Clinical trial NCT03434119
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi
Start date: 2018-02-20; Completion date: 2019-01-07
Enrollment: 241 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

* To demonstrate the superiority of Soliqua 100/33 versus Lantus in the hemoglobin A1c (HbA1c) change within the overall population.
* To demonstrate the benefit of Soliqua 100/33 versus Lantus in the HbA1c within each ethnic/racial subgroup evaluated (ie, Hispanics of any race, non-Hispanic black/African Americans and non-Hispanic Asians).

Secondary Objective:

* To assess the effects of Soliqua 100/33 versus Lantus on the secondary efficacy parameters within each ethnic/racial subgroup evaluated.
* To assess the change in daily insulin glargine dose within each ethnic/racial subgroup.
* To evaluate the safety and tolerability (e.g., gastrointestinal tolerability) of Soliqua 100/33 versus Lantus within each ethnic/racial subgroup.

Detailed description:
The study duration was approximately 29 weeks including 2 weeks screening period, 26 weeks open label treatment period, and a 3 days follow-up period.

Arms: arm 1: Soliqua 100/33 (Insulin glargine/lixisenatide) once daily in the morning within 1 hour before breakfast, on top of oral anti-diabetic drug (OAD) therapy for 26 weeks. arm 2: Lantus (Insulin glargine) once daily at any time of the day but at about the same time every day on top of OAD therapy for 26 weeks.
Interventions: intervention 1: Insulin glargine/Lixisenatide intervention 2: Insulin glargine (HOE901) intervention 3: Background therapy
Intervention descriptions: intervention 1: Insulin glargine (100 units per milliliter \[U/mL\]) and lixisenatide (33 micrograms per milliliter \[mcg/mL\]) self administered by a subcutaneous injection using a prefilled pen. Dose was individually titrated to achieve target fasting self-monitoring of plasma glucose (SMPG) of 80 to 100 milligrams per deciliter (mg/dL) (4.4 to 5.6 millimoles per liter \[mmol/L\]) while avoiding hypoglycemia. intervention 2: Insulin glargine 100 U/mL self-administered by a subcutaneous injection using a prefilled pen. Dose was individually titrated to achieve target fasting SMPG of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia. intervention 3: Oral Anti diabetics Drugs (OADs) administered orally according to the locally approved label.

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
COMPOUND: SOLIQUA™ 100/33 
A 26-week randomized, open-label, active-controlled, 2-treatment arm, 
parallel-group multi-center study, comparing the efficacy and safety of 
Soliqua™100/33 versus Lantus® in ethnically/racially diverse patients with Type 2 
diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic 
agents  
STUDY NUMBER: LPS14860 
STUDY NAME: LixiLan-D (DIVERSITY) 
VERSION DATE / STATUS: Approval date (18-Dec-2017) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 18-Dec-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 17-Jul-2017 
EudraCT  
Not applicable 
IND Number(s) 
105157 
Version Number: 
1 
WHO universal trial number 
Not applicable 
Date: 
18-Dec-2017 
Total number of pages: 
99 
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NCT Number: NCT03434119


Amended Clinical Trial Protocol 01  
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: SOLIQUA 100/33 
STUDY No.: LPS14860  
STUDY NAME: LixiLan-D (Diversity) 
TITLE 
A 26-week randomized, open-label, active-controlled, 2-treatment arm, 
parallel-group  
multi-center study, comparing the efficacy and safety of Soliqua™ 100/33 
versus Lantus® in ethnically/racially diverse patients with Type 2 diabetes 
mellitus inadequately controlled on basal insulin and oral antidiabetic agents 
INVESTIGATOR/TRIAL LOCATION 
United States: Multicenter 
PHASE OF DEVELOPMENT 
3b 
STUDY OBJECTIVES 
 
Primary objective: 
• 
To demonstrate the superiority of Soliqua 100/33 versus Lantus in 
the hemoglobin A1c (HbA1c) change from baseline to Week 26 
within the overall population 
• 
To demonstrate the benefit of Soliqua 100/33 versus Lantus in the 
HbA1c change from baseline to Week 26 within each ethnic/racial 
subgroup evaluated (ie, Hispanics of any race, non-Hispanic 
black/African Americans and non-Hispanic Asians)  
Secondary objectives: 
• 
To assess the effects of Soliqua 100/33 versus Lantus on the 
secondary efficacy parameters to Week 26 (see “Study 
Endpoints”) within each ethnic/racial subgroup evaluated 
• 
To assess the change from baseline to Week 26 in daily insulin 
glargine dose within each ethnic/racial subgroup 
• 
To evaluate the safety and tolerability (eg, gastrointestinal 
tolerability) of Soliqua 100/33 versus Lantus to Week 26 within 
each ethnic/racial subgroup 
Other objectives: 
• 
To assess the effects of Soliqua 100/33 versus Lantus on the 
other efficacy parameters to Week 26 for the selected endpoints 
(see “Study Endpoints”) within each ethnic/racial subgroup 
evaluated 
• 
To assess the effects of Soliqua 100/33 versus Lantus on efficacy 
and safety parameters to Week 26 in the overall population 
• 
To evaluate and compare the effect of Soliqua 100/33 versus 
Lantus on Patient Reported Outcome (PRO) measures to Week 26 
within each ethnic/racial subgroup 
STUDY DESIGN 
Open-label, 1:1 randomized, active-controlled, 26-week duration,  
parallel-group, multicenter, US-only, Phase 3b study to compare the efficacy 
and safety of Soliqua 100/33 to Lantus overall and in ethnically/racially 
diverse groups with Type 2 diabetes mellitus (T2DM) inadequately controlled 
on basal insulin and on 1 or 2 oral antidiabetic (OAD) agents. The patients 
will be randomized according to their self-reported ethnicity/race 
(ie, Hispanics of any race, non-Hispanic black/African Americans and 
non-Hispanic Asians); randomization will be capped to include an 
approximately similar numbers of patients (ie, 400) within each ethnic/racial 
subgroup, with approximately 200 patients per ethnic/racial group receiving 
Soliqua 100/33 and approximately 200 receiving Lantus. Additionally, to 
ensure a balanced investigational medicinal product (IMP) allocation, 
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randomization will be stratified by their self-reported ethnic/racial group, 
screening HbA1c value (<8.5% versus ≥8.5%), the background use of 
sodium-glucose co-transporter 2 (SGLT-2) inhibitors (yes/no) and the 
background use of sulfonylureas (SUs) (yes/no). Patients will participate in 1 
of 2 ways, either at a traditional ‘brick & mortar’ investigational site, or fully 
remotely through a virtual (telemedicine) arrangement.  
The study will consist of 3 periods: 
• 
An up to 2-week screening period  
• 
A 26-week open-label randomized treatment period: at the end of 
the screening period (Week 0, Visit 2) patients will be randomized 
to receive either Soliqua 100/33 or Lantus  
• 
A 3-day post-treatment safety follow-up period: patients will 
perform the safety follow-up visit 3 days after the Week 26 visit, 
except for those who prematurely and permanently discontinued 
IMP administration during the randomized treatment period, who 
should continue all study visits and assessments per protocol 
(except for the follow-up visit). 
The maximum study duration per patient will be approximately 29 weeks. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Patients with T2DM diagnosed at least 1 year prior to the 
screening visit (signing of informed consent); 
• 
Uncontrolled diabetes as demonstrated by a screening 
centrally-measured HbA1c between 7.5% and 10% (inclusive); 
• 
Patients who are Hispanics of any race, non-Hispanic 
black/African Americans or non-Hispanic Asians; 
Note: Decision for ethnic/racial inclusion will be made based on the 
patient’s self-identification. Mixed-race patients must select 1 of 
the above-mentioned categories. If such selection cannot be 
made, the candidate will be ineligible to participate in the study. 
• 
Patients who have been treated with any basal insulin (ie, glargine 
(100 U/mL or 300 U/mL), detemir, degludec, intermediate-acting 
[human NPH]) for at least 6 months prior to Visit 1; 
• 
The basal insulin regimen (ie, type of insulin and time/frequency of 
the injection) has been stable for at least 3 months prior to Visit 1; 
• 
The basal insulin dose has been stable (defined as up to ±20% 
[1/5 of the dose] variability) for at least 2 months prior to Visit 1 
within the following dose ranges: 
- 
15 to 50 units/day if HbA1c at Visit 1 is ≤8.5% and 
- 
15 to 40 units/day if HbA1c at Visit 1 is >8.5% 
• 
Patients receiving 1 or 2 of the following oral antidiabetic (OAD) 
drugs: metformin, pioglitazone/rosiglitazone, an SGLT-2 inhibitor 
or a SU, at stable doses for at least 12 weeks prior to Visit 1; 
• 
Metformin dose must have been ≥1500 mg/day or the Maximum 
Tolerated Dose (MTD), according to the Investigator’s judgment. 
• 
Sulfonylurea dose must be ≥ the half maximum approved dose 
according to the local label. For patients with an HbA1c <8%, the 
SU dose must be reduced by 50% starting with the day of initiation 
of IMP administration; subsequently, the dose can be up-titrated 
according to the Investigator’s judgment up to the dose previously 
taken by the patient. Additional increases in SU dose (above 
baseline dose) should not be made unless the patient is rescued, 
according to the protocol rescue procedures. 
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• 
Patients willing and able to perform self-monitoring of plasma 
glucose (SMPG); 
• 
Signed written informed consent. 
Exclusion criteria: 
• 
Age <18 years of age at Visit 1; 
• 
A body mass index (BMI) ≤20 or >40 kg/m2 at Visit 1; 
• 
Fasting plasma glucose (FPG) >200 mg/dL (by central lab 
measurement) at Visit 1 (1-time repeat measurement before Visit 2 
is permitted); 
• 
Type 1 diabetes mellitus or any diabetes other than T2DM; 
• 
Any use of OAD drugs other than those described in the inclusion 
criteria (eg, but not limited to, glucagon-like peptide-1 receptor 
agonist [GLP-1 RA], dipeptidyl peptidase 4 [DPP4] inhibitors) 
within 12 weeks prior Visit 1; 
• 
Use of any other type of insulin except for basal insulin 
(eg, prandial or premixed insulin, insulin pump) within 6 months 
prior to Visit 1; 
Note: History of short-term treatment (ie, ≤10 days) with other 
insulin types due to intercurrent illness is permitted at the 
discretion of the Investigator. 
• 
Known history of discontinuation of treatment with a GLP-1 
receptor agonist due to safety/tolerability reasons; 
• 
Use of systemic glucocorticoids for a total duration of >7 days 
within 12 weeks prior to Visit 1; 
• 
Initiation/change in type or dose of a weight loss drug within 
12 weeks prior to Visit 1; 
• 
Use of an investigational drug within 1 month or 5 times the 
duration of the pharmacodynamic effect, whichever is longer, prior 
to Visit 1; 
• 
History of metabolic acidosis, including diabetic ketoacidosis within 
12 months prior to Visit 1; 
• 
History of stroke, myocardial infarction, unstable angina or heart 
failure requiring hospitalization within 6 months prior to Visit 1; 
planned hospitalization for any reason during the duration of the 
study; 
• 
Known history of drug or alcohol abuse within 6 months prior to 
Visit 1; 
• 
Clinically significant laboratory findings at Visit 1, including: 
- 
Amylase and/or lipase >3 times the upper limit of the normal 
(ULN) laboratory range 
- 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 times ULN 
- 
Positive serum pregnancy test; 
• 
Contraindication to Soliqua 100/33 or Lantus use, according to 
local label;  
• 
History of hypersensitivity to insulin glargine or lixisenatide, or to 
any of the excipients; 
• 
Contraindications to the specific background OADs that each 
individual patient is taking (as applicable), according to the local 
label; 
• 
An estimated glomerular filtration rate <30 mL/min/1.73m2 (more 
stringent renal function restrictions, depending on the patient’s 
background OAD use are to be applied, according to the local 
label and the Investigator’s judgment); 
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• 
History of pancreatitis (unless pancreatitis was related to 
gallstones and cholecystectomy was already performed), chronic 
pancreatitis, pancreatitis during a previous treatment with incretin 
therapies, pancreatectomy, stomach/gastric surgery; 
• 
Known history or presence of clinically-significant gastroparesis; 
• 
Pregnancy or lactation; women of childbearing potential not 
protected by highly-effective contraceptive methods (as defined in 
the Informed Consent) and/or who are unwilling or unable to be 
tested for pregnancy; planning pregnancy during the duration of 
the study; 
• 
Conditions/situations such as: 
- 
Patients with conditions/concomitant diseases making them 
non evaluable for the primary efficacy endpoint (eg, sickle cell 
anemia, hemoglobinopathy or hemolytic anemia, severe 
anemia [screening Hgb <8.0 g/dL; transfusion indicated], 
receipt of blood or plasma products within 12 weeks of  
Visit 1), 
- 
Patients with conditions/concomitant diseases precluding 
their safe participation in this study (eg, active malignant 
tumor, clinically-significant psychiatric disorders, major 
systemic diseases, presence of clinically significant diabetic 
retinopathy or presence of macular edema likely to require 
treatment within the study period), 
- 
Impossibility to meet specific protocol requirements (eg, 
scheduled visits, patients unable to fully understand patient’s 
study documents and to complete them), 
- 
Uncooperative patient or any condition that could make the 
patient potentially non-compliant to the study procedures (eg, 
patient unable or unwilling to do self-injections or blood 
glucose monitoring using the sponsor-provided blood glucose 
meter at home, etc), 
• 
Patient is the Investigator or any Sub-Investigator, research 
assistant, pharmacist, study coordinator, other staff or relative 
thereof directly involved in the conduct of the protocol. 
Total expected number of patients 
A sufficient number of patients will be screened to ensure randomization of 
approximately 1200 patients (approximately 600 in each treatment arm) with 
an approximately similar number of patients (ie, 400) within each 
ethnic/racial group (approximately 200 per group/treatment arm). 
Expected number of sites 
A sufficient number of sites including traditional brick and mortar and/or 
virtual (telemedicine) sites within the United States will be employed.  
STUDY TREATMENTS 
Tested drug:  
Investigational medicinal products 
formulation 
Soliqua 100/33 (insulin glargine/lixisenatide fixed ratio combination) is 
supplied for subcutaneous (SC) injection as a sterile aqueous solution in a 
3:1 ratio SoloStar® pen-injector. The prefilled disposable pen-injector 
contains 3 ml of sterile solution of 100 U/mL insulin glargine and 33 µg/mL 
lixisenatide in a ratio of 3 units (U) of insulin glargine to 1 µg lixisenatide and 
it allows administration of daily combination doses between 15 U/5 µg and 
60 U/20 µg. The dose of the combination is titrated according to the patient’s 
need for insulin. Only the insulin glargine dose appears in the device dosing 
window; the lixisenatide dose does not appear in the dose window although 
lixisenatide is premixed in the cartridge. The lixisenatide dose is increased or 
decreased concomitantly with insulin glargine dose change. 
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Control drug: 
Lantus (insulin glargine) is being supplied for SC injection as a sterile 
aqueous solution in a prefilled (disposable) Lantus SoloStar pen-injector 
containing a 3 mL solution of insulin glargine 100 U/mL. The disposable 
SoloStar pen-injector allows for a dose setting in the range of 1-80 U with a 
minimum dose increment of 1 U. 
Mixing of Soliqua 100/33 and Lantus with other insulins or dilution of the test 
drug is not permitted. 
Route(s) of administration: 
Subcutaneous injection 
Dose regimen: 
Injection time: 
Soliqua 100/33 should be self-administered once daily in the morning within 
1 hour (0 to 60 minutes) before breakfast. 
Lantus should be self-administered once daily at any time of the day but at 
about the same time every day. The injection time will be determined at the 
discretion of the patient and Investigator at the time of randomization and it 
should remain about the same (±120 minutes) until the end of the 
randomized treatment period. 
The first dose of IMP will be administered on the day of randomization 
(Day 1), either at the site (Soliqua 100/33 and Lantus on a morning (AM) 
dosing regimen) or outside the site location (Lantus administered on a 
regimen other than morning [PM]). If, due to logistical reasons, 
administration of IMP on the day of randomization is not possible, 
administration within the 3 days following randomization is permitted. 
Starting Dose: 
Soliqua 100/33  
• 
Patients on a background basal insulin dose <30 U/day (at the 
time of randomization): starting dose should be 15 U of insulin 
glargine (corresponding to 5 µg lixisenatide) 
• 
Patients on a background basal insulin dose ≥30 U/day (at the 
time of randomization): starting dose should be 30 U of insulin 
glargine (corresponding to 10 µg lixisenatide) 
Lantus: The initial dose will be the same as the background basal insulin 
dose at which the patient is randomized unless transitioning from U300 
insulin glargine, insulin administered twice daily or insulin detemir, when a 
20% (1/5) reduction in dose is required to initiate Lantus. 
Note: The 20% dose reduction recommendation for Lantus does not 
apply to Soliqua 100/33. 
Dose Adjustments: 
The same dose adjustment algorithm is recommended for Soliqua 100/33 
and Lantus. The insulin doses will be up-titrated by 2 U or a maximum of 
4 U/week (see algorithm in the table below), until the patient reaches a 
target fasting SMPG of 80 to 100 mg/dL (4.4 to 5.6 mmol/L), inclusive, 
without clinically significant hypoglycemia episodes.  
Good clinical judgment should be exercised when titrating the basal insulin 
dose. Study patients should be trained and retrained on an ongoing basis to 
ensure proper understanding of titration procedures and a very close 
communication between the patient and the study site will be required to 
ensure adequate titration with minimization of associated risks. 
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Week 12. Once the target SMPG has been achieved and until the end of the 
study, the basal insulin dose will be adjusted as necessary to maintain this 
fasting SMPG target according to the dose adjustment guidelines in  
Section 8.1.1.  
Recommended dose changes are to be based on a median of fasting 
SMPG values from the last 3 days (including the day of titration) measured 
by the patient using glucometers and accessories supplied by the Sponsor. 
Notes: A titration dose increase of 2 or 4 U for Soliqua 100/33 or Lantus 
may be split into 2 incremental dose steps, rather than implementing the 
entire dose increase at one time, if it is considered by the Investigator or 
medically-qualified designee to be in the best interest of the patient. 
Median of fasting SMPG values from 
last 3 days 
Insulin glargine 
dose adjustments (U/day) 
>140 mg/dL (>7.8 mmol/L) 
+ 4  
>100 and ≤140 mg/dL (>5.6 and 
≤7 8
l/L)
+ 2  
Glycemic target: >80 and ≤100 mg/dL 
(>4.4 and ≤5.6  mmol/L), inclusive 
No change 
≥60 and <80 mg/dL (≥3.3 and 
<4.4 mmol/L) 
-2  
<60 mg/dL (<3.3 mmol/L) or occurrence of 
2 (or more) symptomatic hypoglycemic 
episodes or  1 severe hypoglycemia. 
-2 to -4 or at the discretion of 
the Investigator or medically 
qualified designee 
Non-investigational medicinal 
products 
 
Background OAD Therapy 
Route(s) of administration: 
Dose regimen: 
 
Background OAD agents and rescue therapy will be considered as 
non-investigational medicinal products (NIMPs). 
 
 
Oral 
The type and dose of OAD (except rescue treatment or adjustment of the SU 
dose as per protocol) received by the patient at the time of Visit 1 will not be 
modified until the end of the study unless there is a specific safety 
issue/medical need related to this treatment.  
Rescue Therapy 
 
A rescue treatment is to be initiated, according to the Investigator’s judgment 
in the event that at (or after) Week 12, the HbA1c is >8%. 
AND IF: 
No explanation can be found for the insufficient glucose control (eg, 
infectious disease, lack of compliance with study treatment, non-compliance 
with diet and lifestyle requirements)  
The appropriate actions to correct potential triggering factors fail  
For patients randomized to Soliqua 100/33, an insulin glargine dose 
>60 units/day is necessary to decrease HbA1c below the threshold values 
(ie, further dose titration is not possible) and 
The HbA1c value exceeding the threshold is confirmed by repeat test 
(performed at the central laboratory) approximately 4 weeks after the initial 
measurement (or at a time point considered appropriate by the Investigator) 
Note: The 4-week HbA1c repeat may be waived if, according to the 
Investigator’s judgment, the patient does not have any precipitating factors 
leading to an elevated HbA1c that must be addressed and it is in the best 
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interest of the patient to initiate rescue therapy immediately. 
Rapid acting insulin (glulisine) is suggested to be utilized as rescue therapy 
and it should be started as a once-daily regimen administered prior to the 
main meal of the day (excluding breakfast). If, according to the Investigator’s 
judgment, rapid-acting insulin is not in the best interest of the patient, 
addition of an OAD (within the category of permitted background 
medications) or increases in the OAD doses already taken by the patient 
(according to the local label) may be considered as a secondary option for 
rescue therapy. 
Note: GLP-1 receptor agonists are not permitted as rescue therapy. 
All assessments planned for the 26-week end-of-treatment visit are to be 
performed before initiating rescue therapy. 
After these assessments are completed and rescue therapy is initiated, the 
patient should remain in the study and continue to administer the study 
treatment (including background therapy). The planned visits and 
assessments should be performed until the last scheduled visit.  
ENDPOINTS 
 
Primary endpoint  
• 
Change from baseline to Week 26 in HbA1c (%) 
Secondary endpoints:  
Efficacy 
• 
Percentage (%) of patients achieving the HbA1c target of <7% at 
Week 26 
• 
Change in 2-hour postprandial glucose (PPG) as measured 
utilizing a standardized meal test at Week 26 (for patients that 
performed the standardized meal test) 
• 
Change in 2-hour glycemic excursions as measured utilizing a 
standardized meal test at Week 26 (for patients that performed the 
standardized meal test) 
• 
Change from baseline to Week 26 in daily insulin glargine dose  
• 
Change from baseline to Week 26 in body weight  
Safety 
• 
Hypoglycemia 
- 
Documented hypoglycemia (plasma glucose values  
≤70 mg/dL [3.9 mmol/L]) 
- 
Symptomatic hypoglycemia  
- 
Documented hypoglycemia (plasma glucose values  
<54 mg/dL [3.0 mmol/L]) 
- 
Symptomatic hypoglycemia  
- 
Severe hypoglycemia 
• 
Adverse events (AEs), including gastrointestinal AEs 
• 
Serious adverse events (SAEs) 
• 
Adverse events of special interest (AESI): serious 
allergic/hypersensitivity reactions, pregnancy, ALT>3 x ULN, 
symptomatic overdose of IMP/NIMP  
• 
Vital sign parameters (change from baseline) 
Other efficacy endpoints: 
• 
HbA1c change from baseline to Week 12  
• 
Fasting plasma glucose change from baseline to Week 26 
• 
Percent of patients requiring rescue therapy by Week 26 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 
26 with no body weight gain  
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• 
Percentage of patients reaching the HbA1c target of <7% at Week 
26 with no documented symptomatic hypoglycemia (SMPG ≤70 
mg/dL [3.9 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 
26 with no documented symptomatic hypoglycemia (SMPG <54 
mg/dL [3.0 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 
26 with no body weight gain and no documented symptomatic 
hypoglycemia (SMPG ≤70 mg/dL [3.9 mmol/L] 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 
26 with no body weight gain and no documented symptomatic 
hypoglycemia (SMPG <54 mg/dL [3.0 mmol/L]) 
• 
Patient Reported Outcome measures: 
- 
Treatment Related Impact Measure – Diabetes (TRIM-D) 
- 
Patient and Physician Global Treatment Effectiveness 
Evaluation Scales 
ASSESSMENT SCHEDULE 
Visit schedule:  
The schedule of study-related procedures/assessments is detailed in the 
Study Flow Chart (Table 1). 
Early termination: 
Patients who prematurely and permanently discontinue IMP administration 
for any reason should have a visit as soon as possible for the assessments 
normally planned for the last dosing day with the IMP, ie, Week 26. 
Afterward, these patients should continue in the study up to their scheduled 
date of study completion. 
They should be followed up according to the study procedures as specified 
in the protocol (except for the 3-day safety follow-up visit). 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Based on clinical trial data, along with additional modeling exercises (to 
evaluate the impact of the differences in study design between this study 
and the preapproval studies, eg, lack of placebo run-in), assuming a true 
difference of 0.4% for HbA1c change, and a standard deviation of 
0.95%, 200 patients per ethnic/racial subgroup would provide 96% power for 
superiority of iGlarLixi to iGlar in an individual ethnic/racial subgroup at the 1-
sided 0.025/3 significance level. This would also provide 90% power for 
superiority in all 3 subgroups. In order to ensure an overall family-wise 2-
sided error rate of 0.05, a Hommel procedure will be used. 
Calculations were made using nQuery Advisor 7.0. 
A total sample size of 1200 patients for inclusion in the intent-to-treat (ITT) 
population is planned.  
Analysis population: 
Efficacy analyses will be based on the ITT population, defined as all 
randomized patients. Patients will be analyzed for efficacy analyses 
according to the treatment group to which they are randomized. 
Safety data will be summarized using the Safety Population, defined as all 
randomized patients who actually received at least 1 dose of IMP, analyzed 
according to the treatment actually received. 
 
