778)
week 26 - Basal average	0.212 (0.0941)	0.207 (0.1192)
week 26 - 15 min	0.278 (0.1294)	0.260 (0.1426)
week 26 - 30 min	0.391 (0.1857)	0.368 (0.2150)
week 26 - 60 min	0.534 (0.2463)	0.511 (0.2967)
week 26 - 90 min	0.569 (0.2606)	0.552 (0.3101)
week 26 - 120 min	0.592 (0.2703)	0.552 (0.2907)
week 26 - 180 min	0.504 (0.2189)	0.466 (0.2362)
week 52 - Basal average	0.168 (0.1070)	0.178 (0.1068)
week 52 - 15 min	0.228 (0.1606)	0.249 (0.1616)
week 52 - 30 min	0.321 (0.2231)	0.314 (0.1826)
week 52 - 60 min	0.430 (0.2693)	0.440 (0.2671)
week 52 - 90 min	0.463 (0.2806)	0.465 (0.2881)
week 52 - 120 min	0.503 (0.3085)	0.492 (0.2717)
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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0242
	Confidence Interval	(2-Sided) 95%; -0.0174 to 0.0658
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0236
	Confidence Interval	(2-Sided) 95%; -0.0188 to 0.066
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0059
	Confidence Interval	(2-Sided) 95%; -0.0485 to 0.0367
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	50	26
Screening - basal average	6.965 (1.6858)	6.855 (1.9507)
Screening - 15 min	8.108 (1.8453)	8.013 (2.0941)
Screening - 30 min	10.438 (2.2282)	10.096 (2.4694)
Screening - 60 min	12.146 (2.9387)	12.068 (2.9204)
Screening - 90 min	12.350 (3.4122)	12.076 (3.9156)
Screening - 120 min	11.400 (3.4561)	11.827 (4.0204)
Screening - 180 min	9.478 (3.6320)	9.652 (4.0549)
Week 13 - Basal average	7.074 (1.9973)	6.644 (2.1145)
Week 13 - 15 min	8.231 (2.1415)	7.836 (2.2409)
Week 13 - 30 min	10.727 (2.5691)	10.224 (2.3600)
Week 13 - 60 min	12.614 (3.1536)	12.871 (2.6908)
Week 13 - 90 min	12.553 (3.7998)	13.092 (3.1608)
Week 13 - 120 min	11.773 (4.0990)	12.260 (3.7590)
Week 13 - 180 min	9.761 (3.9834)	9.984 (3.8597)
Week 26 - Basal average	7.496 (2.0261)	7.600 (2.6387)
Week 26 - 15 min	8.750 (2.0827)	9.058 (2.7026)
Week 26 - 30 min	10.927 (2.3901)	11.240 (2.6187)
Week 26 - 60 min	13.494 (2.8623)	14.222 (2.8795)
Week 26 - 90 min	13.665 (3.8399)	15.020 (3.4469)
Week 26 - 120 min	13.240 (4.1302)	14.424 (3.7761)
Week 26 - 180 min	10.956 (4.2031)	12.028 (3.8832)
Week 52 - Basal average	7.457 (2.3045)	8.163 (2.2251)
Week 52 - 15 min	8.939 (2.7210)	9.544 (2.2230)
Week 52 - 30 min	11.374 (2.6806)	11.688 (2.6411)
Week 52 - 60 min	14.315 (3.1205)	14.725 (2.9631)
Week 52 - 90 min	14.911 (3.5768)	15.276 (3.7144)
Week 52 - 120 min	14.354 (3.9162)	15.140 (3.7514)
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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.0253
	Confidence Interval	(2-Sided) 95%; -0.5986 to 0.548
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.7236
	Confidence Interval	(2-Sided) 95%; -1.2989 to -0.1483
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	-0.5979
	Confidence Interval	(2-Sided) 95%; -1.1775 to -0.0184
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	50	26
FU week 13	0.0 (0.0)	0.0 (0.0)
FU Week 26	0.0 (0.14)	0.0 (0.20)
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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	49	26
FU Week 13	96.0	88.5
FU week 26	86.0	84.6
FU Week 52	78.0	76.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1171
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6586
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5056
	Comments
	Method	Fisher Exact
	Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	49	25
FU Week 13	90.0	73.1
FU week 26	78.0	50.0
FU Week 52	62.0	53.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	at week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0779
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 26
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0248
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	At week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4504
	Comments
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	C-peptide AUC(15 to 120 Mins) Above Fasting Value