 
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Primary analysis: 
Analyses of the primary efficacy endpoint (change from baseline to Week 26 
in HbA1c) will be performed using the ITT population, using HbA1c values 
obtained during the 26-week randomized treatment period, including those 
obtained after IMP discontinuation or rescue medication use. 
The baseline value is defined as the last available value prior to the first 
dose administration of investigational medicinal product or the last available 
value on or before the date of randomization if not treated with open-label 
IMP. 
The change in HbA1c from baseline to Week 26 (primary endpoint) will be 
analyzed with missing values imputed by control-based jump to reference 
multiple imputation method. This approach assumes missing at random 
mechanism for missing data in the Lantus (control) group. However, it does 
not assume such a missing at random mechanism for missing data in the 
Soliqua 100/33 group. For a patient in the Soliqua 100/33 group, it assumes 
that the patient will lose the Soliqua 100/33 treatment benefit and uses the 
parameters of the Lantus (control) group to calculate the patient’s post-
dropout mean response for the conditional mean in the imputation model.  
Each of the completed datasets will be analyzed by the analysis of 
covariance (ANCOVA) model with treatment groups, randomization strata of 
ethnicity/race, SGLT-2 use (Yes, No), and SU use (Yes, No), as fixed 
effects, and baseline HbA1c as the covariate. Results from each complete 
dataset will be combined to provide the adjusted mean change in HbA1c 
from baseline to Week 26 for each treatment group, as well as the between-
group difference. If the upper bound of the 2-sided 95% CI for the adjusted 
mean difference (Soliqua 100/33 vs. Lantus) in HbA1c change from baseline 
to Week 26 is <0, then superiority of Soliqua 100/33 will be declared. 
Analysis of secondary and other endpoints: 
Analysis of secondary and other endpoints will be done utilizing the data 
obtained up to Week 26 during the randomized treatment period. 
All categorical secondary efficacy endpoints including the proportion of 
patients reaching HbA1c targets will be analysed using a logistic regression 
model adjusting for treatment and appropriate baseline covariates. 
Summaries and appropriate inferential analyses will be provided for all 
continuous secondary efficacy endpoints. 
Summaries will be prepared for safety and tolerability findings and PRO 
measures. 
To control the Type I error, a Hommel testing procedure will be applied for 
the primary endpoint. For the primary analysis (change from baseline to 
Week 26 in HbA1c), no multiplicity adjustment is needed to control the 
Type I error in the overall population since only 1 comparison of Soliqua 
100/33 versus Lantus will be performed. Once it passes statistical 
significance at the 2.5% level (1-sided), the Hommel procedure will be 
utilized for testing the primary endpoint in each ethnic/racial group. If the 
largest p-value from the 3 ethnic/racial groups is less than or equal to 0.05 
then statistical significance is achieved at all 3 ethnic/racial groups; if the 
largest p-value is greater than 0.05 but the second-largest p-value is less 
than or equal to 0.025 then statistical significance is achieved for  the 2 
ethnic/racial groups corresponding to the 2 smaller p-values; if the second-
largest p-value is greater than 0.025 and the smallest p-value is less than or 
equal to 00167 OR the smallest p-value is less than or equal to 0.025 and 
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the second-smallest p-value is between 0.025 (exclusive) and 0.0333 
(inclusive), then statistical significance is only achieved for the ethnic/racial 
group corresponding to the smallest p-value. This procedure has statistical 
validity since the testing is among different and independent subgroups of 
patients. 
Details of any testing procedure for key secondary endpoints to control the 
Type 1 error will be described in the study protocol.    
DURATION OF STUDY PERIOD (per 
patient)  
A maximum of 29 weeks per patient. 
STUDY COMMITTEES 
Steering Committee:  
 
 Yes    
 No 
Data monitoring committee: 
 Yes    
 No 
Adjudication committee:  
 Yes    
 No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
 
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1.2 
STUDY FLOW CHART 
Table 1 - Screening and randomized treatment period flow chart  
Study Period 
Screening 
Open-label Randomized Treatment 
Follow-Up Visit 
1 
1.2b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19c 
19 + 3 
VISITa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEK 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
15 
18 
21 
24 
26 
26+3 days 
Inclusion criteria including Informed Consentd 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history (including diabetes) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and BMIe 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Vital signsf 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Diet and lifestyle counselingg 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
IRT contacth 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of IMP (as appropriate)  
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
 
 
Pen-injector and self-injection training and re-
trainingi 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Review and evaluation/adjustment of IMP doses 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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Study Period 
Screening 
Open-label Randomized Treatment 
Follow-Up Visit 
1 
1.2b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19c 
19 + 3 
VISITa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEK 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
15 
18 
21 
24 
26 
26+3 days 
Collection of used and unused IMP pens; 
compliance check 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Glucometer/supplies/diary dispensation 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucometers, SMPG, hypoglycemia, insulin dose 
titration, diary training and re-trainingi  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
SMPGj 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Two-hour standardized meal test (a sub-set of 
patients only) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
HbA1c (central laboratory) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
FPG (central laboratory) (A 1-time repeat 
measurement before Visit 2 is permitted) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
PRO questionnairesk  
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
Hematologyl 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistrym 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisn 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRo 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum calcitonin 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testp 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Concomitant medications 
Continuously assessed and recorded throughout the study 
AEs/SAEs/AESIs/hypoglycemia collection 
Continuously assessed and recorded throughout the study 
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 = Remote visit (telephone or videoconference); all other visits will be performed in person, at the site location, except for the patients that will be enrolled through the virtual site model, who will complete all study 
visits in a remote setting (as described in Section 10).  
a. Screening period duration is of up to 2 weeks (ie, it can be less than 2 weeks if all required procedures have been performed and patient’s eligibility has been confirmed). Starting with Visit 3 through (and 
including) Visit 14, a ±2-day window, calculated relative to the Randomization Visit (Visit 2) is permitted; for Visits 15 through 18, a ±3-day window is permitted, while for Visit 19 a +3-day window is permitted. If a 
study visit is performed outside of the permitted window, the subsequent visits must be scheduled according to the original schedule (ie, relative to the date of Visit 2, Randomization Visit). The date of the follow-up 
visit must be determined relative to the date of Visit 19. Additional remote visits should be scheduled as often as deemed necessary by the Investigator. 
b. Mandatory for all patients until at least 75 randomized patients per treatment/ethnicity/race group completed the test during the screening period; the visit can be performed any time prior to Visit 2, once the 
patient’s eligibility based on Visit 1 criteria has been confirmed. Sponsor or designee will communicate when/if this evaluation is no longer required for study patients. 
c. In case of rescue therapy initiation or if IMP is being permanently discontinued, Week 26 (Visit 19) procedures should be performed before starting rescue therapy/IMP discontinuation; subsequently, patients 
should continue study treatment and all visits/procedures should be performed per protocol. 
d. Informed consent should be collected at Visit 1 only, before any other study procedures are performed (or when amendments to the consent are created by the Sponsor or designee). 
e. BMI will be calculated by the site at Visit 1 only using the following formula: BMI=weight (kg)/(height in m)2. 
f. Blood pressure and heart rate will be measured after 5 minutes rest in seated position. 
g. Additional counseling will be performed as appropriate throughout the study. 
h. IRT will be contacted by the site at the pre-specified timepoints, as well as any other time when the patient needs re-dispensation of the IMP. 
i. Repeated as often as necessary, including during remote visits. 
j. SMPG monitoring is to be performed to guide insulin titration and for hypoglycemia evaluation, as appropriate, by study patients after Visit 2  and throughout the study duration 
1. 
Fasting (prebreakfast/preinjection) SMPG should be performed daily until the FPG target has been achieved. Thereafter, the number of fasting SMPG measurements could be reduced, according to the 
Investigator’s judgment, however at least 3 fasting SMPG measurements per week must be done. 
Note: After randomization the fasting SMPG will follow the window for the preinjection SMPG 
2. 
Preinjection SMPG (within 30 minutes prior to the injection of Soliqua 100/33 or Lantus - if the latter is administered in the morning) during the randomized treatment period. 
k. PROs will be assessed per the following schedule: 
1. 
TRIM-D – to be done at Baseline, W12 and W26 
2. 
Patient/Physician assessments: W26. 
l. Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. 
m. Serum chemistry: AST, ALT, ALP, total bilirubin (if >ULN, then the direct and indirect sub-fractions must be measured), creatinine, uric acid, sodium, potassium 
n. Urinalysis: pH, glucose, ketones, leukocytes, blood/hemoglobin, protein. 
o. Using the Modification of Diet in Renal Disease (MDRD) equation. 
p. Women of childbearing potential only; serum pregnancy test at Visit 1; urine pregnancy test at all subsequent visits for patients at traditional sites (if needed, a confirmatory serum pregnancy test can be 
performed). Investigators may conduct additional locally analyzed urine pregnancy tests as per their judgment. For patients participating at the designated site for the virtual study model, all pregnancy tests will be 
serum and for Visit 2, this may be done up to 1 week prior to the Visit 2 date (ie, it may be done at Visit 1.2, if patient performs this visit; the results must be obtained prior to patient randomization).  
AE=adverse event; AL=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BMI=body mass index; eGFR=estimated glomerular filtration rate; FP=fasting plasma glucose; HbA1c 
=hemoglobin A1c; IMP=investigational medicinal product; IRT=interactive response technology; PRO=patient reported outcome; SAE=serious adverse event; SMPG=self-monitoring of plasma glucose; ULN=upper 
limit of normal.   
 = Remote visit (telephone or videoconference); all other visits will be performed in person, at the site location, except for the patients that will be enrolled through the virtual (telemedicine) site model, who will 
complete all study visits in a remote setting. 
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................17 
2.1 
LIST OF TABLES...........................................................................................................................22 
2.2 
LIST OF FIGURES.........................................................................................................................22 
3 
LIST OF ABBREVIATIONS ..........................................................................................................23 
4 
INTRODUCTION AND RATIONALE.............................................................................................24 
5 
STUDY OBJECTIVES ...................................................................................................................29 
5.1 
PRIMARY.......................................................................................................................................29 
5.2 
SECONDARY ................................................................................................................................29 
5.3 
OTHER...........................................................................................................................................29 
6 
STUDY DESIGN ............................................................................................................................30 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................30 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................30 
6.2.1 
Duration of study participation for each patient .............................................................................30 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................30 
6.3 
INTERIM ANALYSIS......................................................................................................................30 
6.4 
STUDY COMMITTEES..................................................................................................................31 
7 
SELECTION OF PATIENTS..........................................................................................................32 
7.1 
INCLUSION CRITERIA..................................................................................................................32 
7.2 
EXCLUSION CRITERIA ................................................................................................................32 
7.2.1 
Exclusion criteria related to study methodology ............................................................................33 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......34 
7.2.3 
Exclusion criteria related to the current knowledge of Soliqua 100/33..........................................34 
8 
STUDY TREATMENTS .................................................................................................................35 
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8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................35 
8.1.1 
Dose adjustments ..........................................................................................................................36 
8.1.1.1 
Injection devices.............................................................................................................................37 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................38 
8.2.1 
Background oral antidiabetic treatment .........................................................................................38 
8.2.2 
Rescue therapy..............................................................................................................................38 
8.3 
BLINDING PROCEDURES............................................................................................................39 
8.3.1 
Methods of blinding........................................................................................................................39 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................39 
8.5 
PACKAGING AND LABELING ......................................................................................................40 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................40 
8.7 
RESPONSIBILITIES ......................................................................................................................40 
8.7.1 
Treatment accountability and compliance .....................................................................................41 
8.7.2 
Return and/or destruction of treatments ........................................................................................41 
8.8 
CONCOMITANT MEDICATION.....................................................................................................42 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................43 
9.1 
PRIMARY ENDPOINT ...................................................................................................................43 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................43 
9.2.1 
Secondary efficacy endpoints........................................................................................................43 
9.2.2 
Observation Period for Efficacy Variables .....................................................................................43 
9.2.3 
Safety endpoints ............................................................................................................................43 
9.2.4 
Observation Period for Safety Variables........................................................................................44 
9.2.4.1 
Hypoglycemia.................................................................................................................................44 
9.2.4.2 
Adverse events ..............................................................................................................................44 
9.2.4.3 
Vital signs.......................................................................................................................................44 
9.3 
OTHER ENDPOINTS ....................................................................................................................44 
9.3.1 
Other efficacy endpoints ................................................................................................................44 
9.3.1.1 
Fasting plasma glucose .................................................................................................................45 
9.3.1.2 
Percent of patients requiring rescue therapy.................................................................................45 
9.3.1.3 
Soliqua 100/33 and Lantus doses..................................................................................................45 
9.3.2 
Patient reported outcome endpoints..............................................................................................45 
9.3.2.1 
Treatment Related Impact Measure – Diabetes............................................................................45 
9.3.2.2 
Patient and Physician Global Treatment Effectiveness Evaluation Scales ...................................46 
9.3.3 
HbA1c measurement .....................................................................................................................46 
9.3.4 
Standardized meal test ..................................................................................................................46 
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9.3.5 
Self-monitored plasma glucose......................................................................................................47 
9.3.6 
Body weight....................................................................................................................................47 
9.3.7 
Dose of IMP ...................................................................................................................................48 
9.4 
APPROPRIATENESS OF MEASUREMENTS..............................................................................48 
10 
STUDY PROCEDURES ................................................................................................................50 
10.1 
VISIT SCHEDULE..........................................................................................................................50 
10.1.1 
Diet and Exercise...........................................................................................................................50 
10.1.2 
Glucometer, patient diaries and IMP titration training....................................................................50 
10.1.3 
Hypoglycemia training....................................................................................................................51 
10.1.4 
Screening period (Week -2 up to Week 0).....................................................................................51 
10.1.4.1 Visit 1 (screening visit, Week-2); Visit 2 (baseline visit, Week 0) ..................................................52 
10.1.5 
Open-label randomized treatment period (Week 0 to Week 26) ...................................................54 
10.1.5.1 Baseline visit (Week 0; Visit 2).......................................................................................................54 
10.1.5.2 Visits: Weeks 1-5 (Visits 3-7), Weeks 7-11 (Visits 9-13), Week 15 (Visit 15), Week 21 (Visit 
17) and Week 24 (Visit 18) ............................................................................................................55 
10.1.5.3 Visits: Week 6 (Visit 8), Week 12 (Visit 14) and Week 18 (Visit 16)..............................................55 
10.1.5.4 Final on-treatment assessment/end-of-treatment visit (Week 26 [Visit 19])..................................56 
10.1.6 
Post-treatment follow-up visit (Week 26 +3 days [Visit 19 +3]) .....................................................56 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................56 
10.2.1 
Source data to be found in the patient’s file...................................................................................56 
10.2.2 
Source data verification requirements for patients not randomized ..............................................57 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................57 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................57 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s)...........................58 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................58 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................58 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................59 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................59 
10.4.1 
Definitions of adverse events.........................................................................................................59 
10.4.1.1 Adverse event ................................................................................................................................59 
10.4.1.2 Serious adverse event ...................................................................................................................59 
10.5 
INTERIM ANALYSIS......................................................................................................................60 
10.5.1 
Adverse event of special interest...................................................................................................60 
10.5.2 
General guidelines for reporting adverse events...........................................................................61 
10.5.3 
Instructions for reporting serious adverse events..........................................................................62 
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10.5.4 
Guidelines for reporting adverse events of special interest...........................................................63 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................64 
10.7 
SAFETY INSTRUCTIONS.............................................................................................................64 
10.7.1 
Allergic or allergic-like reaction ......................................................................................................64 
10.7.2 
Hypoglycemia.................................................................................................................................65 
10.7.3 
Local tolerability at injection site ....................................................................................................66 
10.7.4 
Monitoring of renal function in case of prolonged and severe nausea and vomiting.....................66 
10.8 
ADVERSE EVENTS MONITORING..............................................................................................66 
11 
STATISTICAL CONSIDERATIONS..............................................................................................67 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................67 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................67 
11.3 
ANALYSIS POPULATIONS...........................................................................................................68 
11.3.1 
Efficacy population.........................................................................................................................68 
11.3.2 
Safety population ...........................................................................................................................68 
11.4 
STATISTICAL METHODS .............................................................................................................69 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................69 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................69 
11.4.1.2 Compliance ....................................................................................................................................70 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................70 
11.4.2.1 Analysis of Primary Efficacy Endpoint ...........................................................................................70 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................71 
11.4.2.3 Multiplicity considerations ..............................................................................................................72 
11.4.3 
Analyses of other endpoints...........................................................................................................74 
11.4.4 
Analyses of Patient Reported Outcome variables .........................................................................74 
11.4.5 
Analyses of safety data..................................................................................................................74 
11.4.5.1 Analyses of adverse events ...........................................................................................................75 
11.4.5.2 Analyses of hypoglycemia .............................................................................................................76 
11.4.5.3 Analyses of vital sign variables......................................................................................................76 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................78 
12.1 
ETHICAL AND REGULATORY STANDARDS..............................................................................78 
12.2 
INFORMED CONSENT .................................................................................................................78 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................78 
13 
STUDY MONITORING ..................................................................................................................80 
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13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................80 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................80 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................81 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST .............81 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................81 
14 
ADDITIONAL REQUIREMENTS...................................................................................................82 
14.1 
CURRICULUM VITAE ...................................................................................................................82 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................82 
14.3 
CONFIDENTIALITY .......................................................................................................................82 
14.4 
PROPERTY RIGHTS.....................................................................................................................83 
14.5 
DATA PROTECTION.....................................................................................................................83 
14.6 
INSURANCE COMPENSATION....................................................................................................83 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................84 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................84 
14.8.1 
By the Sponsor...............................................................................................................................84 
14.8.2 
By the Investigator .........................................................................................................................85 
14.9 
CLINICAL TRIAL RESULTS..........................................................................................................85 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................85 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................86 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................87 
17 
APPENDICES................................................................................................................................90 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION......................................................................................................90 
APPENDIX B 
TREATMENT-RELATED IMPACT MEASURE FOR DIABETES (TRIM-D)........................93 
APPENDIX C PATIENT AND PHYSICIAN GLOBAL TREATMENT EFFECTIVENESS 
EVALUATION SCALES .................................................................................................................96 
APPENDIX D GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES (ALT) BY SANOFI............................................................................................98 
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APPENDIX E 
BACK-UP PLAN FOR SAE AND OTHER INVESTIGATOR EXPEDITED EVENTS 
REPORTING PROCESS WHEN THE ECRF SYSTEM FAILS.....................................................99 
 
2.1 
LIST OF TABLES 
Table 1 - Screening and randomized treatment period flow chart ................................................................14 
Table 2 - Summary of investigational medicinal products.............................................................................35 
Table 3 - Dose adjustment algorithm ............................................................................................................37 
Table 4 - Summary of adverse event reporting instructions..........................................................................64 
Table 5 - Alternate power calculations given recruitment shortcomings.......................................................67 
 
2.2 
LIST OF FIGURES 
Figure 1 - Multiple testing procedure.............................................................................................................73 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CDC: 
Center for Disease Control 
CDE: 
certified diabetes educator 
CV: 
curriculum vitae 
DPP4: 
dipeptidyl peptidase 4 
eCRF: 
electronic case report form 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose 
GLP-1 RA: 
glucagon-like peptide-1 receptor agonist 
HbA1c: 
hemoglobin A1c 
HLGT: 
high level group term 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
MTD: 
Maximum Tolerated Dose 
NIMP: 
non-investigational medicinal product 
OAD: 
oral antidiabetic, oral anti-diabetic 
PCSA: 
potentially clinically significant abnormality 
PPG: 
postprandial glucose 
PRO: 
patient-reported outcomes 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SC: 
subcutaneous 
SD: 
standard deviation 
SGLT-2: 
sodium-glucose co-transporter 2 
SMPG: 
self-monitoring of plasma glucose 
SU: 
sulfonylurea 
T2DM: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent AE 
TRIM-D: 
Treatment Related Impact Measure - Diabetes 
U.S.: 
United States 
ULN: 
upper limit of normal 
USPI: 
United States package insert 
WOCBP: 
women of childbearing potential 
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4 
INTRODUCTION AND RATIONALE 
As of 23 February 2017, the United States (U.S.) has a total resident population of 324 590 124, 
making it the third most populous country in the world (1). This population is characterized by 
significant ethnic and racial diversity, with 6 races (including the option for multiple races) being 
officially recognized by the U.S. Census Bureau as of 2000 (2).  
According to the 2010 Census data, significant shifts have occurred in the ethnic and racial 
distribution of the U.S. population during the interval between 2000 and 2010, with increases in 
the percentage of minority groups. Specifically, the percentage of individuals identified as whites 
“alone” (ie, not reporting multiple races) decreased from 75% in 2000 to 72% in 2010; within this 
category, the percentage of non-Hispanic whites decreased from 69.1% in 2000 to 63.7% in 
2010 (3). During the same decade, the overall Hispanic or Latino population increased from 
12.5% to 16.3%, with noted variability among populations of different Hispanic origins (4); the 
black or African American population (alone or in combination) increased from 12.9% to 
13.6% (5) and the U.S. Asian population increased from 4.2% to 5.6% (6). Consistently, the U.S. 
population projections developed by Pew Research Center as of February 2008 suggest that, by 
2050, the non-Hispanic white population will represent 47% of the total U.S. population, while 
Hispanics or Latinos will make up 29% of the total population, non-Hispanic blacks 13%, and 
non-Hispanic Asians 9% (7). 
Diabetes is a major cause of morbidity and mortality in the U.S. At the beginning of the 
millennium there were 15 million adults living with diabetes, with ethnic/racial minority 
populations bearing a disproportionate burden of the diabetes epidemic. The Behavioral Risk 
Factor Surveillance System reported in 2000 that 7% of Americans have diabetes, with prevalence 
rates of 7% among non-Hispanic whites, compared to 9% among Hispanics and 11% among 
African Americans (8). Furthermore, The Center for Disease Control (CDC) has reported that 
between 2010 and 2012, 29.1 million people (9.3% of U.S. population) had diabetes with Type 2 
diabetes mellitus (T2DM) accounting for 90% to 95% of the cases in adults; the prevalence was 
7.6% for non-Hispanic whites aged 20 years or older, 9% for Asian Americans, 12.8% for 
Hispanics, 13.2% for non-Hispanic blacks, and 15.9% for American Indians/Alaskan Natives of 
the same age (9). In addition to the differences in prevalence rates, higher rates of complications 
and worse control of diabetes are known to exist within the minority populations (8). These 
disparities are often the result of genetic variants but socioeconomic and lifestyle factors also 
influence outcomes (10).  
Ethnic/racial differences in the pathogenesis and evolution of diabetes have been noted. For 
example, intensive treatment of African Americans with newly diagnosed diabetes can lead to 
remission of diabetes in 30% to 40% of patients (11, 12) while African Americans exhibit lower 
glucagon-like peptide-1 concentrations and increased inflammatory responses which may act 
synergistically to enhance the predisposition of obese African Americans to T2DM (13). Hispanic 
individuals are less likely to achieve glycemic goals during treatment, when compared to 
non-Hispanic whites and non-Hispanic blacks (14) and it is hypothesized that there is more rapid 
gastric occurring in these patients, leading to an increase in postprandial glucose and insulin 
resistance (15). T2DM in East Asians is characterized by beta cell dysfunction rather than insulin 
resistance. Also, meta-analyses suggest that incretin agents are more efficacious in Asian 
populations (16). 
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Considering the current and projected demographic shifts within the U.S. population as detailed 
above, as well as the disparities in the burden of diabetes and its complications/comorbidities 
among various ethnic/racial groups, it becomes critical to demonstrate that the efficacy and safety 
profile of medications is similar among these groups and/or to identify and address any significant 
differences, if applicable. However, as stated in the U.S. Food and Drug Administration (FDA) 
April 2013 Consumer Health Information Sheet (17), historically minorities and women have 
been under-represented in clinical trials and there is a paucity of randomized controlled trials that 
specifically investigate pharmacological treatment in minority populations. For example, 
according to a 2011 report from the conference “Dialogues on Diversifying Clinical Trials,” 
sponsored by FDA’s Office of Women’s Health and the Society for Women’s Health Research 
and supported by the Office of Minority Health: 
• 
African Americans represent 12% of the U.S. population but only 5% of clinical trial 
participants; 
• 
Hispanics make up 16% of the population but only 1% of clinical trial participants; and 
• 
Men make up more than 2/3 of participants in clinical tests of cardiovascular (heart and 
blood vessel) devices. 
The lack of minority population participation in clinical trials has previously been 
documented (18). This was also confirmed by a Sanofi internal comprehensive literature search 
(ie, review of PubMed clinical trial results from 1995 to 2015 on glucose-lowering agents in 
African American and Hispanic populations), which has shown that clinical trials in these 
2 ethnic/racial groups are limited to “older” diabetes drugs (ie, metformin, sulfonylurea, 
rosiglitazone, and linagliptin). Similar findings were noted in a 2015 article by Ferdinand et al. 
(19) in which the objective was to evaluate the prevalence of diabetes and disease-related 
comorbidities as well as the primary endpoints of clinical studies assessing glucose-lowering 
treatments in African Americans, Hispanics, and Asians. Overall, the majority of publications that 
fit the search criteria pertained to native Asian patient populations (ie, Asian patients in Asian 
countries). Sulfonylureas, glucosidase inhibitors, miglitol, metformin, and rosiglitazone have been 
evaluated in African American and Hispanic populations, as well as in Asians. The literature on 
other glucose-lowering drugs in non-white races/ethnicities was found to be more limited (20). 
Consistent with these general trends, during the clinical development of Soliqua 100/33, minority 
populations were not significantly represented in the pivotal trials, with Study EFC12404 
enrolling 7% African American, 19% Hispanic and 2% Asian patients and Study EFC12405 
enrolling 5% African American, 18% Hispanic, and 3% Asian patients. 
Considering that racial health disparities are often influenced by lack of access to both quality 
healthcare as well as appropriate health awareness, this directly influences the lack of minority 
clinical trial populations. Consequently, it is our intention to conduct a diversity trial for 
Soliqua 100/33 employing many of the strategies that have been documented to recruit Hispanic, 
African American, and other minority populations. These strategies include recruiting minority 
Investigators to undertake this research, building a communication platform that is culturally 
sensitive and transparent in terms of the benefits and risks of the research, and to engage in an 
awareness campaign in the appropriate locations with respect to diabetes education, race/ethnicity 
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based differences in disease prevalence and symptoms and finally, the opportunity and 
mechanism by which to become involved in this important research. 
Additionally, to expand access to the trial, a proportion of the participants enrolled may take part 
via a distributed clinical trial model. This includes operationalizing the trial by utilizing virtual 
electronic consent, telemedicine encounters using video-conferencing, and shipment of 
Investigational Medicinal Product (IMP) direct to patient to conduct trial activities that allow 
patients to take part in the trial who would otherwise be unable or unwilling to travel to a 
traditional study site (details to be documented in the appropriate virtual-site model Project Plan). 
The use of technologies to augment or replace traditional face-to-face interactions has become an 
important component of medical practice in many communities. Telemedicine is an important 
technology and its use is rapidly increasing. While telemedicine is a relatively new care-delivery 
model, it is not a departure from standard medical practice; in particular, the California Medical 
Board describes it as a “tool in medical practice, not a separate form of medicine.” Providers 
using telemedicine are held to the same standard-of-care for telemedicine visits as they are for 
face-to-face, in person visits. 
T2DM is particularly well-suited to telemedicine since it can provide an effective way to monitor 
and provide much-needed educational and motivational support to patients with this diagnosis 
(21, 22, 23, 24). In light of the fact that T2DM affects minority populations in large numbers, 
telemedicine studies have focused on under-served populations with successful results (21, 25).  
Additionally, although some studies of older adults from minority and medically underserved 
communities have noted a proportion of patients with lower levels of computer familiarity, this 
digital divide can be successfully addressed with patient education and development of smaller, 
more portable, and easier to use devices and technologies, which are rapidly evolving (21).  
Previous studies have used many such tools and devices to great effect. For example, bluetooth-
enabled blood glucose meter linked to a mobile app was used successfully as part of the diabetes 
intervention, which also included a standard algorithm for self-titration with an electronic diary to 
record insulin doses integrated into the software; participants were provided with immediate 
feedback of their blood glucose data, and nurses provided review and follow-up via video and/or 
phone (22). In such studies, the engagement of nurses, who are consistently accessible to address 
various routine questions about titration protocols or telemedicine procedures, is seen as highly 
valuable (22, 23). Overall, the support team approach, which includes not only nurses but also 
dietitians and potentially certified diabetes educators (CDEs) in additional to physicians, was 
effectively utilized in rural, underserved, and ethnically diverse settings (25), and no differences 
were noted regarding intervention provided by nurses compared to physicians. 
Studies also report participants’ enthusiastic engagement with the telemedicine model (22) and 
quick adoption of it, even in cases where some additional training needed to be provided. With 
64% to 68% of adults in America owning a smartphone in 2015 vs 35% in 2011, the use of 
smartphones is steadily increasing, and this increase is evident across ages and ethnic groups. As 
45% of American adults who own a smartphone are reportedly using it to manage various aspects 
of their lives including their health, transition to telemedicine should be seamless.  
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In addition, some public and private payors are now accepting telemedicine for diabetes 
management, and with the demonstrated evidence that proactive management is helping patients 
avoid damaging and costly complications (such as blindness, amputations, etc) this trend is likely 
to continue.  
Taking all these factors into consideration, certain participating sites will be designated as a 
virtual study model. As part of this model, certain study visits will be completed using 
telemedicine technology; additional aspects of this model are outlined throughout the 
protocol/virtual site model Project Plan where they differ operationally from traditional study 
sites.  
The primary objective of the current study is to demonstrate the superiority of Soliqua 100/33 
versus Lantus in the hemoglobin A1c (HbA1c) change from baseline to Week 26 in both the 
overall population and within each ethnic/racial subgroup evaluated (ie, Hispanics of any race, 
non-Hispanic black/African Americans, and non-Hispanic Asians). Patients enrolled in the trial 
will be insufficiently controlled on basal insulin and 1 or 2 oral antidiabetic (OAD) agents. 
Additionally, multiple secondary and “other” endpoints will be evaluated, focusing not only on 
glucose-lowering effects and HbA1c but also on hypoglycemia, body weight, need for rescue 
therapy, treatment dose, and patient-reported outcomes (PRO). These endpoints are considered 
appropriate to demonstrate the expected benefits of Soliqua 100/33 in the overall population and 
within each of the ethnic/racial groups evaluated. This objective is in line with the U.S. FDA’s 
strong interest in encouraging participation of a more diverse population in clinical trials (26).  
Soliqua 100/33 is a combination of a long-acting human insulin analog with a GLP-1 receptor 
agonist initially approved in the U.S. in 2016, indicated as an adjunct to diet and exercise to 
improve glycemic control in adults with T2DM inadequately controlled on basal insulin (less than 
60 units daily) or lixisenatide. Other information concerning Soliqua 100/33 is available in the 
Soliqua 100/33 U.S. Package Insert (USPI) (27). The patient population selected for this study is 
consistent with the target population according to the approved label indication. 
Lantus, an analog of human insulin, provides 24-hour blood glucose control after a single 
subcutaneous injection. Lantus has been marketed since June 2000 in Europe and since May 2001 
in the U.S. and other parts of the world. Lantus is indicated for the treatment of adult and pediatric 
patients with Type 1 diabetes or adult patients with T2DM who require basal (long-acting) insulin 
for the control of hyperglycemia. Other information concerning Lantus is available in the Lantus 
USPI (28). 
The current study (LixiLan-D, Diversity) will be an open-label, 1:1 randomized, active-controlled, 
26-week duration, parallel-group, multicenter, U.S.-only, Phase 3b study to compare the efficacy 
and safety of Soliqua 100/33 to Lantus in the  overall population and in ethnically/racially diverse 
groups. Patients with T2DM inadequately controlled on a background of basal insulin and 1 or 2 
OAD agents will be enrolled. To ensure a balanced IMP allocation, randomization will be first 
stratified by self-reported ethnicity/race (ie, Hispanics of any race, non-Hispanic black/African 
Americans. and non-Hispanic Asians) and will be capped to allow randomization of 
approximately similar number of patients within each ethnic/racial subgroup. Randomization will 
be secondarily stratified by the screening HbA1c value (<8.5% versus ≥8.5%), the background 
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use of sodium glucose co-transporter 2 (SGLT-2) inhibitors (yes/no), and by the background use 
of sulfonylureas (yes/no).  
The study will consist of 3 periods: 
• 
An up to a 2-week screening period  
• 
A 26-week open-label randomized treatment period: at the end of the screening period 
(Week 0, Visit 2) patients will be randomized to receive either Soliqua 100/33 or Lantus. 
• 
A 3-day post-treatment safety follow-up period. 
Patients who prematurely and permanently discontinue IMP administration during the randomized 
treatment period should continue all study visits and assessments per protocol (except for the 
follow-up visit). The maximum study duration per patient will be of approximately 29 weeks. 
This type of study design is considered adequate to address the objectives of the study. 
Conclusion on the benefit risk assessment in this study 
The IMPs administered in this study (Soliqua 100/33 and Lantus) have demonstrated 
glucose-lowering properties and are both approved for the treatment of adult patients with T2DM. 
Given the safety profile observed during development, Soliqua 100/33 is considered well tolerated 
and with properties reflective of the individual components. No new risk has been identified for 
the population to be included in Study LPS14860. Treatment with both Soliqua 100/33 and Lantus 
is in line with current FDA-approved label indications. Therefore, the risk for patients 
participating in this study and using daily doses of Soliqua 100/33 up to 60 U of insulin glargine 
and 20 µg of lixisenatide is considered acceptable. All patients entering this study will receive 
treatment with Soliqua 100/33 or Lantus in combination with 1 or 2 OADs. As participants in the 
trial, all patients will benefit from close management of their T2DM. Rescue therapy is planned 
and described in the clinical study protocol for patients whose glycemia remains poorly 
controlled. 
Given the expected improvement of metabolic control and the additional measures to improve 
diabetes management as part of the trial, these benefits are considered to outweigh any potential 
risk associated with Soliqua 100/33 and Lantus. Therefore, the benefit-risk ratio for patients 
participating in Study LPS14860 is considered favorable. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
• 
To demonstrate the superiority of Soliqua 100/33 versus Lantus in the HbA1c change from 
baseline to Week 26 within the overall population. 
• 
To demonstrate the benefit of Soliqua 100/33 versus Lantus in the HbA1c change from 
baseline to Week 26 within each ethnic/racial subgroup evaluated (ie, Hispanics of any 
race, non-Hispanic black/African Americans and non-Hispanic Asians). 
5.2 
SECONDARY  
• 
To assess the effects of Soliqua 100/33 versus Lantus on the secondary efficacy parameters 
to Week 26 for the selected endpoint (see “Study Endpoints”) within each ethnic/racial 
subgroup evaluated. 
• 
To assess the change from baseline to Week 26 in daily insulin glargine dose within each 
ethnic/racial subgroup.  
• 
To evaluate the safety and tolerability (eg, gastrointestinal tolerability) of Soliqua 100/33 
versus Lantus to Week 26 within each ethnic/racial subgroup. 
5.3 
OTHER 
• 
To assess the effects of Soliqua 100/33 versus Lantus on other efficacy parameters to 
Week 26 for the selected endpoint (see “Study Endpoints”) within each ethnic/racial 
subgroup evaluated. 
• 
To assess the effects of Soliqua 100/33 versus Lantus on efficacy and safety parameters to 
Week 26 in the overall population. 
• 
To evaluate and compare the effect of Soliqua 100/33 versus Lantus on Patient Reported 
Outcome (PRO) measures to Week 26 within each ethnic/racial subgroup. 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is an open-label, 1:1 randomized, active-controlled, 26-week duration, parallel-group, 
multicenter, US-only, Phase 3b study to compare the efficacy and safety of Soliqua 100/33 with 
Lantus overall and in ethnically/racially diverse groups with T2DM inadequately controlled on 
basal insulin and 1 or 2 OAD agents. The patients will be randomized according to their self-
reported ethnicity/race (ie, Hispanics of any race, non-Hispanic black/African Americans and 
non-Hispanic Asians); randomization will be capped to include approximately similar numbers of 
patients (ie, 400) within each ethnic/racial subgroup, with approximately 200 patients per 
ethnic/racial group receiving Soliqua 100/33 and approximately 200 receiving Lantus. 
Additionally, to ensure a balanced IMP allocation, randomization will be stratified by their self-
reported ethnic/racial group, screening HbA1c value (<8.5% versus ≥8.5%), the background use 
of SGLT-2 inhibitors (yes/no) and the background use of SUs (yes/no). Patients will participate in 
1 of 2 ways, either at a traditional ‘brick & mortar’ investigational site, or fully remotely through 
a virtual (telemedicine) arrangement.  
The study will consist of 3 periods: 
• 
An up to 2-week screening period  
• 
A 26-week open-label randomized treatment period: at the end of the screening period 
(Week 0, Visit 2) patients will be randomized to receive either Soliqua 100/33 or Lantus  
• 
A 3-day post-treatment safety follow-up period (not required for patients who prematurely 
and permanently discontinued IMP administration but stayed in the study though 
Week 26; these patients should continue all study visits except for the follow-up visit). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient  
The maximum study duration per patient will be of approximately 29 weeks (comprised of an up 
to 2-week screening period, a 26-week open-label randomized treatment period, and a 3-day 
post-treatment safety follow-up period). 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned within the protocol, 
including follow-up visit. 
The Sponsor can terminate the trial prematurely at any time for any reason, including any 
unforeseen developments. 
6.3 
INTERIM ANALYSIS 
No formal interim analysis is planned. 
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6.4 
STUDY COMMITTEES 
No study committees are planned. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patient with T2DM diagnosed for at least 1 year prior to the screening visit (signing of 
informed consent); 
I 02. Uncontrolled diabetes as demonstrated by a screening centrally measured HbA1c between 
7.5% and 10% (inclusive); 
I 03. Patients who are Hispanics of any race, non-Hispanic black/African Americans or 
non-Hispanic Asians; 
Note: Decision for ethnic/racial inclusion will be made based on the patient’s 
self-identification. Mixed-race patients must select 1 of the above-mentioned categories. If 
such selection cannot be made, the candidate will be ineligible to participate in the study; 
I 04. Patients who have been treated with any basal insulin, ie, glargine 100 U/mL or 300 U/mL, 
detemir, degludec, intermediate-acting [human NPH]) for at least 6 months prior to Visit 1; 
I 05. The basal insulin regimen (ie, type of insulin and time/frequency of the injection) has been 
stable for at least 3 months prior to Visit 1; 
I 06. The basal insulin dose has been stable (defined as up to ±20% [1/5 of the dose] variability) 
for at least 2 months prior to Visit 1 within the following dose ranges: 
• 
15 to 50 units/day if HbA1c at Visit 1 is ≤8.5% and 
• 
15 to 40 units/day if HbA1c at Visit 1 is >8.5% 
I 07. Patients receiving 1 or 2 of the following OADs: metformin, pioglitazone/rosiglitazone, an 
SGLT-2 inhibitor or a SU, at stable doses for at least 12 weeks prior to Visit 1 
• 
Metformin dose must have been ≥1500 mg/day or the Maximum Tolerated Dose (MTD), 
according to the Investigator’s judgment; 
• 
Sulfonylurea dose must be ≥ than the half maximum approved dose according to the local 
label. For patients with an HbA1c <8%, the SU dose must be reduced by 50% starting with 
the day of initiation of IMP administration; subsequently, the dose can be up-titrated 
according to the Investigator’s judgment up to the dose previously taken by the patient. 
Additional increases in the SU dose (above baseline dose) should not be done unless the 
patient is rescued, according the protocol rescue procedures.  
I 08. Patients willing and able to perform self-monitoring of plasma glucose (SMPG); 
I 09. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
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7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years of age at Visit 1; 
E 02. A body mass index (BMI) ≤20 or >40 kg/m2 at Visit 1; 
E 03. Fasting plasma glucose (FPG) >200 mg/dL (by central lab measurement) at Visit 1 (1-time 
repeat measurement before Visit 2 is permitted); 
E 04. Type 1 diabetes mellitus or any diabetes other than T2DM; 
E 05. Any use of OAD drugs other than those described in the inclusion criteria (eg, but not 
limited to GLP-1  receptor agonists, DPP-4 inhibitors) within 12 weeks prior to Visit 1; 
E 06. Use of any other type of insulin except for basal insulin (eg, prandial or premixed insulin, 
insulin pump) within 6 months prior to Visit 1; 
Note: History of short-term treatment (ie, ≤10 days) with other insulin types due to 
intercurrent illness is permitted at the discretion of the Investigator. 
E 07. Known history of discontinuation of treatment with a GLP-1 receptor agonist due to 
safety/tolerability reasons; 
E 08. Use of systemic glucocorticoids for a total duration of >7 days within 12 weeks prior to 
Visit 1; 
E 09. Initiation/change in type or dose of a weight loss drug within 12 weeks prior to Visit 1; 
E 10. Use of an investigational drug within 1 month or 5 times the duration of the 
pharmacodynamic effect, whichever is longer, prior to Visit 1; 
E 11. History of metabolic acidosis, including diabetic ketoacidosis within 12 months prior to 
Visit 1; 
E 12. History of stroke, myocardial infarction, unstable angina or heart failure requiring 
hospitalization within 6 months prior to Visit 1; planned hospitalization for any reason 
during the duration of the study; 
E 13. Known history of drug or alcohol abuse within 6 months prior to Visit 1; 
E 14. Clinically significant laboratory findings at Visit 1, including: 
• 
Amylase and/or lipase >3 times the upper limit of the normal (ULN) laboratory range 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3  imes the ULN 
• 
Positive serum pregnancy test 
E 15. Conditions/situations such as: 
• 
Patients with conditions/concomitant diseases making them non evaluable for the primary 
efficacy endpoint (eg, sickle cell anemia, hemoglobinopathy or hemolytic anemia, severe 
anemia [screening Hgb <8.0 g/dL; transfusion indicated], receipt of blood or plasma 
products within 12 weeks of Visit 1), 
• 
Patients with conditions/concomitant diseases precluding their safe participation in this 
study (eg, active malignant tumor, clinically-significant psychiatric disorders, major 
systemic diseases, presence of clinically significant diabetic retinopathy or presence of 
macular edema likely to require treatment within the study period), 
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• 
Impossibility to meet specific protocol requirements (eg, scheduled visits, patients unable 
to fully understand patient’s study documents and to complete them), 
• 
Uncooperative patient or any condition that could make the patient potentially 
non-compliant to the study procedures (eg, patient unable or unwilling to do self-injections 
or blood glucose monitoring using the sponsor-provided blood glucose meter at home, 
etc), 
• 
Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 16. Any contraindication to Lantus use, according to local labeling; 
E 17. History of hypersensitivity to Lantus or to any of the excipients; 
E 18. Contraindications to the specific background OADs that each individual patient is taking 
(as applicable), according to the local label. 
7.2.3 Exclusion criteria related to the current knowledge of Soliqua 100/33  
E 19. Contraindication to use of Soliqua 100/33 according to local labeling;  
E 20. History of hypersensitivity to Soliqua 100/33, or to any of the excipients; 
E 21. Pregnancy or lactation; women of childbearing potential (WOCBP) not protected by 
highly-effective contraceptive methods (as defined in the Informed Consent) and/or who 
are unwilling or unable to be tested for pregnancy; planning pregnancy during the duration 
of the study; 
E 22. Known history or presence of clinically-significant gastroparesis; 
E 23. History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy 
has now been performed), pancreatitis during previous treatment with incretin therapies, 
chronic pancreatitis, pancreatectomy, stomach/gastric surgery; 
E 24. An estimated glomerular filtration rate (e-GFR) <30 mL/min/1.73 m2 (more stringent renal 
function restrictions, depending on the patient’s background OAD use are to be applied, 
according to the local label and the Investigator’s judgment); 
One-time re-test of screening laboratory values is allowed during the permitted screening period 
for this study (see Section 10.1.4 for additional details). A patient must not be randomized more 
than once. 
In case of screen failure due to reasons expected to change at rescreening and based upon the 
Investigator’s clinical judgment, the patient can be rescreened one time for this study. A new 
informed consent will be signed and a new patient number will be assigned by IRT for such 
subjects. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMPs are Soliqua 100/33 (insulin glargine/lixisenatide) and Lantus (insulin glargine).  
Table 2 provides a summary of each IMP.  
Table 2 - Summary of investigational medicinal products 
IMP 
Soliqua 100/33 
Lantus 
Pharmaceutical 
Formulation 
Soliqua 100/33 (insulin glargine/lixisenatide) is supplied 
for SC injection as a sterile aqueous solution in a 3:1 
ratio SoloStar pen-injector. The prefilled disposable 
SoloStar pen-injector contains 3 ml of sterile solution of 
100 U/mL insulin glargine and 33 µg/mL lixisenatide in 
a ratio of 3 U of insulin glargine to 1 µg lixisenatide and 
allows administration of daily combination doses 
between 15 U/5µg and 60 U/20µg. 
Lantus (insulin glargine) is supplied for SC injection 
as a sterile aqueous solution in a prefilled 
disposable Lantus SoloStar pen-injector containing 
a 3 mL solution of insulin glargine 100 U/mL. The 
disposable SoloStar pen-injector allows for dose 
setting in the range of 1-80 U with a minimum dose 
increment of 1 U. 
Dose, Timing 
and Route of 
Administration* 
Soliqua 100/33 should be self-administered by SC 
injection once daily in the morning in the hour (0 to 60 
minutes) before breakfast.  
Starting dose for patients on a background basal 
insulin dose <30 U/day (at the time of 
randomization): 15 U of insulin glargine 
(corresponding to 5 µg lixisenatide). 
Starting dose for patients on a background basal 
insulin dose ≥30 U/day (at the time of 
randomization): 30 U of insulin glargine 
(corresponding to 10 µg lixisenatide).  
Note: The 20% dose reduction recommendation 
described for Lantus does not apply to Soliqua 100/33. 
Details on dose adjustments are presented in  
Section 8.1.1. 
Lantus should be self-administered by SC injection 
once daily at any time of the day but at about the 
same time every day. The injection time will be 
determined at the discretion of the patient and 
Investigator at the time of randomization and it 
should remain about the same (±120 minutes) until 
the end of the randomized treatment period. 
The initial dose will be the same as the 
background basal insulin dose at which the patient 
is randomized unless transitioning from U300 
insulin glargine, insulin administered twice daily or 
insulin detemir, when a 20% reduction in dose is 
required to initiate Lantus. 
Details on dose adjustments are presented in 
Section 8.1.1. 
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IMP 
Soliqua 100/33 
Lantus 
Storage 
conditions 
Prior to first use, Soliqua 100/33 pen should be stored 
in a refrigerator, 36°F to 46°F (2°C to 8°C). Do not 
freeze. Protect from light. Discard after the expiration 
date printed on the label. Each pen should not be used 
for more than 14 days after the first use. 
Soliqua 100/33 should not be stored in the freezer and 
should not be allowed to freeze. Discard Soliqua 
100/33 if it has been frozen. 
After first use, store at room temperature below 77°F 
(25°C). Replace the pen cap after each use to protect 
from light. 
Discard pen 28 days after first use. 
Always remove the needle after each injection and 
store the Soliqua 100/33 pen without a needle 
attached. This prevents contamination and/or infection, 
or leakage of the pen, and will ensure accurate dosing. 
Always use a new needle for each injection to prevent 
contamination. 
Store new (unopened) pens in a refrigerator, 
between 36°F to 46°F (2°C to 8°C). Do not freeze. 
Store used (open) pens at room temperature, below 
86 degrees F (30 degrees C). Do NOT store used 
(open) pens in the refrigerator. Store away from 
heat and light. If a Lantus SoloStar pen has been 
frozen or overheated, discard. Discard 
unrefrigerated or used pens after 28 days, even if 
they still contain medicine. 
Always remove the needle after each injection and 
store the Lantus pen without a needle attached. 
This prevents contamination and/or infection, or 
leakage of the Lantus pen, and will ensure accurate 
dosing. Always use a new needle for each injection 
to prevent contamination. 
IMP: Investigational medicinal product; SC subcutaneous. 
NOTE: Mixing of Soliqua 100/33 or Lantus with other insulins or dilution of solutions is not permitted. 
* The first dose of IMP will be administered on the day of  randomization (Day 1), either at the site (Soliqua 100/33 
and Lantus on a morning dosing regimen) or outside the site location (Lantus administered on a regimen other than 
morning). If, due to logistical reasons, administration of IMP on the day of  randomization is not possible, 
administration within 3 days following randomization is permitted. 
8.1.1 Dose adjustments 
The same dose adjustment algorithm is recommended for Soliqua 100/33 and Lantus.  
The insulin doses will be up-titrated by 2 U or a maximum of 4 U/week (see algorithm in 
Table 3), until the patient reaches a target fasting SMPG of 80 to 100 mg/dL (4.4 to 5.6 mmol/L), 
inclusive, without clinically-significant hypoglycemia episodes.  
Good clinical judgment should be exercised when titrating the basal insulin dose. Study patients 
should be trained and retrained on an ongoing basis to ensure proper understanding of titration 
procedures and a very close communication between the patient and the study site will be required 
to ensure adequate titration with minimization of associated risks.  
Every effort should be made to reach the fasting SMPG target ranges by Week 12. Once the target 
SMPG has been achieved and until the end of the study, the basal insulin dose will be adjusted as 
necessary to maintain this fasting SMPG target.  
Recommended dose changes are to be based on a median of fasting SMPG values from the last 
3 days (including the day of titration) measured by the patient using glucometers and accessories 
supplied by the Sponsor. 
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For study sites using the virtual (telemedicine) study model, study staff will be available to 
patients to assist with any dose adjustments as needed and at any point during the study via 
telemedicine and/or phone and close communication with the study staff will be encouraged. 
Study patients will be continuously trained and re-trained to ensure proper understanding of 
titration procedures. 
Table 3 details the dose adjustment algorithm for Soliqua 100/33 and Lantus. 
Table 3 - Dose adjustment algorithm 
Median of fasting SMPG values for last 3 days 
Insulin glargine dose adjustments (U/day) 
>140 (>7.8 mmol/L) 
+4a 
>100 and ≤140 mg/dL (>5.6 and ≤7.8 mmol/L) 
+2a 
Glycemic target: >80 and ≤100 mg/dL (>4.4 and ≤5.6 mmol/L), 
inclusive 
No change 
≥60 and <80 mg/dL (≥3.3 and <4.4 mmol/L) 
-2  
<60 mg/dL (3.3 mmol/L) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or 1 severe hypoglycemia. 