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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	50	26
FU Week 13	3.3736	3.2334
FU week 26	3.2419	3.0649
FU week 52	2.9733	2.9282

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.1402
	Confidence Interval	(2-Sided) 95%; -0.2015 to 0.4819
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.177
	Confidence Interval	(2-Sided) 95%; -0.2039 to 0.558
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	adjusted mean difference
	Estimated Value	0.0451
	Confidence Interval	(2-Sided) 95%; -0.3948 to 0.4851
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	26	11
FU Week 13	3.8085 (0.45692)	3.4543 (0.86632)
FU Week 26	3.8202 (0.48142)	3.3178 (0.91906)
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
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.354
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.502
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.223
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	26	11
FU week 13	3.1590 (0.56135)	2.7959 (1.07745)
FU week 26	27.7841 (15.10337)	18.6842 (15.46837)
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
Statistical Test of Hypothesis	p-Value	0.1847
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.3631
	Confidence Interval	(2-Sided) 95%; -0.1817 to 0.908
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.6304
	Confidence Interval	(2-Sided) 95%; 0.0609 to 1.1998
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.6299
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.1639
	Confidence Interval	(2-Sided) 95%; -0.5202 to 0.8479
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 Ladarixin: Ladarixin oral capsule	Placebo oral capsule Placebo: Placebo oral capsule
Measure Participants	26	11
FU week 13	88.5	63.6
FU week 26	88.5	36.4
FU week 52	65.4	45.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.163
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 26
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ladarixin, Placebo
	Comments	Week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4437
	Comments
	Method	Fisher Exact
	Comments

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
Arm/Group Title	Ladarixin		Placebo
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/26 (0%)
Serious Adverse Events
	Ladarixin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/50 (6%)		1/26 (3.8%)
Gastrointestinal disorders
Gastrointestinal disorder	1/50 (2%)	1	0/26 (0%)	0
Injury, poisoning and procedural complications
Clavicle fracture	1/50 (2%)	1	0/26 (0%)	0
Laceration	0/50 (0%)	0	1/26 (3.8%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/50 (2%)	1	0/26 (0%)	0
Psychiatric disorders
mental disorder	1/50 (2%)	1	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	Ladarixin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/50 (74%)		21/26 (80.8%)
Blood and lymphatic system disorders
Anaemia	1/50 (2%)	1	0/26 (0%)	0
Eosinophilia	1/50 (2%)	1	0/26 (0%)	0
Iron deficiency anaemia	1/50 (2%)	1	0/26 (0%)	0
Lymphadenopathy	1/50 (2%)	2	0/26 (0%)	0
Lymphocytosis	0/50 (0%)	0	1/26 (3.8%)	2
Neutropenia	1/50 (2%)	1	1/26 (3.8%)	1
Polycythaemia	0/50 (0%)	0	1/26 (3.8%)	1
Cardiac disorders
Palpitations	0/50 (0%)	0	1/26 (3.8%)	1
Ear and labyrinth disorders
Ear discomfort	1/50 (2%)	2	0/26 (0%)	0
Ear pain	1/50 (2%)	1	0/26 (0%)	0
Gastrointestinal disorders
abdominal discomfort	1/50 (2%)	1	0/26 (0%)	0
Abdominal pain	1/50 (2%)	1	0/26 (0%)	0
Abdominal pain upper	3/50 (6%)	4	2/26 (7.7%)	2
Constipation	2/50 (4%)	3	0/26 (0%)	0
Dental caries	1/50 (2%)	1	0/26 (0%)	0
Diarrhoea	2/50 (4%)	2	2/26 (7.7%)	2
Dyspepsia	6/50 (12%)	9	0/26 (0%)	0
Dysphagia	1/50 (2%)	1	0/26 (0%)	0
Faeces hard	1/50 (2%)	1	0/26 (0%)	0
Gatroesophageal reflux disease	1/50 (2%)	1	1/26 (3.8%)	1
Hyperchlorhydria	2/50 (4%)	2	0/26 (0%)	0
Nausea	3/50 (6%)	4	3/26 (11.5%)	4
Odynophagia	1/50 (2%)	1	0/26 (0%)	0
Pancreatitis chronic	1/50 (2%)	1	0/26 (0%)	0
Toothache	1/50 (2%)	1	1/26 (3.8%)	1