-2 to -4 or at the discretion of the Investigator or medically 
qualified designee 
a A titration dose increase of 2 or 4U for Soliqua 100/33 or Lantus may be split into 2 incremental dose steps, rather than implementing the 
entire dose increase at 1 time, if it is considered by the Investigator or medically-qualified designee to be in the best interest of the patient. 
SMPG: self-monitoring of plasma glucose 
8.1.1.1 Injection devices  
Soliqua 100/33 and Lantus will be self-administered with a prefilled disposable SoloStar 
pen-injector. 
The dose of Soliqua 100/33 is titrated according to the patient’s need for insulin. Note that only 
the dose of insulin glargine appears in the pen dosing window. The dose (µg) of lixisenatide does 
not appear in the dose window even though lixisenatide is premixed in the cartridge.   
Soliqua 100/33: prefilled disposable SoloStar pen-injector containing 3 mL of a sterile solution of 
100 U/mL of insulin glargine and 33 µg/mL of lixisenatide in a ratio of 3:1 (3 units of insulin 
glargine per 1 µg lixisenatide).  
The lixisenatide dose is thereafter increased or decreased along with insulin glargine dose 
changes.  
Lantus: prefilled disposable SoloStar pen-injector containing Lantus are provided to patients 
randomized to the Lantus group at baseline (Week 0, Visit 2) and thereafter. Doses can be set 
from 1 to 80 units in steps of 1 unit.  
Designated study sites using virtual study model will provide the IMP and all required study 
supplies via direct-to-patient shipments, as outlined in the virtual site model Project Plan. 
Shipments will be tracked and confirmed as delivered to patient by the study staff, with 
appropriate documentation in the patient study records. The IMP kit will be confirmed as received 
in good condition and within the acceptable temperature range (ie, fit for use). A virtual visit via 
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telemedicine will be completed to instruct patient on correct use and dosing of study medication, 
which will also be documented as part of the patient’s study record. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
The protocol-mandated background OADs (Section 8.2.1) and rescue medication(s) used to treat 
hyperglycemia (Section 8.2.1) are considered non-investigational medicinal products (NIMP).  
8.2.1 Background oral antidiabetic treatment 
Patients in both treatment groups will continue with their permitted background OADs at stable 
doses and regimens until the end of the study unless there is a specific safety issue related to this 
treatment. Background OAD will be administered orally according to the locally approved label. 
8.2.2 Rescue therapy 
Rescue treatment is to be initiated, according to the Investigator’s judgment in the event that at (or 
after) Week 12, HbA1c is >8%. 
AND IF: 
1. No explanation can be found for the insufficient glucose control (eg, infectious disease, 
lack of compliance with study treatment, non-compliance with diet and lifestyle 
requirements)  
2. The appropriate actions to correct potential triggering factors fail  
3. For patients randomized to Soliqua 100/33, an insulin glargine dose >60 units/day is 
necessary to decrease HbA1c below the threshold values (ie, further dose titration is not 
possible) and 
4. The HbA1c value exceeding the threshold is confirmed by repeat test (performed at the 
central laboratory) approximately 4 weeks after the initial measurement (or at a time point 
considered appropriate by the Investigator). 
Note: The 4-week HbA1c repeat may be waived if, according to the Investigator’s judgment, the 
patient does not have any precipitating factors leading to an elevated HbA1c that must be 
addressed, and that it is in the best interest of the patient to initiate rescue immediately. 
Rapid acting insulin (glulisine) is suggested as rescue therapy and it should be started as a once-
daily regimen administered prior to the main meal of the day (excluding breakfast). If, according 
to the Investigator’s judgement, rapid-acting insulin is not in the best interest of the patient, 
addition of an OAD (within the category of permitted background medications) or increases in the 
OAD doses already taken by the patient (according to the local label) may be considered as a 
secondary option for rescue therapy. 
Note: GLP-1 receptor agonists are not permitted as rescue therapy. 
After these assessments are completed and rescue therapy is initiated, the patient should remain in 
the study and continue to administer the study treatment (including background therapy). The 
planned visits and assessments should be performed until the last scheduled visit. 
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8.3 
BLINDING PROCEDURES 
This study is open-label.  
8.3.1 Methods of blinding 
This study has an open-label design with respect to treatment assignment (ie, Soliqua 100/33 and 
Lantus) and individual efficacy/safety data.  
To compensate for the lack of blinding in the data review process, summary statistics (including 
for the primary efficacy parameter) will be tabulated by dummy treatment arm. The actual 
randomized treatment assignments will not be applied to aggregate summary statistics until the 
database has been locked for the primary analysis. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Patients will be randomized at Visit 2 to one of the two following treatment arms: 
• 
Soliqua 100/33 once daily, or 
• 
Lantus once daily. 
The randomization ratio is 1:1. The patients will be randomized according to their self-reported 
ethnicity/race (ie, Hispanics of any race, non-Hispanic black/African Americans, and non-
Hispanic Asians); randomization will be capped to include an approximately similar numbers of 
patients (ie, 400) within each ethnic/racial subgroup, with approximately 200 patients per 
ethnic/racial group receiving Soliqua 100/33 and approximately 200 receiving Lantus. 
Additionally, to ensure a balanced IMP allocation, randomization will be stratified by the patients’ 
self-reported ethnic/racial group, screening HbA1c value (<8.5% versus ≥8.5%), the background 
use of SGLT-2 inhibitors (yes/no), and the background use of SUs (yes/no). 
The randomization and the treatment allocation are performed centrally by an interactive response 
technology (IRT). The randomized treatment kit number list is generated centrally by Sanofi and 
the Study Biostatistician provides the randomization scheme (including stratification) to the IRT. 
Then, the IRT generates the patient randomization list according to which it allocates treatment 
groups to the patients.  
As part of the screening procedures the Investigator or designee has to contact the IRT vendor to 
receive the patient number. The patient identification (patient number) is composed of a 12-digit 
number containing the 3-digit country code (840 = USA), 4-digit center code, and the 5-digit 
patient chronological number (which is 00001 for the first patient screened in a center, 00002 for 
the second patient screened in the same center, etc.). 
A patient cannot be randomized more than once in the study. 
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8.5 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
The appropriate number of kits will be dispensed to provide patients with IMP coverage up to the 
next dispensing visit (please refer to Table 1). Storage conditions and use-by-end date are part of 
the label text. 
Treatment labels will indicate the treatment number (used for treatment allocation and reported in 
the eCRF). The patient number, visit number, date of dispensation, and any other applicable 
information as required per site will be entered manually by the site staff on the treatment box 
label prior to dispensing. 
Soliqua 100/33 SoloStar pens containing a 3 ml solution of insulin glargine 100 U/ml and 
lixisenatide 33 µg/mL are supplied as open-label treatment kits containing 3 prefilled 
Soliqua 100/33 SoloStar pens. 
Lantus SoloStar pens containing a 3 ml solution of insulin glargine 100 U/mL are supplied as 
open-label treatment kits containing 3 prefilled Lantus SoloStar pens. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists, IMP managers) are responsible for 
storing IMP in a secure and safe place in accordance with local regulations, labeling 
specifications, policies and procedures. 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. 
The study sites that will employ the virtual (telemedicine) study model will have IMP shipped 
directly to study patients. These sites will receive IMP from sponsor and store it as required per 
protocol until ready to send to the patient per study schedule. IMP management software will be 
used for IMP accountability and management. Storage conditions are temperature-controlled, with 
continuous temperature monitoring and alarm system. All direct to participant IMP shipments 
require temperature controlled shipment conditions, be protected from light, and must not be 
frozen.  
The expiry date is mentioned on the IMP labels and storage conditions are written on the IMP 
labels.   
8.7 
RESPONSIBILITIES 
The Investigator or other personnel designated by the Investigator and allowed to store and 
dispense the IMP will be responsible for ensuring that IMP used in the clinical trial is securely 
maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. 
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All IMP will be dispensed in accordance with the Investigator's responsibilities and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly communicated to the 
Sponsor or designee. Some deficiencies may be recorded through a complaint procedure. 
Certain defects in the quality of IMP may be subject to potential initiation of a recall procedure by 
the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct-to-
patient shipment, for which a courier company has been approved by the Sponsor), allow the IMP 
to be used other than as directed by this clinical trial protocol, or dispose of IMP in any other 
manner. 
8.7.1 Treatment accountability and compliance 
At each contact with the patient, either by phone/videoconference or during on-site visits, the 
Investigator or his/her medically-qualified designee must ask the patient about the administered 
doses of IMP (additional details are to be found in the study-specific operational documents).  
Returned and dispensed IMP will be documented into tracking logs. Upon IMP return, a visual 
check has to be performed by site staff.   
For NIMP OAD therapy, name, start and end date of treatment, total daily dose, etc, will be 
documented in the source documents and appropriate electronic case report form (eCRF pages. 
Compliance to NIMP OAD therapy will be checked by interviewing the patient at each visit and 
be documented in the source documents and in the eCRF.  
8.7.2 Return and/or destruction of treatments 
Patients within the traditional group (ie, ‘brick & mortar’ sites) have to return all used, in-use and 
unused IMP at either in-person visits or by mail (see more information below). Re-supply will be 
planned according to the study schedule (see Table 1), the in-use IMP and the upcoming planned 
doses.  
Patients have to return all used, in-use, and unused IMP after completing their designated dose 
administrations for the open-label treatment period (or as part of their final assessment procedures 
in case of permanent premature discontinuation).   
All used, partially used, or unused treatments will be retrieved by the Investigator. A detailed 
treatment log of the returned IMP will be established with the Investigator or other personnel 
designated by the Investigator, and countersigned by the Investigator and the Monitoring Team. 
The Investigator will not destroy any IMP unless the Sponsor provides written authorization. 
Authorization for destruction will be given by the Sponsor once reconciliation has been completed 
and all discrepancies have been resolved. Destruction can be performed by site if local regulation 
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permits and on capability of site; alternatively, study drug may be returned to the Sponsor or 
designee for destruction. 
For NIMP, which is not provided by the Sponsor, returns and destructions are not required. Sites 
are required to appropriately maintain source documents and to record data in the eCRF as 
requested by Sponsor or designee. 
For the designated sites using a virtual (telemedicine) study model, all used, in-use, and unused 
IMP will be returned to study site. Patients will collaboratively work with site staff to return IMP 
as required. Once returned, reconciliation will be completed and managed accordingly. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
Any treatment which are continued during the study or are initiated/changed during the study 
must be recorded in the source documents and the eCRF. 
The following drugs are not permitted during the screening period or the treatment periods of the 
study: 
• 
Any type of glucose-lowering agents other than the IMP (including insulins or OADs), 
authorized background anti-diabetic therapy and rescue therapy, if necessary; 
Note:  
- 
Short-term use (≤10 days) of short/rapid-acting insulin due to acute illness or surgery 
(eg, infectious disease) is allowed; 
- 
If, according to the Investigator’s judgment, rapid-acting insulin is not in the best 
interest of the patient, dose increases for concomitant OADs (except for up-titration of 
SUs) to manage uncontrolled hypoglycemia will be considered rescue therapy.  
• 
Systemic (ie, oral or injectable) glucocorticoids for more than 7 days, whereas topical or 
inhaled applications are allowed with no time limit; 
Any weight-loss medication, if applicable, should be maintained at a stable dose throughout the 
study duration. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary efficacy endpoint is the change from baseline to Week 26 in HbA1c (%).  
Blood samples for HbA1c measurements will be collected at Screening and at study time points 
listed in Table 1 and will be measured at a central laboratory.  
If a patient needs to receive rescue antidiabetic medication or if a decision to permanently 
discontinue the IMP is made, an assessment of HbA1c should be performed before the 
introduction of rescue medication/permanent discontinuation. Following introduction of rescue 
medication, the patient should continue in the study and all study procedures according to the 
protocol should be performed. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoints 
• 
Percentage (%) of patients achieving the HbA1c target of <7% at Week 26 
• 
Change in 2-hour postprandial glucose (PPG) as measured utilizing a standardized meal 
test at Week 26 (for patients that performed the standardized meal test) 
• 
Change in 2-hour glycemic excursions as measured utilizing a standardized meal test at 
Week 26 (for patients that performed the standardized meal test) 
• 
Change from baseline to Week 26 in daily insulin glargine dose  
• 
Change from baseline to Week 26 in body weight 
9.2.2 Observation Period for Efficacy Variables 
The on-treatment period for primary and other efficacy variables is defined as the time from the 
first injection of open-label IMP up to 14 days for HbA1c; 0 days for standardized meal test 
parameters and SMPG and insulin glargine dose; 1 day for FPG; and 3 days for body weight after 
the last injection of IMP or up to the introduction of rescue therapy, whichever is the earliest. 
9.2.3 Safety endpoints 
• 
Hypoglycemia 
- 
Documented hypoglycemia (plasma glucose values ≤70 mg/dL [3.9 mmol/L]) 
- Symptomatic hypoglycemia  
- 
Documented hypoglycemia (plasma glucose values <54 mg/dL [3.0 mmol/L]) 
- Symptomatic hypoglycemia  
- 
Severe hypoglycemia 
• 
Adverse events (AEs), including gastrointestinal AEs 
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• 
Serious adverse events (SAEs) 
• 
Adverse events of special interest (AESI): serious allergic/hypersensitivity reactions, 
pregnancy, ALT >3 times the upper limit of normal, pregnancy, and symptomatic 
overdose of IMP/NIMP  
• 
Vital sign parameters (change from baseline) 
9.2.4 Observation Period for Safety Variables 
The observation period for safety data will be divided into 3 segments: 
• 
The pre-treatment period is defined as the time between the date of signing of the 
informed consent and the first injection of IMP, 
• 
The on-treatment period is defined as the time from the first injection of IMP up to and 
including 3 days after the last injection of IMP (treatment-emergent AE [TEAE] period), 
• 
The post-treatment period is defined as the time starting 4 days after last injection of IMP 
(after the TEAE period). 
9.2.4.1 Hypoglycemia 
See Section 10.7.2.  
9.2.4.2 Adverse events 
Refer to Section 10.4 for details. 
9.2.4.3 Vital signs  
Vital signs (systolic and diastolic blood pressure, heart rate) will be measured in sitting position 
(patient must be sitting for approximately 5 minutes prior to the measurements). 
9.3 
OTHER ENDPOINTS 
9.3.1 Other efficacy endpoints 
• 
HbA1c change from baseline to Week 12  
• 
Fasting plasma glucose change from baseline to Week 26  
• 
Percentage of patients requiring rescue therapy by Week 26 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no documented 
symptomatic hypoglycemia (SMPG ≤70 mg/dL [3.9 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no documented 
symptomatic hypoglycemia (SMPG <54 mg/dL [3.0 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain and no documented symptomatic hypoglycemia (SMPG ≤70 mg/dL [3.9 mmol/L] 
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• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain and no documented symptomatic hypoglycemia (SMPG <54 mg/dL [3.0 mmol/L]) 
• 
PRO measures: 
- 
Treatment Related Impact Measure – Diabetes (TRIM-D) 
- 
Patient and Physician Global Treatment Effectiveness Evaluation Scales 
9.3.1.1 Fasting plasma glucose 
Fasting plasma glucose samples will be taken according to the schedule listed in Table 1 and 
measured by a central laboratory. 
9.3.1.2 Percent of patients requiring rescue therapy 
The use of rescue medications for hyperglycemia will be assessed up to Week 26 of treatment.  
9.3.1.3 Soliqua 100/33 and Lantus doses 
The patients are to record their IMP dose daily or any missed IMP injections in the patient diary. 
9.3.2 Patient reported outcome endpoints 
• 
TRIM-D; 
• 
Patient and Physician Global Treatment Effectiveness Evaluation Scales. 
9.3.2.1 Treatment Related Impact Measure – Diabetes 
The general treatment-related impact on patients’ health related quality of life, treatment 
satisfaction and treatment behavior will be assessed using the TRIM-D questionnaire according to 
the schedule listed in Table 1. 
The TRIM-D questionnaire (see Appendix B for an example) is a 28-item measure with 
5 domains assessing Treatment Burden, Daily Life, Diabetes Management, Compliance and 
Psychological Health. This PRO measure can be scored independently for each domain or as a 
total score. 
The 5-point Likert like response options, for all items, range from (1) Not at all 
satisfied/convenient, Never to Extremely/Almost always, Always or Extremely 
dissatisfied/inconvenient to (5) Extremely satisfied/convenient, depending upon the item stem and 
are scored on a scale of 0 to 100 so that a higher score indicates a better health state (less negative 
impact). 
The TRIM-D variables include TRIM-D scores (total and domain scores) and the change in 
TRIM-D scores from baseline to endpoint. 
A domain score is calculated if a respondent answers at least half of the items in a multi-item 
domain (or half plus 1 in the case of domains with an odd number of items). 
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9.3.2.2 Patient and Physician Global Treatment Effectiveness Evaluation Scales 
Patient- and physician-rated global treatment effectiveness evaluation scales are instruments that 
will be measuring whether patient’s overall response to treatment is excellent, good, moderate, 
poor, or whether the patient’s condition is worsening. The variables related to these patient-rated 
and physician-rated global treatment effectiveness scales include the response to each question, 
given according to the schedule listed in Table 1. 
Example patient- and physician-rated global treatment effectiveness evaluation scales are 
provided in Appendix C. 
9.3.3 HbA1c measurement 
For the eligibility and efficacy assessments of the study, HbA1c will be measured by a central 
laboratory to allow estimation of the change from baseline to Week 12 in HbA1c and other 
HbA1c endpoints (eg, <7% at Week 26, <7% at Week 26 with no body weight gain, or <7% at 
Week 26 with no body weight gain and no documented symptomatic hypoglycemia, or <7% at 
Week 26 with no documented symptomatic hypoglycemia).  
9.3.4 Standardized meal test 
At least 75 randomized patients per treatment arm/race/ethnic group will undergo a standardized 
meal challenge to assess fasting and postprandial glucose (tested at a central laboratory), as well 
as the postprandial glycemic excursion, as part of the screening procedures and during Week 26. 
The standardized liquid meal test contains approximately 530 calories per serving, 46 grams of 
total carbohydrate, 22 grams of protein, and 30 grams of fat. The composition and the quantity of 
the standardized meal must be identical throughout the study. 
If a patient participating in the standardized meal test needs to receive a rescue antidiabetic 
medication, the standardized meal test should be performed before the introduction of the rescue 
medication and at the end of the study (Week 26). 
In case of permanent discontinuation of treatment with IMP, the standardized meal test should be 
performed only if the patient receives treatment on the day of the visit. The meal test should also 
be performed at the end of study as planned. 
If the patient drops out of the study, at the time of IMP discontinuation, regardless of whether the 
patient received IMP or not on the day of the meal test, the meal test should be performed. 
On the day of the standardized meal test, the patients must not eat any food or drink, except water, 
for at least 8 hours before the scheduled meal test (to be completed in the morning, if possible). 
Patients in the Soliqua or Lantus AM dosing groups will inject their treatment 30-60 minutes prior 
to the meal. Patients in the Lantus PM dosing group will inject their Lantus at their usual injection 
time. 
The standardized meal for all patients should be consumed within a 15-minute period.  
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Blood for plasma glucose is drawn 5 times:  
• 
30 minutes prior to the start of the meal (during Screening and at end-of-treatment for 
patients randomized to the Lantus PM dosing group) or before IMP administration (at 
Week 26 for the Soliqua 100/33 arm and for the Lantus AM dosing group); 
• 
Just before the start of the standardized meal (Minute 0), at least 30 minutes after the 
Soliqua or Lantus AM dosing injection;  
• 
30 minutes after the start of the standardized meal; 
• 
60 minutes after the start of the standardized meal; 
• 
120 minutes after the start of the standardized meal. 
NOTE: On the day of the Week 26 (end-of-treatment) standardized meal test, morning IMP 
administration (ie, for the Soliqua 100/33 arm and for the Lantus patients administering IMP in 
the morning before breakfast) must be done within the interval between the initial (-30 minutes) 
plasma glucose collection and the Minute 0 plasma glucose collection. The exact times of the IMP 
injection and the standardized meal intake and the blood draws are to be documented.  
Patients who are participating as part of the designated virtual study model will complete this 
meal test at a local laboratory testing facility. 
9.3.5 Self-monitored plasma glucose 
The SMPG will be used to titrate and adjust IMP doses, monitor glycemic control, and also as part 
of hypoglycemia management (Section 8.2.2). The fasting SMPG should be measured by the 
patient before breakfast and before the administration of IMP at least once a day starting from 
Week 0 until target FPG has been met; subsequently, the frequency of SMPG measurements can 
be reduced, according to the Investigator’s judgement, however it should be done at least 3 times 
per week. Patients on PM Lantus dose should perform SMPG prior to administering their IMP. 
Additional SMPG measurements may be performed, as necessary during the study, including at 
any time when suspected symptoms of hypoglycemia are experienced by the patient.  
SMPG during symptomatic hypoglycemia 
Whenever patients experience hypoglycemic symptoms, plasma glucose should be measured by 
the patient (or others, if applicable), if possible. Patients should be instructed to measure plasma 
glucose levels prior to carbohydrate intake/administration of glucose whenever symptomatic 
hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation with the SMPG. Patients must contact the 
Investigator as soon as possible following significant events for review and for decision on any 
necessary actions to be taken. 
9.3.6 Body weight 
Body weight will be measured according to the schedule listed in Table 1. 
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Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. If possible, the same scale should be used throughout 
the study, and calibrated on a regular basis as recommended by the manufacturer. 
Body weight is read and recorded in source data and the eCRF. Self-reported weights are not 
acceptable; patients must not read the scales themselves. 
Patients who are taking in the study as part of the designated virtual study model site will visit 
their local laboratory samples collection site to complete this measurement. 
9.3.7 Dose of IMP 
The study investigator/medically-qualified designee will obtain IMP dosing information during 
each on-site and remote (telephone, video) visit though a patient interview. At the minimum, 
details related to IMP dose and timing during the last 3 days prior to the visit, as well as 
information about any dose changes and IMP dosing interruptions will be collected from the 
patient’s source documents and recorded as appropriate in the eCRF. 
The Investigator will actively monitor the IMP dose on an ongoing basis in order to evaluate 
alignment with the protocol-recommended dosing algorithm.  
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The combination of basal insulin with a GLP-1 receptor agonist in a single daily injection is 
expected to lower HbA1c, with a complementary action on both fasting and postprandial glucose, 
with no or little weight gain or even weight loss, and a limited increased risk of hypoglycemia.  
The primary efficacy analysis of this study comparing Soliqua 100/33 to Lantus will be based on 
the primary endpoint: change in HbA1c from baseline to Week 26 in the overall population and 
within the ethnic/racial sub-groups.  
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. Moreover, 
HbA1c has been shown to correlate with the development of long-term complications of diabetes, 
and reduction of HbA1c is known to reduce the risk of long-term microvascular complications. 
Therefore, HbA1c is considered an appropriate primary endpoint for assessing the effect of a 
treatment on glycemic control. In addition to the analysis of the change from baseline in HbA1c, 
the responder analysis allows the clinical relevance of the reduction observed in HbA1c to be 
demonstrated. The duration of study treatment is considered to be sufficient for achieving stable 
conditions with IMP and for enabling an adequate assessment of time-dependent changes in 
HbA1c and the concomitant risk of hypoglycemia. 
The problem of weight gain in T2DM is widely recognized. More than 80% of individuals with 
T2DM are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not 
only unwelcome, but represents an important clinical issue that can become a barrier to the 
successful management of glycemic control. In this LixiLan-D (Diversity) study it is postulated 
that treatment intensification with the combination product will mitigate the burden of weight gain 
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that is typical when adding or uptitrating basal insulin. Taking into account the major impact of 
insulin-related body weight gain, it is appropriate to include body weight as an element of 
secondary and other endpoints.  
Insulin glargine targets primarily, although not exclusively, fasting hyperglycemia, and 
lixisenatide effectively acts on postprandial glycemia mainly by slowing down gastric emptying. 
Therefore, assessment of both fasting and postprandial glucose (after a standardized meal) is 
relevant in this study. These two parameters are also considered by regulatory agencies to be 
supportive of efficacy of an antidiabetic agent. 
Safety will be evaluated by standard clinical measurements and recording of any gastrointestinal 
events in particular. As both IMPs are approved products with well-established safety profiles, 
routine post-baseline laboratory testing are not planned in the study; however, “for-cause” 
assessments and evaluations will be performed as appropriate as part of AE/SAE management. 
Specific safety parameters of interest for a glucose-lowering injectable peptide such as 
symptomatic hypoglycemia, injection site reactions, and potential allergic reactions will also be 
assessed.  
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments listed in the “Study Flow Chart” in Table 1 are not 
repeated in this section. The aim of this section is to provide details on how some of the 
procedures/assessments have to be performed.  
This is an outpatient study and consists of up to 7 on-site visits (brick & mortar sites) or 
laboratory visits (for patients participating virtually through telemedicine) and 14 phone/video 
visits completed during the open-label randomized treatment period. Additional, optional 
phone/video visits to monitor insulin titration should be scheduled whenever considered necessary 
by the Investigator or designated site staff. 
The patient has to be fasting for all sample collection procedures. As much as possible, these 
procedures should be completed in the morning, at approximately the same time. The patient 
should take OAD treatment and inject the Soliqua 100/33 or morning Lantus (if appropriate) after 
the fasting blood sample has been drawn. For patients administering Lantus in the afternoon or at 
bedtime, dose timing will be in the afternoon/evening, at times as agreed-upon between the patient 
and the Investigator at the time of randomization. 
For the designated sites using the virtual study model, sample collection procedures will be 
completed at the local testing center. 
The fasting condition is defined as an overnight fast of no less than 8 hours that consisted of no 
food or liquid intake, other than water.  
Note: If the patient is not fasting at the time of blood collection visits (both for tradition and 
virtual sites), the blood sample will not be collected and a new appointment for laboratory 
samples collection should be made within the visit window, with instruction to be fasted.   
10.1.1 Diet and Exercise  
Lifestyle and diet counseling will be conducted during the study (in person and/or via 
telemedicine). This will be given by a medically qualified person (eg, registered dietician, 
diabetes educator, nurse, or physician) and should be consistent with the recommendations of the 
national or local guidelines for Type 2 diabetic patients (with regard to the distribution of calories 
among carbohydrates, proteins, and fats, exercise, etc.).  
Compliance with the diet and lifestyle counseling will be discussed with the patient throughout 
the study and more specifically in case of insufficient glucose control (please refer to  
Section 8.2.2). 
10.1.2 Glucometer, patient diaries and IMP titration training 
All patients will be supplied with a glucometer, the corresponding supplies (lancets, test strips, 
etc.), a leaflet, and with electronic diaries at Visit 2/Week 0.  
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The glucometers should be calibrated according to instructions given in the package leaflet and 
the study personnel should also review the use of the glucometers with the patient regularly using 
the provided control solutions for data validity.  
As part of the baseline procedures, patients are trained by the Investigator or qualified designee to 
appropriately utilize the glucometers and the associated supplies. Additionally, the patients will be 
trained on diary data entry (electronic diaries will be utilized in the study) and IMP titration 
requirements (see Section 8.1.1). Training is repeated as often as necessary during the study visits. 
It is the Investigator’s responsibility to ensure appropriate training and re-training of the patients. 
10.1.3 Hypoglycemia training 
As part of the baseline procedures, patients are trained by the Investigator or qualified designee on 
the signs and symptoms of hypoglycemia, hypoglycemia unawareness and the appropriate 
corrective actions (including prompt timing), in order to ensure prevention and mitigation of 
serious/severe hypoglycemia occurrences in the study. Additionally, patients will be trained on the 
hypoglycemia diary completion requirements and the need to contact the Investigator as soon as 
possible in case of a significant hypoglycemia occurrence, so that appropriate actions can be 
taken. Training is repeated as often as necessary during the study visits. It is the Investigator’s 
responsibility to ensure appropriate training and re-training of the patients. The Investigator will 
perform the medical validation of hypoglycemia reported by the study patients. 
10.1.4 Screening period (Week -2 up to Week 0) 
The screening period duration is up to 2 weeks, from the beginning of screening (Week -2) to the 
baseline visit (Visit 2, Week 0). During the screening period, participating patients will undergo 
the 2-hour standardized meal test, which will be completed as part of Visit 1.2 procedures 
(Table 1). This meal test can be performed at any time prior to Visit 2 procedures, once the 
patient’s eligibility based on screening criteria has been confirmed. Once at least 75 randomized 
patients per treatment group/race/ethnicity have completed the screening meal test, this test may 
be stopped for that specific group, at the decision of the Sponsor.   
Only patients who meet the inclusion criteria as noted in Section 7.1 may be randomized. It will 
be the Investigator’s responsibility to confirm that all eligibility criteria have been met prior to 
randomizing the patient.  
During the screening period the patients should continue the anti-hyperglycemic treatment they 
were receiving prior to screening, ie, their background therapy (please see Section 8 for details).  
A one-time re-test of individual screening laboratory tests is permitted, if considered appropriate 
by the Investigator or if any of the laboratory test results are not available at the end of the 
screening period (eg, sample material damaged during transport). Exception to this rule is the 
HbA1c test, which cannot be re-tested during screening unless the result is missing or it is invalid. 
Exceptionally, if justified according to the Investigator and after discussion with the Sponsor or 
designee, the screening period can be extended by 1 additional week (7 days). This may occur in, 
but is not limited to, situations such as when source documentation (eg, from patient’s primary 
physician) needs to be obtained to confirm the diagnosis of T2DM, when screening laboratory 
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results demand further clarification, in cases where there is a delay in IMP supply or when the 
patient requires additional training and time to demonstrate compliance. Randomization 
(Visit 2/Week 0) cannot be scheduled later than 3 weeks after initiation of screening procedures 
(ie, signature of the Informed Consent). 
10.1.4.1 Visit 1 (screening visit, Week-2); Visit 2 (baseline visit, Week 0)  
For the complete list and contents of procedures/assessments scheduled for the screening period, 
please refer to the “Study Flow Chart” in Table 1. 
The details of the procedures/assessments to be performed at visits during screening period and 
which are not described elsewhere are provided below: 
Informed consent: 
For both paper and electronic consent documentation processes, the patient will receive verbal 
information concerning the aims and methods of the study, its constraints and risks and the study 
duration at the screening visit. Written information will be provided to the patient and must be 
signed by the patient and Investigator prior to starting any study procedures.  
For those patients who are participating as part of the designated site using virtual study model, a 
secure link will be provided by the study staff to the electronic consent web portal via email, 
along with unique login credentials. Study investigator will complete the informed consent 
process with the patient by telephone/videoconference. Patients who agree to take part in the 
study will provide their handwritten signature using a computer mouse, touchscreen, or stylus on a 
computer tablet in the designated signature block, with study investigator countersigning. 
Once consented, a study device (ie, study specific portable electronic device with preloaded study 
applications) will be sent out to study patients, along with any other supplies required for the 
screening visit, such as lab kits. Instructional information will be included in the delivery and 
delivery will be confirmed by study staff; fit for use of the study portable electronic device and 
study supplies will be confirmed as well via telephone/videoconference and further instructions 
will be provided, if needed. Additional study supplies will be sent to patients as needed 
throughout the study per study schedule, and all study supplies will be returned once study 
participation is completed. 
Telemedicine visits and phone calls will be completed as needed throughout the screening period 
to collect the information noted below. Additional details are provided in the virtual site model 
Project Plan.  
Demography, diabetes and medical/surgical history and medications: 
Demography data that may include, but is not limited to age and/or birth date, gender, and 
ethnicity/race will be collected. Eligible patients must be one of the following: Hispanics of any 
race, non-Hispanic black/African American, or non-Hispanic Asian. The decision for ethnic/racial 
inclusion will be made based on the patient’s self-identification. Mixed-race patients must select 
one of the above-mentioned categories according to their self-identification. If such a selection 
cannot be made, the candidate will be ineligible to participate in the study. 
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Collection of diabetes history will include documentation of duration of diabetes and history of 
microvascular complications (retinopathy, neuropathy, and nephropathy). Medical/surgical history 
including patient’s cardiovascular and allergy history and patient’s family allergy history may be 
recorded. Medical records may be obtained and reviewed during the screening period. 
A check of previous and/or current (concomitant) medications refers to documentation of all 
medications taken at any time during the 6 months prior to Visit 1, including the glucose-lowering 
agents (e.g., insulins, GLP-1 receptor agonists, OADs etc.) and all prescription/over-the-counter 
medications. In women of childbearing potential, the contraceptive methods have to be 
documented. Additional demographic and medical/surgical information may be collected, as 
appropriate. 
Diet and lifestyle counseling: 
Please see Section 10.1.1. 
IRT contact: 
IRT will be contacted for notification of screening and patient number allocation (Section 8.4). 
The IRT contact should occur before any blood sample is drawn because the patient number is 
given by IRT and must be reported on the laboratory requisition forms. 
Glucometer dispensation and training: 
Please see Section 9.3.5. 
Central laboratory testing: 
Blood and urine samples are collected for all central laboratory tests, as noted below, including 
those needed for confirming the patients eligibility for participation in the study. 
Patients who are participating as part of the designated site using a virtual study model will 
complete blood/urine sample collection procedures at the local testing center. These locations are 
available across the country and provide standardized collection and processing of samples. Study 
staff will work closely with patients to arrange these visits. With the exception of screening and at 
Week 26, study patients who are not able to attend a local testing center will be able to complete 
these procedures via a home visit from a nurse or a phlebotomist. All necessary supplies to 
complete sample collections will be shipped to patient with instructions. All samples collected 
will be sent to a central laboratory facility for processing and analysis. For those patients 
participating in the standardized meal test during the screening period, refer to Section 9.3.4. 
Hematology tests will include erythrocytes, hemoglobin, hematocrit, leukocytes, and platelets. 
Serum chemistry tests will include aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, total bilirubin (if >ULN, then the direct and indirect sub-fractions must be 
measured), creatinine, uric acid, sodium, and potassium. Urinalysis tests will include pH, glucose, 
ketones, leukocytes, blood/hemoglobin, and protein. 
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10.1.5 Open-label randomized treatment period (Week 0 to Week 26)  
Patients meeting all eligibility criteria at the end of the screening period will be randomized into 
the open-label randomized treatment period. The duration of the open-label treatment period is 
26 weeks ±3 days from baseline visit (Week 0, Visit 2) to the end-of-treatment visit (Week 26). 
Each patient self-administers IMP (Soliqua 100/33 or Lantus) once daily from Week 0 (Visit 2) 
up to the end of the open-label treatment period (Week 26). The IMP dose will be adjusted 
according to fasting SMPG values (Section 8.1.1). 
10.1.5.1 Baseline visit (Week 0; Visit 2)  
For the complete list and contents of procedures/assessments scheduled for the baseline visit, 
please refer to the “Study Flow Chart” in Table 1 and for detailed description of assessments in 
Section 9. 
The details of the procedures/assessments to be performed at this visit and which are not 
described elsewhere are provided below. 
As part of this visit, all patients at traditional sites will complete a serum sample collection for 
calcitonin. A urine pregnancy sample collection procedure will be performed if the women are of 
childbearing potential. For patients that are women of childbearing potential and are participating 
as part of a designated site using the virtual study model, all pregnancy test will be serum and 
Visit 2 test may be done up to 1 week prior to the Visit 2 date (ie, it may be done at Visit 1.2, if 
the patient performs this visit; however, the results must be obtained prior to patient 
randomization). Calcitonin serum sample collection will be performed for all telemedicine 
patients before any study medication intake (at Visit 2 or Visit 1.2, if the patient performs this 
visit). Sample collection procedures will be completed at a local testing center. Additional 
baseline procedures will be completed via telemedicine. 
Patients must fast for at least 8 hours prior to this visit (for IMP dosing purposes), and must not 
administer OAD(s) at home. 
IRT contact: 
After the screening assessments are completed and eligibility is confirmed, the Investigator or 
designated site staff contacts IRT for randomization. The treatment group (ie, Soliqua 100/33 or 
Lantus) is identified by IRT and patients will enter a 26-week open-label randomized treatment 
period. 
An appointment for 1-week later is scheduled with the patient for the next visit. 
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10.1.5.2 Visits: Weeks 1-5 (Visits 3-7), Weeks 7-11 (Visits 9-13), Week 15 (Visit 15), Week 21 
(Visit 17) and Week 24 (Visit 18) 
The patient is contacted by the Investigator or qualified designee at a scheduled time. If the call or 
video visit has been completed by site staff other than the Investigator, the Investigator has to be 
consulted if an AE/SAE/other significant event (eg, severe/serious hypoglycemia) is suspected, 
and has to be informed in case an AE/SAE has occurred. In case of an AE, the patients may be 
asked to come to the investigational site, as appropriate. A phone/video visit can optionally be 
performed as a clinical visit in case of symptomatic hypoglycemia/AE or for other reasons. 
Detailed instructions for the remote visits are provided in the appropriate study document.   
An appointment should be scheduled for subsequent visits and a reminder for fasting requirements 
should be provided as necessary. 
10.1.5.3 Visits: Week 6 (Visit 8), Week 12 (Visit 14) and Week 18 (Visit 16)  
For the complete list and contents of procedures/assessments scheduled for the treatment period, 
please refer to the “Study Flow Chart” in Table 1 and for detailed description of assessments to 
Section 9. For virtual sites, these procedures will be conducted as per the virtual site model 
Project Plan.  
The details of the procedures/assessments to be performed at visits and which are not described 
elsewhere are provided below. 
Patients enrolled at designated sites using the virtual study model will complete their sample 
collection procedures at the local testing facility, where vital sign and body weight measurements 
will also be performed as required per study schedule. Additional study procedures for these visits 
will be completed via telemedicine and/or phone as appropriate.  
Compliance check 
Compliance check include compliance to IMP and OAD treatment and use of glucometer, review 
of daily fasting SMPG values, and patient diary. 
For all visit procedures that include sample collection, patients are instructed to be fasting for 
8 hours prior to the collection. The glucose meter measurement results, diary entries, and the used 
/in-use pens will be reviewed by the site staff, as required for these visits. When re-supply is 
planned/necessary, site staff will collect the unused pens from patients. If patient is not compliant 
to the study, the training has to be repeated by the site staff. 
Upon completion of each visit, an appointment for the next visit will be made. 
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10.1.5.4 Final on-treatment assessment/end-of-treatment visit (Week 26 [Visit 19]) 
For the complete list and contents of procedures/assessments scheduled for the treatment period, 
please refer to the “Study Flow Chart” in  Table 1 and for detailed descriptions of assessments to 
Section 9. 
The same procedures/assessments including IRT contact as planned at Week 26 have to be 
performed in case of early permanent treatment discontinuation. The IRT has to be contacted in 
order to register the end of treatment. 
Patients enrolled at sites using the virtual study model will complete the required sample 
collections and vital sign and/body weight measurement, as required per schedule, at the local 
testing center. Study staff and investigators will complete additional required study procedures 
with the patient via telemedicine and/or phone as appropriate.  
An appointment for the post-treatment follow-up phone/video visit should be made. 
10.1.6 Post-treatment follow-up visit (Week 26 +3 days [Visit 19 +3]) 
Following the last injection of Soliqua 100/33 or Lantus, either as scheduled or prematurely, a 
post-treatment follow-up phone/video visit is performed 3 (+3) days after the end-of-treatment 
visit for patients who complete the study or withdrew from the study at the time of IMP 
discontinuation. This visit can be a phone/video visit, a telemedicine visit for the designated sites 
using the virtual study model, or if needed a sample collection study visit in case of an ongoing or 
new adverse event during the post-treatment period, if necessary. The patient is called by the 
Investigator or medically qualified designee at a previously agreed-upon time point. 
The post-treatment follow-up phone/video visit is not performed for patients who prematurely 
discontinue IMP treatment and stay in the study though Week 26. 
Detailed instructions for the remote visits are provided in the virtual site model Project Plan.   
10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in the patient’s file 
Evaluations that are reported in the eCRF must be supported by appropriately identified source 
documentation, whether paper or electronic, for items below, but not limited to the following: 
• 
Agreement and signature of informed consent mentioning the study identification; 
• 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology; 
• 
Contraception method for women of childbearing potential; 
• 
Reason for lack of childbearing potential for concerned women (e.g. postmenopausal, 
history of hysterectomy); 
• 
Previous and concomitant medication (including background OAD and rescue therapy); 
• 
Study identification; 
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• 
Treatment kit number, dates of administration and doses of Soliqua 100/33 or Lantus 
Solostar pens; 
• 
Compliance to background OAD therapy assessed by interview; 
• 
Dates of visits and assessments including the examination report; 
• 
Vital signs, height, body weight; 
• 
Central lab reports received at site (dated and signed by the Principal Investigator or 
Sub-Investigator); 
• 
IRT confirmation notifications by fax or e-mail (screening, screen failure, randomization, 
treatment reallocation, treatment/study discontinuation, treatment replacement if 
applicable, etc.); 
• 
Adverse events and follow-up; 
• 
In case of an SAE, the site should file in the source document, if obtained, at least copies 
of the hospitalization reports and any relevant examination reports (eg, imaging reports, 
specialists’ reports, etc.) documenting the follow-up of the SAE or AESI; 
• 
Date of premature study discontinuation (if any) and reason. 
10.2.2 Source data verification requirements for patients not randomized 
For patients not randomized, the source data that must be checked include the patient's 
identification details, the informed consent signed by the patient, the study identification, the dates 
of study visits and the main reasons preventing randomization. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the 
patient should remain in the study and complete all protocol-mandated procedures as long as 
possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs or for other reasons. In case of treatment interruption due to an AE, reinitiating IMP 
treatment will be done under close and appropriate clinical/and or laboratory monitoring if the 
Investigator considers that the relationship of the event to the IMP is unlikely and if the study 
inclusion criteria are still met (refer to Section 7). 
All durations of temporary treatment discontinuation should be recorded in the appropriate eCRF 
pages. 
Temporary treatment discontinuation corresponds to more than 1 dose not administered to the 
patient. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is defined as any treatment discontinuation based on the 
Investigator or patient’s final decision not to re-expose the patient to the IMP at any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP, at any time and for any reason, or the 
Investigator may make the treatment discontinuation decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
Patients may withdraw from treatment with IMP at any time, for reasons including but not limited 
to the following: 
• 
At patient’s own request; 
• 
If, in the Investigator's opinion, continuation with administration of IMP would be 
detrimental to the patient's well-being; 
• 
At the specific request of the Sponsor. 
A patient must withdraw from treatment with IMP in case of the following:  
• 
Intercurrent condition that requires discontinuation of IMP: eg, diagnosis of acute 
pancreatitis confirmed by gastroenterologic evaluation and imaging and calcitonin value 
≥50 pg/mL (14.75 pmol/L) or serious life-threatening hypersensitivity reaction; 
• 
Pregnancy of patient. 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent IMP discontinuation for the patient concerned. 
10.3.4 Handling of patients after permanent treatment discontinuation 
If possible, prior to permanent discontinuation of treatment regardless of the reason or as soon as 
possible after the decision for discontinuation has been made, the patients will undergo the 
procedure normally planned for the last dosing day with the IMP (Week 26/End-of-treatment 
visit). 
Patients will be requested to continue the study procedures specified in this protocol up to the 
scheduled date of study completion (except for the Follow-up Visit), or up to recovery or 
stabilization of any AE, whichever comes last. More specifically, when treatment is prematurely 
discontinued before Week 26, all patients’ data (efficacy and safety, including hypoglycemia) will 
be collected continuously up to the scheduled Week 26 visit unless the patient withdraws consent 
for any further participation in the study.   
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
eCRF and in the patient’s source documents, as appropriate. The IRT should be notified when a 
patient prematurely discontinues treatment. 
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10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion at any time and irrespective of 
reason. Withdrawal of consent for treatment should be distinguished from withdrawal of consent 
for study visits and from withdrawal of consent for non-patient contact follow-up, eg, medical 
records check. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records when confirmed. At the minimum, the date of the 
withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to contact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including his/her vital status. Attempts to contact such patients must be documented 
in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a 
registered letter). 
The Statistical Analysis Plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the patient was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe. 
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• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect, or 
• 
Is a medically important event. Note: The following list of medically important events is 
intended to serve as a guideline for determining which condition has to be considered a 
medically important event. The list is not intended to be exhaustive. 
- Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm;  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc);  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- Development of drug dependence or drug abuse; 
- ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN; 
- Suicide attempt or any event suggestive of suicidality; 
- Syncope, loss of consciousness (except if documented as a a consequence of blood 
sampling); 
- Bullous cutaneous eruptions; 
- Cancers diagnosed during the study or aggravated during the study;  
- Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention (ie, specific measures or corrective treatment) to prevent one of 
the other outcomes listed in the definition above. 
10.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy or safety is planned for this study. The study will not be 
terminated early for excellent efficacy. 
10.5.1 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. AESIs may be added or 
removed during a study by protocol amendment. 
All AESI will be reported to the Sponsor in the same time frame as SAEs, ie, within 24 hours as 
detailed in Section 10.4.1.2. 
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AESI are listed below: 
• 
ALT >3 x ULN (see Appendix D) 
• 
Serious allergic/hypersensitivity reactions (see Section 10.7.1); 
• 
Pregnancy occurring in a female patient administered IMP/NIMP; 
Pregnancy will be recorded as an AESI with immediate notification in all cases. It will be 
qualified as an SAE only if it fulfills one of the seriousness criteria (see Section 10.4.1.2). In the 
event of pregnancy in a female patient, IMP should be discontinued. Follow-up of the pregnancy 
is mandatory until the outcome has been determined. 
• 
Symptomatic overdose of IMP/NIMP. An overdose (accidental or intentional) with the 
IMP/NIMP is an event suspected by the Investigator or spontaneously notified by the 
patient (not based on systemic pen counts) and defined as follows: 
- 
For Soliqua 100/33: any dose greater than 2-fold above the recommended/planned or 
prescribed dose administered per day within this clinical trial (ie, greater than 40 µg for 
lixisenatide and greater than 120 U for insulin glargine); 
- 
For Lantus: any dose administration which, in the Investigator’s opinion based on 
clinical judgment, is considered significantly greater than the prescribed dose of 
insulin; 
- 
For OADs: any dose greater than 2-fold above the recommended/planned or prescribed 
dose administrated per day within this clinical trial. 
The circumstances of the overdose (ie, accidental or intentional) should be clearly specified in the 
verbatim and symptoms, if any, entered on separate AE forms. 
Note: Asymptomatic overdose with IMP does not need immediate notification; the definition is 
the same as described above. Asymptomatic overdose is to be reported in the standard AE page in 
the eCRF. 
10.5.2 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that patient, are 
to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms (both 
the symptoms and the diagnosis should not be separately reported). The Investigator should 
specify the date of onset, severity, action taken with respect to IMP, corrective treatment/therapy 
given, additional investigations performed, outcome, and his/her opinion as to whether there is a 
reasonable possibility that the AE was caused by the IMP/NIMP or by the study procedure(s).  
The Investigator should take appropriate measures to follow all AEs that meet the serious 
criteria/AESI until clinical recovery is complete and laboratory results have returned to normal, 
until progression has been stabilized, or until death, in order to ensure the safety of the patients. 
This may imply that observations will continue beyond the last planned visit per protocol, and that 
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additional investigations may be requested by the monitoring team up to as noticed by the 
Sponsor. For non-serious AEs, the outcome at the time of last patient contact should be 
documented in the source documents and appropriate eCRF pages. 
When treatment is prematurely discontinued, the patient’s observations will continue until the end 
of the study as defined by the protocol for that patient or until the AE is resolved or stabilized. 
Laboratory or vital signs abnormalities are to be recorded as AEs only if:  
• 
Symptomatic and/or  
• 
Requiring either corrective treatment or consultation, and/or  
• 
Leading to IMP discontinuation or modification of dosing, and/or  
• 
Fulfilling a seriousness criterion.  
Instructions for AE reporting are summarized in Table 4. 
10.5.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• 
SEND (preferably by fax or e-mail) a photocopy of documentation for all examinations 
carried out and the dates on which these examinations were performed, to the 
representative of the monitoring team whose name, fax number, and email address appear 
on the clinical trial protocol. Care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the clinical trial are properly mentioned on any 
copy of a source document provided to the Sponsor. For laboratory results, include the 
laboratory normal ranges. 
• 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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10.5.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.5.3, even if not fulfilling a seriousness criterion, 
using the screens in the eCRF. 
Instructions for AE reporting are summarized in Table 4. 
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Table 4 - Summary of adverse event reporting instructions 
CASE REPORT FORM 
COMPLETION 
EVENT CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS 
CATEGORY 
AE 
form 
Safety 
Comple-
mentary Form 
or equivalent 
Other 
specific 
forms 
Adverse Event (non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
Serious allergic/hypersensitivity reactions 
Yes 
Yes 
Yes 
Pregnancy of female patient/subject 
Yes 
Yes 
Yes 
Symptomatic overdose with IMP/NIMP* 
Yes 
No 
Yes 
Adverse Event of Special 
Interest (non-SAE) 
Expedited 
(within 24 hours) 
Increase in ALT 
Yes 
No 
Yes 
Adverse Event (non-SAE, 
non-AESI) leading to 
discontinuation 
Routine 
Others (eg, leading to IMP discontinuation) 
Yes  
No 
Yes 
*: Asymptomatic overdose is reported in the AE form and does not require expedited reporting. 
AE adverse event; AESI adverse event of special interest; IMP investigational medicinal product, SAE serious adverse event.  
10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators.   
• 
All SAEs that are expected and at least reasonably related to IMPs to the regulatory 
authorities, according to local regulations. 
Any AE not listed as an expected event in the Soliqua 100/33 or Lantus USPI will be considered 
as an unexpected event.  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 
10.7 
SAFETY INSTRUCTIONS 
10.7.1 Allergic or allergic-like reaction 
If a patient experiences a serious allergic/hypersensitivity reaction, this has to be reported 
appropriately in the eCRF. 
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10.7.2 Hypoglycemia 
Hypoglycemia will be evaluated in accordance with the 2017 joint position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes on 
reporting hypoglycemia in clinical trials (29). 
The following categories of interest will be presented: 
• 
Documented hypoglycemia with plasma glucose cut-off of ≤70 mg/dL (3.9 mmol/L): 
any hypoglycemia documented by a measured PG ≤70 mg/dL (3.9 mmol/L) regardless of 
symptoms. 
• 
Documented hypoglycemia with plasma glucose cut-off of <54 mg/dL (3.0 mmol/L): 
any hypoglycemia documented by a measure PG <54 mg/dL (3.0 mmol/L) regardless of 
symptoms. 
• 
Severe hypoglycemia: Severe hypoglycemia is an event requiring assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, 
unconsciousness or coma. Plasma glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration.  
The definition of severe hypoglycemia includes all episodes in which neurological impairment 
was severe enough to prevent self-treatment and which were thus thought to place patients at risk 
for injury to themselves or others.  
Note that “requires assistance” means that the patient could not help himself or herself. Assisting 
a patient out of kindness, when assistance is not required, should not be considered a “requires 
assistance” incident.  
Clinical symptoms that are considered to result from a hypoglycemic episode can include (but are 
not necessarily limited to): increased sweating, nervousness, asthenia, tremor, dizziness, increased 
appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and coma. 
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria. All hypoglycemic 
events associated with seizure, unconsciousness or coma must be reported as SAEs. Only 
hypoglycemia events fulfilling the criteria of an SAE will also be documented on AE and SAE 
complementary forms in the eCRF. 
Additional hypoglycemia categories that may be collected include (30): 
• 
Pseudohypoglycemia: is an event during which the patient reports typical symptoms of 
hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a 
measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L). 
• 
Probable symptomatic hypoglycemia: an event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination, (but that was 
presumably caused by a plasma glucose concentration ≤70 mg/dL [≤3.9 mmol/L]) ie, 
symptoms treated with oral carbohydrate without a test of plasma glucose. 
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All hypoglycemia episodes will be recorded by the patients in the study diary and that data will be 
incorporated in the eCRF or an associated, 21 CFR Part 11-compliant database, for access by the 
Investigator, local and central monitoring team, and or generation of the analysis data sets.  
10.7.3 Local tolerability at injection site 
If the Investigator or the patient recognizes any signs of local intolerability at the injection site, 
this should be recorded on the appropriate eCRF pages.  
10.7.4 Monitoring of renal function in case of prolonged and severe nausea and vomiting 
In case of prolonged or severe nausea and vomiting, if clinically indicated, serum creatinine 
measurement has to be centrally performed. If there is an acute increase of serum creatinine, and 
the patient is on metformin, this has to be discontinued until resolution of renal dysfunction. 
10.8 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
All adverse events, including events noted above, will be continuously reviewed and recorded 
throughout the study by the study investigators. Patients who are participating as part of the 
designated site using the virtual study model will also be able to contact study investigators about 
adverse events as needed to either request an immediate telemedicine appointment or to discuss 
the event via a call with the study investigator and/or designated member of the study staff. Study 
investigator will coordinate participant’s care and/or lab tests, procedures, and referrals as 
appropriate with the participant’s local health care provider, and medical records from these 
appointments will be obtained. All reports will be documented as part of source documentation. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the primary efficacy variable change in HbA1c from 
baseline to Week 26, with the following assumptions, based on clinical trial data, along with 
additional modeling exercises (to evaluate the impact of the differences in study design between 
this study and the preapproval studies, eg, lack of placebo run-in): 
• 
A common standard deviation of 0.95% and 
• 
A true difference between Soliqua 100/33 and Lantus in mean change from baseline in 
HbA1c of 0.4%. 
Calculations were made using nQuery Advisor® 7.0. 
A total sample size of 1200 patients (400 per ethnic/racial group, 200 per treatment within each 
group) for inclusion in the intent-to-treat (ITT) population is planned. Two hundred patients per 
treatment/ethnic/racial subgroup would provide 96% power for superiority of Soliqua to Lantus in 
an individual ethnic/racial subgroup at the 1-sided 0.025/3 significance level. This would also 
provide 90% power for superiority in all 3 subgroups. In order to ensure an overall family-wise 
2-sided error rate of 0.05, a Hommel procedure will be used.  
Should barriers to recruitment exist within an ethnic group, Table 5 gives examples of power 
achievable under the same assumptions of the treatment effect: 
Table 5 - Alternate power calculations given recruitment shortcomings 
Number of patients /ethnic 
group/treatment arm 
Power for superiority at 
significant level of one-sided 
0.025/3 
power for superiority in all 
three subgroups if one of 
ethnic groups is under-
recruited 
180 
94.5% 
88% 
150 
89.4% 
83% 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented in the CSR: 
• 
Screened patients: patients who signed the informed consent; 
• 
Randomized patients: patients with a treatment kit number allocated and recorded in the 
IRT database, regardless of whether the treatment kit was used or not; 
• 
The safety population (ie, randomized and treated patients); 
• 
The intent-to-treat (ITT) population (as defined in Section 11.3.1 and analyzed as 
randomized);  
• 
The randomization strata ie, patient’s self-reported ethnic/racial group (ie, Hispanics of 
any race, non-Hispanic black/African Americans, and non-Hispanic Asians), HbA1c value 
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(<8.5% versus ≥8.5%), background use of SGLT-2 inhibitors (yes/no), and background 
use of SUs (yes/no) will be summarized by race/ethnic group. Any discrepancy between 
the strata assigned by IRT and the information reported on the eCRF will be listed for all 
randomized patients; 
• 
Patients who completed the 26-week treatment period; 
• 
Patients who discontinued IMP during the 26-week treatment period, and the reasons for 
treatment discontinuation; 
• 
All patients who attended the Week 26 visit, regardless of whether they discontinued IMP 
during the 26-week treatment period; 
• 
Patients who attended the Week 26 visit and had discontinued IMP during the 26-week 
treatment period. 
For all categories of patients except screened patients, percentages will be calculated using the 
number of randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from treatment, along with reasons for discontinuation, 
will be provided. 
Patients treated but not randomized, patients randomized but not treated, and patients randomized 
but not treated as randomized will be identified and described in separate listings. For any patient 
randomized more than once, only the data associated with the first randomization will be used in 
any analysis population. The safety experience associated with any later randomization will be 
assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients. Patients 
will be analyzed for efficacy analyses according to the treatment group to which they are allocated 
by the IRT according to the randomization schedule at the randomization visit (as randomized), 
irrespective of the treatment actually received. 
11.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
received at least 1 dose of open-label IMP, regardless of the amount of treatment administered. 
Patients will be analyzed for safety analyses according to the treatment actually received. 
In addition:  
• 
Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
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• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
• 
When a patient is exposed to different IMPs, the patient will be analyzed for safety in the 
treatment group (Soliqua 100/33 or Lantus) in which he/she was treated the longest. 
• 
Patients will be excluded from the safety population only if there is documented evidence 
(ie, all study dates recorded as no medication taken) that patients have not taken IMP. 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available, mean, standard deviation (SD), minimum, median, and maximum. 
Categorical data will be summarized by treatment group using count and percentage.  
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The baseline value is defined as the last available value before the first injection of open-label 
IMP or the last available value on or before the date of randomization if not treated with 
open-label IMP. 
Analysis of demographics and baseline characteristics, prior and concomitant medications will be 
provided in detail in the SAP. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received in the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. 
The duration of treatment exposure will be the total number of days of administration of open-
label IMP, regardless of unplanned intermittent discontinuations. 
The duration of IMP exposure will be calculated as: 
(Date of the last open-label IMP injection – Date of the first open-label IMP injection) + 1. 
The number (n) and percentage (%) of patients randomized and exposed to the open-label IMP 
will be presented by categories of cumulative exposure for each treatment group in the safety 
population. The time periods of interest will be defined in the SAP. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient-years will also be presented by treatment 
group in the safety population. 
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11.4.1.2 Compliance  
Overall treatment compliance is defined as the actual number of days with IMP injection 
compared to the planned number of days with IMP injection during the open-label treatment 
period, up to treatment discontinuation. It is calculated according to the following formula: 
Compliance rate (%) = 
100
injection
 