Vomiting	2/50 (4%)	2	1/26 (3.8%)	1
General disorders
Asthenia	1/50 (2%)	1	0/26 (0%)	0
Fatigue	1/50 (2%)	1	0/26 (0%)	0
Injection site reaction	0/50 (0%)	0	1/26 (3.8%)	1
Malaise	0/50 (0%)	0	1/26 (3.8%)	1
Pyrexia	6/50 (12%)	7	2/26 (7.7%)	3
Sensation of foreign body	1/50 (2%)	1	0/26 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/50 (0%)	0	1/26 (3.8%)	1
Immune system disorders
Anaphylactic reaction	0/50 (0%)	0	1/26 (3.8%)	1
Drug hypersensitivity	1/50 (2%)	1	0/26 (0%)	0
Hypersensitivity	0/50 (0%)	0	2/26 (7.7%)	3
Infections and infestations
Bronchitis	0/50 (0%)	0	1/26 (3.8%)	1
Cystitis	1/50 (2%)	1	0/26 (0%)	0
Ear infection	1/50 (2%)	1	0/26 (0%)	0
Eye infection	1/50 (2%)	1	0/26 (0%)	0
Folliculitis	1/50 (2%)	1	0/26 (0%)	0
Gastroenteritis	1/50 (2%)	1	0/26 (0%)	0
Gastroeteritis viral	1/50 (2%)	1	3/26 (11.5%)	3
Gingivitis	1/50 (2%)	1	0/26 (0%)	0
Infected bite	1/50 (2%)	2	0/26 (0%)	0
Influenza	0/50 (0%)	0	1/26 (3.8%)	1
Laryngitis	1/50 (2%)	1	1/26 (3.8%)	2
Oral herpes	2/50 (4%)	2	0/26 (0%)	0
Pharyngitis	1/50 (2%)	1	1/26 (3.8%)	1
Sinusitis	0/50 (0%)	0	1/26 (3.8%)	2
Tinea pedis	1/50 (2%)	1	0/26 (0%)	0
Tonsillitis	1/50 (2%)	1	0/26 (0%)	0
Tooth abscess	1/50 (2%)	1	0/26 (0%)	0
Upper respiratory tract infection	3/50 (6%)	3	1/26 (3.8%)	1
Urinary tract infection	2/50 (4%)	2	1/26 (3.8%)	1
Viral infection	1/50 (2%)	1	0/26 (0%)	0
Viral upper respiratory tract infection	13/50 (26%)	19	4/26 (15.4%)	6
Injury, poisoning and procedural complications
Alcohol poisoning	1/50 (2%)	1	0/26 (0%)	0
Contusion	1/50 (2%)	1	0/26 (0%)	0
Fall	1/50 (2%)	1	0/26 (0%)	0
Joint injury	1/50 (2%)	1	0/26 (0%)	0
Ligament sprain	1/50 (2%)	1	1/26 (3.8%)	1
Limb injury	0/50 (0%)	0	1/26 (3.8%)	1
Muscle injury	1/50 (2%)	1	0/26 (0%)	0
Skin wound	1/50 (2%)	1	0/26 (0%)	0
Sunburn	0/50 (0%)	0	1/26 (3.8%)	1
Investigations
Alanine aminotransferase increased	1/50 (2%)	1	0/26 (0%)	0
Aspartate aminotransferase increased	2/50 (4%)	2	0/26 (0%)	0
Blood bilirubin increased	0/50 (0%)	0	1/26 (3.8%)	1
Blood iron decreased	0/50 (0%)	0	1/26 (3.8%)	1
C-reactive protein increased	0/50 (0%)	0	1/26 (3.8%)	1
Eosinophil count decreased	0/50 (0%)	0	1/26 (3.8%)	1
Glycosylated haemoglobin increased	1/50 (2%)	1	0/26 (0%)	0
Haemoglobin increased	0/50 (0%)	0	1/26 (3.8%)	1
Vitamin D decreased	0/50 (0%)	0	1/26 (3.8%)	1
Weight increased	0/50 (0%)	0	1/26 (3.8%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia	1/50 (2%)	1	1/26 (3.8%)	1
Hyperglycaemia	1/50 (2%)	1	0/26 (0%)	0
Hypoglycaemia	4/50 (8%)	7	1/26 (3.8%)	2
Iron deficiency	1/50 (2%)	1	0/26 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/50 (6%)	4	0/26 (0%)	0
Back pain	1/50 (2%)	1	1/26 (3.8%)	3
Muscle spasms	1/50 (2%)	1	0/26 (0%)	0
Myalgia	1/50 (2%)	3	0/26 (0%)	0
Osteoarthritis	1/50 (2%)	1	0/26 (0%)	0
Pain in extremity	0/50 (0%)	0	1/26 (3.8%)	1
Nervous system disorders
Dizziness	3/50 (6%)	3	1/26 (3.8%)	1
Headache	14/50 (28%)	20	6/26 (23.1%)	8
Migrane	1/50 (2%)	1	0/26 (0%)	0
Syncope	1/50 (2%)	1	1/26 (3.8%)	1
Psychiatric disorders
Depression	1/50 (2%)	1	0/26 (0%)	0
Emotional distress	2/50 (4%)	2	0/26 (0%)	0
Insomnia	2/50 (4%)	2	0/26 (0%)	0
Renal and urinary disorders
Polyuria	0/50 (0%)	0	1/26 (3.8%)	1
Reproductive system and breast disorders
Breast pain	0/50 (0%)	0	1/26 (3.8%)	1
Dysmenorrhoea	2/50 (4%)	4	0/26 (0%)	0
Nipple inflammation	1/50 (2%)	1	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/50 (2%)	1	0/26 (0%)	0
Cough	1/50 (2%)	1	1/26 (3.8%)	1
Increased viscosity of upper respiratiory secretion	1/50 (2%)	4	0/26 (0%)	0
Oropharyngeal pain	4/50 (8%)	5	0/26 (0%)	0
Vocal cord inflammation	0/50 (0%)	0	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Acne	1/50 (2%)	1	0/26 (0%)	0
Alopecia	1/50 (2%)	1	1/26 (3.8%)	1
Rash	0/50 (0%)	0	1/26 (3.8%)	1
Surgical and medical procedures
Diabetes mellitus management	0/50 (0%)	0	1/26 (3.8%)	1
Tooth extraction	2/50 (4%)	2	0/26 (0%)	0
Vascular disorders
Hypertension	0/50 (0%)	0	1/26 (3.8%)	1

Limitations/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.