IMP
 with 
days
 
of
number 
 
Planned
injection
 
IMP
 with 
days
 
of
number 
 
Total
×
⎥⎦
⎤
⎢⎣
⎡
. 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance will be summarized by treatment group using mean, SD, median, and range 
for the safety population. In addition, the percentage of patients who have <60%, ≥60 to <80%, 
≥80 to ≤100%, and >100% compliance will be summarized by treatment group. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of Primary Efficacy Endpoint 
Analyses of the primary efficacy endpoint (change from baseline to Week 26 in HbA1c) will be 
performed using the ITT population, using HbA1c values obtained during the 26-week 
randomized treatment period, including those obtained after IMP discontinuation or rescue 
medication use. 
Primary analysis 
The statistical test will be two-sided at a nominal 5% significance level (α level). 
The change in HbA1c from baseline to Week 26 will be analyzed with missing values imputed by 
multiple imputation with the ‘jump to reference’ method. This approach assumes missing at 
random mechanism for missing data in the Lantus (control) group. However, it does not assume 
such a missing at random mechanism for missing data in the Soliqua 100/33 group. For a patient 
in the Soliqua 100/33 group, it assumes that the patient will lose the Soliqua 100/33 treatment 
benefit and uses the parameters of the Lantus (control) group to calculate the patient’s post-
dropout mean response for the conditional mean in the imputation model. 
• 
For patients in the Lantus group who have no HbA1c values at Week 26, the missing data 
will be considered as missing at random. Missing HbA1c values in this situation will be 
imputed by a regression imputation model where the model parameters are derived using 
the observed data from the Lantus group. The regression imputation model will include the 
patient’s baseline HbA1c values and randomization strata of ethnicity/race, SGLT use 
(Yes, No), and SU use (Yes, No) conditioned on the patient’s HbA1c values observed 
prior to dropout. 
• 
For patients in the Soliqua 100/33 group who have no HbA1c values at Week 26, the 
missing HbA1c values will be imputed using a similar imputation model. However, prior 
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to dropout, the patient’s mean response will be calculated using parameters that are 
derived based on the observed data from the Soliqua 100/33 group; post dropout, the 
patient’s mean response will be calculated using parameters that are derived based on the 
observed data from the Lantus (control) group. 
Each of the completed datasets will be analyzed by the analysis of covariance (ANCOVA) model 
with treatment groups, randomization strata of ethnicity/race, SGLT-use (Yes, No), and SU use 
(Yes, No), as fixed effects, and baseline HbA1c as the covariate. Results from each complete 
dataset will be combined to provide the adjusted mean change in HbA1c from baseline to Week 
26 for each treatment group, as well as the between-group difference. If the upper bound of the 2-
sided 95% CI for the adjusted mean difference (Soliqua 100/33 vs. Lantus) in HbA1c change from 
baseline to Week 26 is <0, the superiority of Soliqua 100/33 will be declared. Details of the 
implementation of multiple imputation will be discussed in the SAP. 
Summary statistics (for screening value, baseline value, observed values, and observed changes 
from baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. 
As a secondary analysis to the primary efficacy endpoint, the treatment differences within each 
ethnic/racial subgroup will also be estimated from the adjusted means of the model. 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following baseline or screening factors: 
• 
Race/ethnicity (Hispanics of any race, non-Hispanic black/African American, non-
Hispanic Asian); 
• 
Baseline HbA1c (<8.5%, ≥8.5%); 
• 
SGLT-2 (Yes, No) at screening; 
• 
SU (Yes, No) at screening 
Inferential comparisons of the treatment difference within each subgroup may be conducted and 
details will be discussed in the SAP.   
11.4.2.2 Analyses of secondary efficacy endpoints 
See Section 9.2.1. 
Analyses of the secondary efficacy endpoints will be performed using the ITT population for all 
patients and, separately, by race/ethnicity.  
All categorical secondary efficacy endpoints defined for the 26-week randomized treatment 
period in Section 9.2.1 will be analyzed using a logistic regression model adjusting for treatment 
group and appropriate baseline covariates. Details of the logistic model will be discussed in the 
SAP. The proportion in each treatment group will be provided, as well as the difference of 
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proportions between groups with associated 2-sided 95% CI. For the categorical secondary 
endpoints in which HbA1c is assessed at Week 26, all values at Week 26 will be used to 
determine whether a patient is a responder or not, even if they are measured after IMP 
discontinuation or introduction or rescue therapy. If no assessment is available at Week 26, 
patients will be treated as failures (non-responders).  
Changes from baseline in 2-hour PPG, 2-hour glycemic excursions, daily dose of insulin glargine, 
and body weight will be tabulated by treatment group and visit, and details of inferential statistics 
to determine treatment differences will be discussed in detail in the SAP. 
11.4.2.3 Multiplicity considerations 
To control the familywise Type I error, two different strategies will be used for the family of 
hypotheses corresponding to the primary efficacy endpoints and the family of hypotheses 
corresponding to the secondary efficacy endpoints (please see Section 11.4.2.2).  
For the primary efficacy endpoint (change from baseline to Week 26 in HbA1c) among all 
patients, no multiplicity adjustment is needed to control the Type I error since only 1 comparison 
of Soliqua 100/33 versus Lantus will be performed. If the hypothesis associated with the primary 
efficacy endpoint in all patients is rejected at the 5% level, the primary efficacy endpoint will be 
tested for each of the 3 race/ethnicity subgroups using the Hommel procedure. Specifically, if the 
largest p-value from the 3 ethnic/racial groups is less than or equal to 0.05, then statistical 
significance is achieved at all 3 ethnic/racial groups; if the largest p-value is greater than 0.05 but 
the second-largest p-value is less than or equal to 0.025 then statistical significance is achieved for 
the 2 ethnic/racial groups corresponding to the 2 smaller p-values; if the second-largest p-value is 
greater than 0.025 and the smallest p-value is less than or equal to 00167 OR the smallest p-value 
is less than or equal to 0.025 and the second-smallest p-value is between 0.025 (exclusive) and 
0.0333 (inclusive), then statistical significance is only achieved for the ethnic/racial group 
corresponding to the smallest p-value. 
If all 3 hypotheses associated with the ethnic/racial groups are rejected (statistically significant) 
for the primary efficacy endpoint, 2-sided 5% α level will be split equally among the 3 
race/ethnicity subgroups (0.01667 for each) and the following secondary efficacy variables will be 
tested in the following prioritized order. Testing will stop for a race/ethnicity subgroup when an 
endpoint is found not to be statistically significant at the 1.667% level: 
1. Percentage of patients achieving the HbA1c target of <7% at Week 26 
2. Change in 2-hour PPG as measured utilizing a standardized meal test at Week 26 
3. Change in 2-hour glycemic excursions as measured utilizing a standardized meal test at 
Week 26 
4. Change in daily dose of insulin glargine from baseline to Week 26 
5. Change from baseline in body weight to Week 26 
 
 
 
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Figure 1 - Multiple testing procedure 
 
Test of HbA1c
All patients 
p<0.05
Stop 
no
yes 
Test of HbA1c
3 race/ethnicity subgroups 
All 3 p-values 
significant by Hommel 
c Primary endpoint 
yes 
d Secondary  
endpoints 
Test % HbA1c<7%: 
Hispanic any race 
Test % HbA1c<7%:
Non-Hispanic Black 
Test % HbA1c<7%: 
Non-Hispanic Asian 
p<0.01667 
p<0.01667
p<0.01667 
Test 2-hr PPG: 
Hispanic any race 
Test 2-hr PPG:
Non-Hispanic Black 
Test 2-hr PPG: 
Non-Hispanic Asian 
p<0.01667 
p<0.01667
p<0.01667 
Test 2-hr PPG 
excursions: 
Hispanic any race 
Test 2-hr PPG 
excursions: 
Non-Hispanic Black 
Test 2-hr PPG 
excursions: 
Non-Hispanic Asian 
p<0.01667 
p<0.01667
p<0.01667 
Test change from 
baseline in daily insulin 
glargine dose: 
Hispanic any race 
Test change from 
baseline in daily 
insulin glargine dose: 
Non-Hispanic Black 
Test change from 
baseline in daily 
insulin glargine dose: 
Non-Hispanic Asian 
p<0.01667 
p<0.01667
p<0.01667 
Test change from 
baseline in body 
weight: 
Hispanic any race
Test change from 
baseline in body 
weight: 
Non-Hispanic Black
Test change from 
baseline in body 
weight: 
Non-Hispanic Asian 
yes 
yes 
yes 
yes  
yes 
yes 
yes 
yes 
yes 
yes 
yes 
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11.4.3 Analyses of other endpoints 
Analyses of other endpoints defined in Section 9.3 will be performed on the ITT population using 
all assessments obtained during the 26-week randomized treatment period, including those 
obtained after IMP discontinuation or introduction of rescue therapy. Descriptive statistics will be 
summarized by treatment group. For selected other endpoints defined in Section 9.3.1, descriptive 
statistics will also be summarized by treatment group for the whole study period. 
11.4.4 Analyses of Patient Reported Outcome variables 
The analyses of TRIM-D and global treatment effectiveness evaluation scales (patient- and 
physician-rated) will be performed on the ITT population. 
Descriptive statistics (mean, median, standard deviation and range) for absolute values and for 
changes from baseline will be presented by treatment group per visit for each score.  
The analyses of the patient-rated and physician-rated global treatment effectiveness evaluation 
scales will be performed on the ITT population. Patient- and physician-rated global treatment 
effectiveness evaluation will be presented in frequency and proportion by level of overall 
response to treatment (ie, complete control of diabetes, marked improvement of diabetes, 
discernible but limited improvement in diabetes, no appreciable change in diabetes, or worsening 
of diabetes) at the end of study for each treatment group. 
Details on analyses for PRO variables will be discussed further in the SAP. 
11.4.5 Analyses of safety data 
See Section 9.2.3. 
The summary of safety results will be presented by treatment group for the 26-week randomized 
treatment period, unless specified otherwise.  
All safety analyses will be performed on the safety population as defined in Section 11.3.2 using 
the following common rules: 
The baseline value is defined as the last available value prior to the first injection of open-label 
IMP. 
The following definitions will be applied to laboratory parameters and vital signs. 
• 
The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. PCSA criteria for parameters not cited in the protocol as 
safety parameters will not be analyzed; 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
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11.4.5.1 Analyses of adverse events 
Pretreatment AEs are AEs that developed or worsened or became serious prior to the treatment 
period. 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened (according to the 
Investigator’s) or became serious during the on-treatment period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the post-
treatment period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables may present by SOC (sorted by internationally agreed order), 
high-level group term (HLGT), HLT and preferred term (PT) sorted in alphabetical order for each 
treatment group, the number (n) and percentage (%) of patients experiencing an AE. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase. The denominator for computation of percentages is the safety population within 
each treatment group. 
Summaries of all TEAEs in each treatment group may include: 
• 
The overview of AEs, summarizing number (n) and percentage (%) of patients with any  
- 
TEAE; 
- 
Serious TEAE; 
- 
TEAE leading to death; 
- 
TEAE leading to permanent treatment discontinuation; 
• 
The number (n) and percentage (%) of patients with at least 1 TEAE by primary SOC, 
HLGT, HLT and PT; 
• 
Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT; 
• 
Summary of TEAEs possibly related to open-label IMP, presented by primary SOC and 
PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
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Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number (n) and percent 
(%) of patients in each treatment group. 
Adverse events leading to permanent treatment discontinuation 
TEAEs leading to permanent treatment discontinuation will be summarized and presented as 
number and percent of patients in each treatment group. 
Local tolerability at injection site 
AEs related to local intolerability at the injection site will be identified by searching the term 
“injection site” in the PTs coded from the Investigator reported terms. The number (%) of patients 
with related events will be summarized by treatment group. 
Allergic reactions 
The number (%) of patients with events as reported by Investigators and judged by the 
Investigator or Sanofi as possibly related to IMP will be summarized by treatment group. All 
allergic events reported by Investigators on the AE form for suspected allergic event and its 
associated complementary forms will be listed. 
ALT increase 
The number (%) of patients with events reported on the AE form for ALT increase and its 
associated complementary forms will be summarized by PT for each treatment group. 
Gastrointestinal adverse events 
The number (%) of patients with events reported on the AE form for gastrointestinal adverse 
events will be summarized by PT for each treatment group. 
11.4.5.2 Analyses of hypoglycemia 
See Section 10.7.2. 
The number (%) of patients experiencing a specific hypoglycemic event and the rates of the 
hypoglycemic event per patient year will be derived for each type of hypoglycemia (severe, 
documented [blood glucose ≤70 mg/dL and <54 mg/dL]) and will be summarized by treatment 
group. The pattern of symptomatic hypoglycemia occurrence over time will also be assessed, if 
appropriate. 
11.4.5.3 Analyses of vital sign variables 
See Section 9.2.4.3. 
The number (n) and percentage (%) of patients with PCSA at any evaluation during the 
on-treatment period will be summarized for each vital sign parameter within each treatment 
group. The summaries will include patients in the safety population who have at least 1 parameter 
to be analyzed during the on-treatment period. When the PCSA definition involves the change 
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from the baseline value, patients need also to have a baseline value to be included in the 
summaries.  
Descriptive statistics will be used to summarize the results for systolic and diastolic blood 
pressure and heart rate, and the changes from baseline by visit and for the last on-treatment value 
within each treatment group.  
Tabular and graphical methods may be used to present the results for parameters of interest. 
Listings will be provided with flags indicating the PCSA values. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Sub-investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All patients should be informed to the fullest extent 
possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written, either paper or electronic, 
informed consent form should be signed, name filled in and personally dated by the patient or by 
the patient’s legally acceptable representative, and by the person who conducted the informed 
consent discussion. A copy of the signed and dated written informed consent form will be 
provided to the patient.  
The informed consent form and any electronic platform used by the Investigator for obtaining the 
patient's informed consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate ethics committee (IRB/IEC) for approval/favorable opinion. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda or labeling documents [summary of product characteristics, package insert], 
Investigator’s curriculum vitae [CV], etc.) and the date of the review should be clearly stated on 
the written (IRB/IEC) approval/favorable opinion. 
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The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol in an accurate manner according to the instructions provided and to ensure direct access 
to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
For the designated sites using virtual study model, remote study monitoring will be completed in 
addition to the on-site monitoring as described above. As part of remote monitoring, study 
monitors will be able to review electronic source documentation with view-only access, including 
medical records which will be available in each participant’s study record. Trial-specific access to 
the electronic source records will be granted only the designated study monitors upon completion 
of training, which will be provided by the study site. Trial reports can be made available for 
review as well. Study monitors will issue queries and request resolutions, which will be completed 
by the study staff under supervision from the study investigators. All study-specific eCRF 
guidelines for resolutions will be followed. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, whether paper or electronic, except for the pre-identified source data directly recorded 
in the CRF, if applicable. The informed consent form will include a statement by which the 
patient allows the Sponsor’s duly authorized personnel, the ethics committee (IRB/IEC), and the 
regulatory authorities to have direct access to original medical records which support the data on 
the CRFs (eg, patient's medical file, appointment books, original laboratory records, etc.). These 
personnel, bound by professional secrecy, must maintain the confidentiality of all personal 
identity or personal medical information (according to confidentiality and personal data protection 
rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner.  
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
Subject race or ethnicity (Hispanic of any race, non-Hispanic black/African Americans and 
non-Hispanic Asians) will be collected in this study because of the study objectives and also 
because these data are required by several regulatory authorities. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRBs/IECs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio; 
• 
Patient enrollment is unsatisfactory; 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• 
Noncompliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
• 
The total planned number of randomized patients has been reached. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator agrees not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, with the understanding that the Sponsor 
will not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
 1. United States Census Bureau. US and World Population Clock. Retrieved February 23, 2017 
2. United States Census Bureau. https://www.census.gov/topics/population/race/about.html 
3. United States Census Briefs. The White Population: 2010. 
https://www.census.gov/prod/cen2010/briefs/c2010br-05.pdf 
4. United States Census Briefs. The Hispanic Population: 2010. 
https://www.census.gov/prod/cen2010/briefs/c2010br-04.pdf 
5. United States Census Briefs. The Black Population: 2010. 
https://www.census.gov/prod/cen2010/briefs/c2010br-06.pdf 
6. United States Census Briefs. The Asian Population: 2010. 
https://www.census.gov/prod/cen2010/briefs/c2010br-11.pdf 
7. Passel JS,Cohn D. U.S. Population Projections: 2005 to 2050.  Pew Research Center. February 
2008. 
8. Peek ME, Cargill A, Huang ES. Diabetes Health Disparities: A Systematic Review of health 
Care Interventions. Med Care Res Rev. 2007 Oct;64(5 Suppl):101S-56S. 
9. Center of Disease Control. National Diabetes Statistics Report. Estimates of Diabetes and Its 
Burden in the United States. 2014. https://www.cdc.gov/diabetes/pubs/statsreport14/national-
diabetes-report-web.pdf 
10. Thomas SB, Quinn SC. Poverty and Elimination of Urban Health Disparities: challenge and 
opportunity. Ann N Y Acad Sci. 2008;1136:111-25. 
11. Marshall MC Jr. Diabetes in African Americans. Postgrad Med J. 2005 Dec;81(962):734-40. 
12. McFarlane SI, Chaiken RL, Hirsch S, Harrington P, Lebovitz HE, Banerji MA. Near-
normoglycaemic remission in African-Americans with Type 2 Diabetes Mellitus is Associated 
with Recovery of Beta Cell Function. Diabet Med. 2001 Jan;18(1):10-6. 
13. Velasquez-Mieyer PA, Cowan PA, Perez-Faustinelli S, Nieto-Martinez R, Villegas-Barreto C, 
Tolley EA, et al. Racial Disparity in Glucagon-Like Peptide 1 and Inflammation Markers 
Among Severily Obese Adolescents. Diabetes Care. 2008 Apr;31(4):770-5. 
14. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The Prevalence of Meeting 
A1C, Blood Pressure, and LDL Goals Among People with Diabetes, 1988-2010. Diabetes 
Care. 2013 Aug;36(8):2271-9. 
15. Phillips WT. Gastric Emptying in Ethnic Populations: Possible Relationship to Development 
of Diabetes and Metabolic Syndrome. Ethn Dis. 2006 Summer;16(3):682-92. 
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16. Yabe D, Seino Y, Fukushima M, Seino S. Beta Cell Dysfunction Versus Insulin Resistance in 
the Pathogenesis of Type 2 Diabetes in East Asians. Curr Diab Rep. 2015 Jun;15(6):602. 
17. U.S. FDA Consumer Health Information. 
https://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM349488.pdf 
18. Hussain-Gambles M, Atkin K, Leese B. Why ethnic minority groups are under-represented in 
clinical trials: a review of the literature. Health Soc Care Community. 2004 Sep;12(5):382-8. 
19. Ferdinand KC, Nasser SA. Racial/ethnic disparities in prevalence and care of patients with 
type 2 diabetes mellitus. Curr Med Res Opin. 2015 May;31(5):913-23. 
20. Keith CF, Samar AN. (2015) Racial/ethnic disparities in prevalence and care of patients with 
type 2 diabetes mellitus, Current Medical Research and Opinion, 31:5, 913-923, DOI: 
10.1185/03007995.2015.1029894 http://dx.doi.org/10.1185/03007995.2015.1029894. 
21. Shea, S, Weinstock RS, Starren J, Teresi J, Palmas W, Field L, et al. A Randomized Trial 
Comparing Telemedicine Case Management with Usual Care in Older, Ethnically Diverse, 
Medically Underserved Patients with Diabetes Mellitus. J Am Med Inform Assoc. 2006 Jan-
Feb;13(1):40–51. 
22. Turner J, Larsen M, Tarassenko L, Neil A, Farmer A. Implementation of telehealth support for 
patients with type 2 diabetes using insulin treatment: an exploratory study. Inform Prim Care. 
2009;17(1),47-53. 
23. Siminerio L, Ruppert K, Huber K, Toledo FG. Telemedicine for Reach, Education, Access, 
and Treatment (TREAT): Linking Telemedicine With Diabetes Self-management Education to 
Improve Care in Rural Communities. Diabetes Educ. 2014 Nov-Dec;40(6):797-805. 
24. Zhai YK, Zhu WJ, Cai YL, Sun DX, Zhao J. Clinical- and Cost-effectiveness of Telemedicine 
in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. Medicine (Baltimore). 
2014 Dec;93(28):e312. 
25. Davis RM, Hitch AD, Salaam MM, Herman WH, Zimmer-Galler IE, Mayer-Davis EJ. 
TeleHealth Improves Diabetes Self-Management in an Underserved Community: Diabetes 
TeleCare. Diabetes Care. 2010 Aug;33(8):1712-7. 
26. U.S. FDA Consumer Update. FDA Encourages More Participation and Diversity in Clinical 
Trials. Published January 10, 2017. 
https://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM535522.pdf. 
27. SOLIQUA™100/33 United States Package Insert 
28. LANTUS® United States Package Insert 
29. Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be Reported in Clinical 
Trials: A Joint Position Statement of the American Diabetes Association and the European 
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Association for the Study of Diabetes. International Hypoglycaemia Study Group. Diabetes 
Care. 2017 Jan;40(1):155-157. 
30. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
Diabetes A Report of a Workgroup of the  American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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17 
APPENDICES 
 
Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
6. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. However, in the absence of 12 months of amenorrhea, these patients 
should be considered to be of childbearing potential and should follow contraception 
guidelines accordingly.  
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
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Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects 
participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce 
the efficacy of the contraceptive method. In this case 2 highly effective methods of contraception 
should be used during the treatment period and for at least [XX, corresponding to time needed to 
eliminate study treatment plus 30 days for study treatments with genotoxic potential] after the last 
dose of study treatment. 
COLLECTION OF PREGNANCY INFORMATION 
Female subjects who become pregnant  
• 
The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study  
• 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or termination of a pregnancy will be reported as an AE or SAE.  
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• 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.5.3. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting.  
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Appendix B 
 
 
 
 
 
 
 
 
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Appendix C 
 
 
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Appendix D 
General Guidance for the follow-up of laboratory abnormalities 
(ALT) by Sanofi  
 
 
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Appendix E 
Back-up Plan for SAE and other Investigator Expedited Events 
reporting process when the eCRF system fails 
 
 
SAE identified
Investigator prints the SAE form from the 
eCRF system
Or
Obtain paper copy of the SAE forms
Investigator 
completes the 
paper SAE 
forms
Local CRU 
Safety 
Office
 
CRU safety 
specialists 
review for 
accuracy and 
completeness 
S-A GPE
        Within        24 hours
         Within next business  day or earlier if possible*
 
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LPS14860 16.1.1 Amended protocol 01
Clinical Approval
20-Dec-2017 14:44 GMT+0100
Regulatory Approval
20-Dec-2017 14:50 GMT+0100
Clinical Approval
20-Dec-2017 15:34 GMT+0100
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
STATISTICAL ANALYSIS PLAN 
A 26-week randomized, open-label, active-controlled, 2-treatment arm, 
parallel-group multi-center study, comparing the efficacy and safety of 
Soliqua™100/33 versus Lantus® in ethnically/racially diverse patients with Type 2 
diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic 
agents 
Soliqua™100/33 -LPS14860
STATISTICIAN:
   
DATE OF ISSUE: 28-Feb-2019 
Initial SAP version number 1.0 dated: 14-MAR-2018 
Total number of pages: 
57 
(electronic 3.0)
NCT Number: NCT03434119


Statistical Analysis Plan  
28-Feb-2019 
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Version number: 3 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................6 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................6 
1.2 
OBJECTIVES...................................................................................................................................6 
1.2.1 
Primary objectives............................................................................................................................6 
1.2.2 
Secondary objectives .......................................................................................................................6 
1.2.3 
Other objectives ...............................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................7 
1.4 
STUDY PLAN...................................................................................................................................7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................8 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................8 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .......................................................................9 
2.1 
ANALYSIS ENDPOINTS..................................................................................................................9 
2.1.1 
Demographic and baseline characteristics ......................................................................................9 
2.1.2 
Prior or concomitant medications...................................................................................................10 
2.1.3 
Efficacy endpoints ..........................................................................................................................12 
2.1.3.1 
Primary efficacy endpoint(s)...........................................................................................................13 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................13 
2.1.3.3 
Other efficacy endpoints ................................................................................................................13 
2.1.4 
Safety endpoints.............................................................................................................................14 
2.1.4.1 
Hypoglycemia.................................................................................................................................14 
2.1.4.2 
Adverse events variables ...............................................................................................................16 
2.1.4.3 
Deaths............................................................................................................................................17 
2.1.4.4 
Laboratory safety variables ............................................................................................................17 
2.1.4.5 
Vital signs variables........................................................................................................................17 
2.1.5 
Pharmacokinetic variables .............................................................................................................17 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................17 
2.1.7 
Quality-of-life endpoints..................................................................................................................18 
2.1.7.1 
Treatment Related Impact Measure – Diabetes ............................................................................18 
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2.1.7.2 
Patient and Physician Global Treatment Effectiveness Evaluation Scales....................................18 
2.1.8 
Health economic endpoints............................................................................................................19 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................19 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................20 
2.3.1 
Efficacy populations .......................................................................................................................20 
2.3.2 
Safety population............................................................................................................................21 
2.4 
STATISTICAL METHODS .............................................................................................................21 
2.4.1 
Demographics and baseline characteristics ..................................................................................21 
2.4.2 
Prior or concomitant medications...................................................................................................22 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................23 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................23 
2.4.3.2 
Compliance ....................................................................................................................................23 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................24 
2.4.4.1 
Analysis of primary efficacy endpoint(s).........................................................................................24 
2.4.4.2 
Analyses of secondary efficacy endpoints .....................................................................................25 
2.4.4.3 
Multiplicity issues............................................................................................................................25 
2.4.4.4 
Additional efficacy analysis ............................................................................................................25 
2.4.5 
Analyses of safety data ..................................................................................................................26 
2.4.5.1 
Hypoglycemia.................................................................................................................................27 
2.4.5.2 
Analyses of adverse events ...........................................................................................................27 
2.4.5.3 
Deaths............................................................................................................................................30 
2.4.5.4 
Analyses of laboratory variables ....................................................................................................30 
2.4.5.5 
Analyses of vital sign variables ......................................................................................................32 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................32 
2.4.7 
Analyses of patient reported outcome variables ............................................................................32 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................32 
2.5.1 
General conventions ......................................................................................................................32 
2.5.2 
Missing data ...................................................................................................................................33 
2.5.3 
Windows for time points.................................................................................................................35 
2.5.4 
Unscheduled visits .........................................................................................................................38 
2.5.5 
Pooling of centers for statistical analyses ......................................................................................38 
2.5.6 
Statistical technical issues .............................................................................................................38 
3 
INTERIM ANALYSIS .....................................................................................................................39 
4 
DATABASE LOCK ........................................................................................................................40 
5 
SOFTWARE DOCUMENTATION..................................................................................................41 
6 
REFERENCES...............................................................................................................................42 
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7 
LIST OF APPENDICES .................................................................................................................43 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......................44 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES.........................................................................52 
APPENDIX C 
STUDY FLOW CHART........................................................................................................54 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AESI: 
adverse event of special interest 
BMI: 
body mass index 
DBP: 
diastolic blood pressure 
eCRF: 
electronic case report form 
HbA1c: 
hemoglobin A1c 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
LLT: 
lower level term 
MedDRA: 
medical dictionary for regulatory activities 
OAD: 
oral antidiabetic drug 
OC: 
observed case 
PCSA: 
potentially clinically significant abnormality 
PPG: 
postprandial glucose 
PRO: 
patient reported outcome 
PT: 
preferred term 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SMPG: 
self-monitoring of plasma glucose 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
WHO-DD: 
world health organization-drug dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This study is an open-label, 1:1 randomized, active-controlled, 26-week duration, parallel-group, 
multicenter, US-only, Phase 3b study to compare the efficacy and safety of Soliqua 100/33 with 
Lantus overall and in ethnically/racially diverse groups with T2DM inadequately controlled on 
basal insulin and 1 or 2 OAD agents. The patients will be randomized according to their self-
reported ethnicity/race (i.e., Hispanics of any race, non-Hispanic black/African Americans and 
non-Hispanic Asians). Additionally, to ensure a balanced IMP allocation, randomization will be 
stratified by their screening HbA1c value (<8.5% versus ≥8.5%), the background use of SGLT-2 
inhibitors (yes/no) and the background use of SUs (yes/no). Patients will participate in 1 of 2 
ways, either at a traditional ‘brick & mortar’ investigational site, or fully remotely through a 
virtual arrangement.  
The study will consist of 3 periods: 
• 
An up to 2-week screening period  
• 
A 26-week open-label randomized treatment period: at the end of the screening period 
(Week 0, Visit 2) patients will be randomized to receive either Soliqua 100/33 or Lantus  
• 
A 3-day post-treatment safety follow-up period (not required for patients who prematurely 
and permanently discontinued IMP administration but stayed in the study though Week 26; 
these patients should continue all study visits except for the follow-up visit). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
• 
To demonstrate the superiority of Soliqua 100/33 versus Lantus in the HbA1c change from 
baseline to Week 26 within the overall population. 
• 
To demonstrate the benefit of Soliqua 100/33 versus Lantus in the HbA1c change from 
baseline to Week 26 within each ethnic/racial subgroup evaluated (i.e., Hispanics of any 
race, non-Hispanic black/African Americans and non-Hispanic Asians). 
1.2.2 Secondary objectives 
• 
To assess the effects of Soliqua 100/33 versus Lantus on the secondary efficacy parameters 
to Week 26 for the selected endpoint within each ethnic/racial subgroup evaluated. 
• 
To assess the change from baseline to Week 26 in daily insulin glargine dose within each 
ethnic/racial subgroup.  
• 
To evaluate the safety and tolerability (egg, gastrointestinal tolerability) of Soliqua 100/33 
versus Lantus to Week 26 within each ethnic/racial subgroup. 
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1.2.3 Other objectives 
• 
To assess the effects of Soliqua 100/33 versus Lantus on other efficacy parameters to 
Week 26 for the selected endpoint within each ethnic/racial subgroup evaluated. 
• 
To assess the effects of Soliqua 100/33 versus Lantus on efficacy and safety parameters to 
Week 26 in the overall population. 
• 
To evaluate and compare the effect of Soliqua 100/33 versus Lantus on Patient Reported 
Outcome (PRO) measures to Week 26 within each ethnic/racial subgroup. 
1.3 
DETERMINATION OF SAMPLE SIZE 
Due to difficulty in recruitment, it has been decided to terminate the trial early, leading to a total 
sample size of 240 patients (120 per treatment), for which efficacy and safety of Soliqua 100/33 
and Lantus will be evaluated using descriptive statistics. 
1.4 
STUDY PLAN 
 
a: Stratified by (1) ethnicity/race, (2) HbA1c at visit 1, (3) background use of SGLT2 inhibitors and (4) background SU use. 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
01 
18-Dec-2017 
Removal of extension 
 
secondary/other efficacy endpoints 
Removal of all analysis related to the 
extension phase 
Order of secondary efficacy endpoint testing 
hierarchy was changed according to the 
current list of secondary efficacy endpoints. 
 
 
 
 
 
 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan. 
 
Table 2 – Statistical analysis plan statistical changes 
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
This version 
 
FDA statistical comments 
 
Safety analysis added: AEs and AESIs 
summarized over the whole on-study period 
(on-treatment and post-treatment) 
This version 
 
 sponsor strategic decision of trial 
early termination 
 Changes on sample size and efficacy endpoint 
analyses 
This version 
 
 
Minor changes in lab test  
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
The endpoints listed in this section correspond to the originally planned endpoints collected per 
protocol. Only the critical endpoints will be analyzed with more details in Section 2.4. 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value prior to the first dose administration of 
investigational medicinal product (IMP) or the last available value on or before the date of 
randomization if not treated with IMP. 
All baseline safety parameters are presented along with the summary statistics in the safety section 
(Section 2.4.5).  Baseline efficacy parameters are provided as part of the baseline characteristics, 
in addition to efficacy summaries in the efficacy section (Section 2.4.4). 
Demographic characteristics 
Demographic characteristics to be summarized are: 
• 
Age (years) derived as: (Date of informed – Date of birth)/365.25, 
• 
Age categories (<50, ≥50 to <65, ≥65 to < 75, ≥75 years), 
• 
Gender (Male, Female), 
• 
Self-reported ethnicity/race (Hispanics of any race, non-Hispanic black/African 
Americans, and non-Hispanic Asians)), 
• 
HbA1c (%) at Screening, 
• 
FPG at screening, 
• 
Body weight at screening, 
• 
BMI at screening, 
• 
Randomization strata of HbA1c (<8.5%, ≥8.5%) at Screening, 
• 
Randomization strata of background use of SGLT-2 inhibitors (yes, no) at Screening, 
• 
Randomization strata of background use of sulfonylureas (yes, no) at Screening, 
• 
Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2, 
• 
Baseline BMI categories (<30, ≥30 kg/m2), 
 
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Medical or surgical history 
Medical history and medical findings include: 
• 
Medical or surgical history, 
• 
Family allergy history, 
• 
Diabetes history information, 
• 
Diabetes complication history, 
• 
Alcohol habits, 
• 
Tobacco smoking habits. 
Medical and surgical history will be coded to a “lower level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline   
Diabetes history includes: 
Duration of diabetes (years) derived as: (Date of informed consent – Date of diagnosis of diabetes 
+ 1)/365.25, 
• 
Duration of diabetes categories: (<10, ≥10 years) 
• 
Age at onset of diabetes (years) derived as: Year of diagnosis of diabetes – Year of birth, 
• 
Type of OADs at Screening 
• 
Type of basal insulin at screening 
• 
History of gestational diabetes (Yes, No) 
• 
Baseline diabetic complications (Yes, No to Diabetic retinopathy, Diabetic neuropathy, 
and Diabetic nephropathy)  
• 
eGFR at screening (mL/min/1.73m2), 
• 
eGFR categories at screening (<15 mL/min/1.73m2 [End stage renal disease], ≥15 to <30 
mL/min/1.73m2 [Severe decrease in GFR], ≥30 to <60 mL/min/1.73m2 [Moderate 
decrease in GFR], ≥60 to <90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 
mL/min/1.73m2 [Normal]). 
2.1.2 Prior or concomitant medications  
All medications taken within 6 months before the screening visit and until the end of the study are 
to be reported in the electronic case report form (eCRF). 
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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• 
Prior medications are those the patient used prior to first administration of IMP.  Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment phase.   
• 
Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the 1st administration of IMP to the date of last administration + 3 days.  A 
given medication can be classified both as a prior medication and as a concomitant 
medication.   
• 
Post-treatment medications are those the patient took (continued or initiated) in the period 
running from the 4th day after the last administration of IMP up to the end of the study. 
Rapid acting insulin (glulisine) is suggested as rescue therapy and it should be started as a once-
daily regimen administered prior to the main meal of the day (excluding breakfast). If, according 
to the Investigator’s judgement, rapid-acting insulin is not in the best interest of the patient, 
addition of an OAD (within the category of permitted background medications) or increases in the 
OAD doses already taken by the patient (according to the local label) may be considered as a 
secondary option for rescue therapy. 
Note: GLP-1 receptor agonists are not permitted as rescue therapy. 
After these assessments are completed and rescue therapy is initiated, the patient should remain in 
the study and continue to administer the study treatment (including background therapy). The 
planned visits and assessments should be performed until the last scheduled visit. 
The following drugs are not permitted during the screening period or the treatment periods of the 
study: 
• 
Any type of glucose-lowering agents other than the IMP (including insulins or OADs), 
authorized background anti-diabetic therapy and rescue therapy, if necessary; 
Note:  
- 
Short-term use (≤10 days) of short/rapid-acting insulin due to acute illness or surgery 
(e.g., infectious disease) is allowed; 
- 
If, according to the Investigator’s judgment, rapid-acting insulin is not in the best 
interest of the patient, dose increases for concomitant OADs (except for up-titration of 
SUs) to manage uncontrolled hyperglycemia will be considered rescue therapy.  
• 
Systemic (i.e., oral or injectable) glucocorticoids for more than 7 days, whereas topical or 
inhaled applications are allowed with no time limit; 
Any weight-loss medication, if applicable, should be maintained at a stable dose throughout the 
study duration. 
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2.1.3 Efficacy endpoints 
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy.  Patients requiring 
rescue are identified as those with the reason for treatment ticked “rescue therapy” in e-CRF 
“Medication” page. 
HbA1c, 2-hour PPG, FPG, glucose excursions are measured/calculated in a central laboratory (see 
study flowchart in Appendix C). Body weight, SBP and DBP are measured at on-site visits by the 
investigator or at the local testing center for subjects enrolled in the virtual sites. Efficacy 
variables will be summarized in both standard international units and conventional units when 
applicable. 
Standardized meal test 
A subset of randomized patients per treatment arm/race/ethnic group will undergo a standardized 
meal challenge to assess fasting and postprandial glucose (tested at a central laboratory), as well as 
the postprandial glycemic excursion, as part of the screening procedures and during Week 26. 
In case of permanent discontinuation of treatment with IMP, the standardized meal test should be 
performed only if the patient receives treatment on the day of the visit. The meal test should also 
be performed at the end of study as planned. 
If the patient drops out of the study, at the time of IMP discontinuation, regardless of whether the 
patient received IMP or not on the day of the meal test, the meal test should be performed. 
Blood for plasma glucose is drawn 5 times:  
• 
30 minutes prior to the start of the meal (during Screening and at end-of-treatment for patients 
randomized to the Lantus PM dosing group) or before IMP administration (at Week 26 for the 
Soliqua 100/33 arm and for the Lantus AM dosing group); 
• 
Just before the start of the standardized meal (Minute 0), at least 30 minutes after the 
Soliqua or Lantus AM dosing injection;  
• 
30 minutes after the start of the standardized meal; 
• 
60 minutes after the start of the standardized meal; 
• 
120 minutes after the start of the standardized meal. 
Patients who are participating as part of the designated virtual study model will complete this meal 
test at a local laboratory testing facility. 
Observation period 
The on-treatment period for primary and other efficacy variables is defined as the time from the 
first injection of open-label IMP up to 14 days for HbA1c; 0 days for standardized meal test 
parameters and SMPG and insulin glargine dose; 1 day for FPG; and 3 days for body weight after 
the last injection of IMP or up to the introduction of rescue therapy, whichever is the earliest. 
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2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the change from baseline to Week 26 in HbA1c (%).  
Blood samples for HbA1c measurements will be collected at Screening and at study time points 
listed in study flow chart and will be measured at a central laboratory.  
If a patient needs to receive rescue antidiabetic medication or if a decision to permanently 
discontinue the IMP is made, an assessment of HbA1c should be performed before the 
introduction of rescue medication/permanent discontinuation. Following introduction of rescue 
medication, the patient should continue in the study and all study procedures according to the 
protocol should be performed. 
2.1.3.2 Secondary efficacy endpoint(s) 
• 
Percentage (%) of patients achieving the HbA1c target of <7% at Week 26 
• 
Change in 2-hour postprandial glucose (PPG) as measured utilizing a standardized meal test at 
Week 26 (for patients that performed the standardized meal test) 
• 
Change in 2-hour glycemic excursions as measured utilizing a standardized meal test at 
Week 26 (for patients that performed the standardized meal test) 
• 
Change from baseline to Week 26 in daily insulin glargine dose  
• 
Change from baseline to Week 26 in body weight 
2.1.3.3 Other efficacy endpoints  
• 
HbA1c change from baseline to Week 12  
• 
Fasting plasma glucose change from baseline to Week 26  
• 
Percentage of patients requiring rescue therapy by Week 26 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no documented 
symptomatic hypoglycemia (SMPG ≤70 mg/dL [3.9 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no documented 
symptomatic hypoglycemia (SMPG <54 mg/dL [3.0 mmol/L]) 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain and no documented symptomatic hypoglycemia (SMPG ≤70 mg/dL [3.9 mmol/L] 
• 
Percentage of patients reaching the HbA1c target of <7% at Week 26 with no body weight 
gain and no documented symptomatic hypoglycemia (SMPG <54 mg/dL [3.0 mmol/L]) 
• 
PRO measures 
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2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events, hypoglycemia, and other safety 
information, such as clinical laboratory data, and vital signs, etc. 
Observation period  
The observation period for safety data will be divided into 3 segments: 
• 
The pre-treatment period is defined as the time between the date of signing of the informed 
consent (inclusive) and the first injection of IMP (exclusive), 
• 
The on-treatment period is defined as the time from the first injection of IMP (inclusive) 
up to and including 3 days after the last injection of IMP (treatment-emergent AE [TEAE] 
period), 
• 
The post-treatment period is defined as the time starting 4 days after last injection of IMP 
(after the TEAE period). 
2.1.4.1 Hypoglycemia 
Hypoglycemia will be identified as events recorded on the dedicated e-CRF “Hypoglycemic event 
information” page, and will be categorized as follows (see study protocol for further details): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. Plasma 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that 
the event was induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those documented as, 
• 
To the question “Countermeasure Administration”, ticked the option “Subject was Not 
Capable of Treating Self and Required Assistance”, and  
• 
To the question “Were Symptoms Present”, ticked “Yes”. 
Documented hypoglycemia with plasma glucose cut-off of≤70 mg/dL (3.9 mmol/L) 
Documented hypoglycemia with plasma glucose cut-off of ≤70 mg/dL (3.9 mmol/L) is any 
hypoglycemia documented by a measured plasma glucose concentration of ≤70 mg/dL (3.9 
mmol/L); and is identified in e-CRF “Hypoglycemic event” page as those documented as, 
• 
To the question “Any Hypoglycemic Events Experienced”, ticked “Yes”, and  
• 
With a plasma glucose value before countermeasure ≤70 mg/dL (3.9 mmol/L).  
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Documented hypoglycemia with plasma glucose cut-off of<54 mg/dL (3.0 mmol/L) 
Documented hypoglycemia with plasma glucose cut-off of <54 mg/dL (3.0 mmol/L) is any 
hypoglycemia documented by a measured plasma glucose concentration of <54 mg/dL (3.0 
mmol/L); and is identified in e-CRF “Hypoglycemic event” page as those documented as,  
• 
To the question “Any Hypoglycemic Events Experienced”, ticked “Yes”, and  
• 
With a plasma glucose value before countermeasure <54 mg/dL (3.0 mmol/L). 
Pseudo hypoglycemia 
Pseudo hypoglycemia is an event during which the patient reports typical symptoms of 
hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured 
plasma glucose concentration >70 mg/dL (3.9 mmol/L). 
Pseudo hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those documented as, 
• 
To the question “Countermeasure Administration”, Do NOT tick the option “Subject was 
Not Capable of Treating Self and Required Assistance” 
• 
To the question “Were Symptoms Present”, ticked “Yes”, and  
• 
With a plasma glucose value before countermeasure >70 mg/dL (3.9 mmol/L). 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤70 mg/dL (3.9 mmol/L)), i.e., symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Probable symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those 
documented as, 
• 
To the question “Countermeasure Administration”, the option “Subject was Not Capable 
of Treating Self and Required Assistance” not ticked, and 
• 
To the question “Were Symptoms Present”, ticked “Yes”, and 
• 
With no plasma glucose value before countermeasure, and  
• 
To the question “Did this countermeasure lead a significant improvement or prompt 
recovery?” ticked “Yes”.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE. Only hypoglycemia events fulfilling the criteria of an SAE 
will also be documented on AE and SAE complementary forms in the eCRF. 
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2.1.4.2 Adverse events variables 
Adverse event observation period  
• 
The pre-treatment period is defined as the time between the date of signing of the informed 
consent and the first injection of IMP, 
• 
The on-treatment period is defined as the time from the first injection of IMP up to and 
including 3 days after the last injection of IMP (treatment-emergent AE [TEAE] period), 
• 
The post-treatment period is defined as the time starting 4 days after last injection of IMP 
(after the TEAE period). 
All adverse events (including SAE, AESI) will be coded to a lower-level term (LLT), preferred 
term (PT), high-level term (HLT), high-level group term (HLGT), and associated primary system 
organ class (SOC) using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database lock. 
The occurrence of adverse events (including SAE and AESI) will be recorded from the time of 
signed informed consent until the end of the study or the resolution/stabilization of all SAE and 
AESI. 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them 
AESI are listed below: 
• 
ALT >3 x ULN;  
• 
Serious allergic/hypersensitivity reactions; 
• 
Pregnancy occurring in a female patient administered IMP/NIMP; 
• 
Symptomatic overdose of IMP/NIMP 
 
Table 3 - Criteria for AESI 
AE Grouping 
Criteria 
AESI 
Serious 
allergic/hypersensitivity 
reactions 
 
eCRF form “Hypersensitivity/Allergic” 
Pregnancy 
eCRF form “Pregnancy” 
Symptomatic overdose  
“Overdose of IMP” or “Overdose of NIMP” checked and “Symptomatic 
overdose” checked in eCRF form “Overdose” 
ALT increase > 3X ULN 
eCRF form “ALT increase”  
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2.1.4.3 Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-study:  deaths occurring during the on-study observation period 
• 
Death on-treatment:  deaths occurring during the treatment-emergent adverse event period  
• 
Death post-study:  deaths occurring after the end of the study  
2.1.4.4 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values will be summarized in both standard international units and 
conventional units when applicable. 
Blood samples for clinical laboratories will be taken at designated visits (see study flowchart in 
Appendix C).  The following laboratory data will be measured at a central laboratory:  
• 
Hematology:  erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. 
• 
Clinical chemistry: AST, ALT, ALP, total bilirubin (if >ULN, then the direct and indirect 
sub-fractions must be measured), creatinine, uric acid, sodium, potassium 
Urine samples will be collected at designated visits (see study flowchart in Appendix C). 
Urinalysis tests will include pH, glucose, ketones, leukocytes, blood/hemoglobin, and protein. 
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables 
Vital signs include: height, weight, BMI, heart rate (HR), systolic and diastolic blood pressure, 
(see study flowchart in Appendix C for designated visits).  They will be performed after the 
patient has been seated for at least 5 minutes. Blood pressure and HR will be assessed 3 times 
with at least 1 minute between each measurement following the 5-minute rest period. The mean of 
the 3 measurements will be analyzed for each vital sign variable (HR, SBP, and DBP). 
 
2.1.5 Pharmacokinetic variables 
N/A. 
2.1.6 Pharmacodynamic/genomics endpoints 
N/A. 
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2.1.7 Quality-of-life endpoints 
The schedule of the following quality of life endpoints are specified in the study flowchart in 
Appendix C.  The sample questionnaires can be found in the study protocol. 
• 
TRIM-D; 
• 
Patient and Physician Global Treatment Effectiveness Evaluation Scales. 
2.1.7.1 Treatment Related Impact Measure – Diabetes 
The general treatment-related impact on patients’ health related quality of life, treatment 
satisfaction and treatment behavior will be assessed using the TRIM-D questionnaire according to 
the study schedules. 
The TRIM-D questionnaire is a 28-item measure with 5 domains assessing Treatment Burden, 
Daily Life, Diabetes Management, Compliance and Psychological Health. This PRO measure can 
be scored independently for each domain or as a total score (1). 
The 5-point Likert like response options, for all items, range from (1) Not at all 
satisfied/convenient, Never to Extremely/Almost always, Always or Extremely 
dissatisfied/inconvenient to (5) Extremely satisfied/convenient, depending upon the item stem and 
are scored on a scale of 0 to 100 so that a higher score indicates a better health state (less negative 
impact). 
The TRIM-D variables include TRIM-D scores (total and domain scores) and the change in 
TRIM-D scores from baseline to endpoint. 
A domain score is calculated if a respondent answers at least half of the items in a multi-item 
domain (or half plus 1 in the case of domains with an odd number of items). 
2.1.7.2 Patient and Physician Global Treatment Effectiveness Evaluation Scales 
Patient- and physician-rated global treatment effectiveness evaluation scales are instruments that 
will be measuring whether patient’s overall response to treatment is excellent, good, moderate, 
poor, or whether the patient’s condition is worsening. The variables related to these patient-rated 
and physician-rated global treatment effectiveness scales include the response to the question 
“Overall, how effective has the treatment been in controlling your diabetes, since the start of study 
medication?” at Week 26.  Physician-rated global treatment effectiveness evaluation will be 
collected in eCRF, and patient-rated global treatment effectiveness evaluation will be collected in 
the hand-held electronic device. 
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2.1.8 Health economic endpoints  
N/A. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as all patients who signed the informed consent.   
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary tables: 
• 
Screened patients 
• 
Screen failure patients and reasons for screen failure 
• 
Nonrandomized but treated patients 
• 
Randomized patients 
• 
Randomized but not treated patients 
• 
Randomized and treated patients 
• 
Patients who have completed the study treatment as scheduled 
• 
Patients who discontinued the study treatment, and the reasons for study discontinuation 
• 
All patients who attended the Week 26 visit, regardless of whether they discontinued IMP 
during the 26-week treatment period; 
• 
Patients who attended the Week 26 visit and had discontinued IMP during the 26-week 
treatment period. 
• 
Patients who have completed the study/ follow up as scheduled 
• 
Patients who discontinued the study /follow up, and the reasons for study discontinuation 
• 
Status at last study contact  
For screened, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator. All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.   
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A summary of the distribution of patients by region and ethnicity/race will also be provided 
(overall number of patients screened, randomized, and treated, as well as number of patients 
randomized, discontinued from study treatment, and discontinued from study for each treatment 
group). 
Patients treated but not randomized, patients randomized but not treated, and patients randomized 
but not treated as randomized will be identified and described in separate listings. The patients 
that are randomized and not treated as randomized will be part of efficacy and safety analyses. 
Patients randomized but not treated will be included in efficacy analysis. Safety data of patients 
treated but not randomized will be reported separately. 
All important deviations including randomization and drug-dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety and efficacy will be summarized in a table by 
number of patients in the randomized population.  
• 
Efficacy population: intent-to-treat (ITT) population 
• 
Safety population 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
Patients who are dispensed study drug without calling the IRT or before calling the IRT are 
considered nonrandomized patients. They are excluded from any population for analysis, 
including safety. However, if these patients experienced any significant safety event, they would 
be documented separately in the clinical study report. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and these 
patients will not be in the safety population. 
2.3.1 Efficacy populations 
Efficacy analyses will be based on the ITT population, defined as all randomized patients. Patients 
will be analyzed for efficacy analyses according to the treatment group to which they are allocated 
by the IRT according to the randomization schedule at the randomization visit (as randomized), 
irrespective of the treatment actually received. 
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2.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
received at least 1 dose of open-label IMP, regardless of the amount of treatment administered. 
Patients will be analyzed for safety analyses according to the treatment actually received. 
In addition:  
• 
Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
• 
When a patient is exposed to different IMPs, the patient will be analyzed for safety in the 
treatment group (Soliqua 100/33 or Lantus) in which he/she was treated the longest. 
• 
Patients will be excluded from the safety population only if there is documented evidence 
(i.e., all study dates recorded as no medication taken) that patients have not taken IMP.  
2.4 
STATISTICAL METHODS 
Due to early termination of the trial with limited sample size, analyses described in this section 
will only be performed if sufficient data is available. 
2.4.1 Demographics and baseline characteristics 
In general, descriptive statistics of quantitative efficacy and safety endpoints (result and change 
from baseline) by scheduled visit will be provided on observed cases (OC), i.e., only including 
patients having a non-missing assessment at a specific visit. 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  Summaries for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population for any treatment group.  
Parameters described in Section 2.1.1 will be summarized by treatment group and overall (pooled 
across treatment groups) using descriptive statistics.  
P-values on the treatment difference for the demographic and baseline characteristic data will not 
be calculated.  
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In general, no specific description of the safety parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each safety/efficacy analysis. 
2.4.2 Prior or concomitant medications  
The concomitant and posttreatment medications will be presented in the randomized population 
for each treatment group using counts and percentages. No statistical test for the between-group 
difference will be performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  A given medication may be 
classified in more than 1 ATC class. All ATC codes corresponding to a medication will be 
summarized, and a patient will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore a patient may be counted several times for the same 
medication.  
Concomitant and post-treatment medications will be presented by anatomic and therapeutic 
categories and sorted by decreasing frequency of ATC based on the incidence in the Soliqua 
100/33 group. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used. 
Prior, concomitant and posttreatment antidiabetic medications classified as antidiabetic insulin 
therapy and antidiabetic non-insulin therapy will be presented separately. 
• 
The antidiabetic insulin therapy will be summarized by pre-defined classification of 
- 
Basal insulin 
- 
Short-acting insulin 
- 
Pre-mixed insulin 
and standardized medication name. 
• 
The antidiabetic non-insulin therapy will be summarized by pre-defined classification of 
- 
Biguanides 
- 
Sulfonylurea 
- 
Glinides 
- 
Thiazolidinedione 
- 
DPP-4 inhibitors 
- 
SGLT-2 inhibitors 
- 
GLP1-RA 
- 
Alpha-glucosidase inhibitors 
- 
Other 
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and standardized medication name. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure.  
Duration of IMP exposure is defined as last dose date of IMP – first dose date of IMP + 1 day, 
regardless of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
• 
1 to 28 days,  
• 
29 to 56 days,  
• 
57 to 84 days,  
• 
85 to 126 days,  
• 
127 to 168 days 
• 
169 to 175 days  
• 
176 to 182 days 
• 
>182 days 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
Number and percentages of patients by final dose at the end of the treatment will also be presented 
by each treatment group. 
 
2.4.3.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
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Percentage of compliance for a patient will be defined as the number of days that the patient was 
compliant divided by the total number of days that the patient was planned to take during the 
treatment period from the first date to the last date of IMP administration.  
Compliance rate (%) = 
100
injection
 
IMP
 with 
days
 
of
number 
 
Planned
injection
 
IMP
 with 
days
 
of
number 
 
Total
×
⎥⎦
⎤
⎢⎣
⎡
 
 
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose than planned divided by the total number of days that the patient was 
planned to take during the treatment period.  
Under-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a lower dose than planned divided by the total number of days that the patient was 
planned to take during the treatment period.  
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). In 
addition, the percentage of patients who have <60%, ≥60 to <80%, ≥80 to ≤100%, and >100% 
compliance will be summarized by treatment group. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and be 
analyzed as such.  
2.4.4 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population using the efficacy assessments 
collected during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy, unless otherwise specified. 
The primary efficacy endpoint will only be summarized by descriptive statistics without formal 
statistical testing due to limited sample size and insufficient power.  
Missing data for efficacy analyses is identified through steps described in Section 2.5.3. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Summaries of the primary efficacy endpoint (change from baseline to Week 26 in HbA1c) will be 
performed using observed cases for each treatment group based on the ITT population, using 
HbA1c values obtained during the 26-week randomized treatment period, including those 
obtained after IMP discontinuation or rescue medication use. The summary will include the 
number of observations, mean, SD, standard error (SE), minimum, median, and maximum. 
  
Summary statistics at scheduled visits 
Summary statistics (for screening value, baseline value, observed post-baseline value and its 
changes from baseline) at scheduled visits (using observed cases) will be provided for each 
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treatment group, both for the overall population and separately for each ethnicity/race subgroup. 
The summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits. 
2.4.4.2 Analyses of secondary efficacy endpoints 
Analyses of the secondary efficacy endpoints will be performed using the ITT population for all 
patients and, separately, by ethnicity/race subgroup. The originally collected change from baseline 
to Week 26 in 2-hour glucose excursion will no longer be considered critical and will not be 
analyzed. 
For all continuous secondary endpoints except 2-hour glucose excursion, summary statistics at 
scheduled visits and the changes from baseline will be provided using observed cases for each 
treatment group, both for the overall population and separately for each ethnicity/race subgroup. 
The summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (± SE) and mean changes from Baseline (± SE) at each of the scheduled visits. For 
percentage (%) of patients achieving the HbA1c target of <7% at scheduled visits, the proportion 
in each treatment group will be provided. All values at scheduled visits will be used to determine 
whether a patient is a responder or not, even if they are measured after IMP discontinuation or 
introduction or rescue therapy. If no assessment is available at scheduled visits, patients will be 
treated as failures (non-responders). 
2.4.4.3 Multiplicity issues 
Not applicable since no formal testing will be performed. 
2.4.4.4 Additional efficacy analysis 
Analyses of other efficacy endpoints will be performed on the ITT population using all 
assessments obtained during the 26-week randomized treatment period, including those obtained 
after IMP discontinuation or introduction of rescue therapy. Descriptive statistics will be 
summarized by treatment group, both for the overall population and separately for each 
ethnicity/race subgroup.  
All other efficacy variables originally collected, except the change from baseline to Week 12 in 
HbA1c and percentage of patients requiring rescue therapy by Week 26, will no longer be 
considered critical and will not be analyzed. The analysis of other endpoints (see Section 2.1.3.3) 
will be descriptive with no formal testing.   
The number (%) of patients who used rescue therapy and a KM curve for the time to first rescue 
therapy will be provided by treatment group. A list of patients who used rescue therapy will also 
be provided. Time to rescue will be defined as the number of days from the first administration of 
IMP until the start date of any rescue medication. Patients who did not take any rescue medication 
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during the 26-week treatment period will be considered as censored observations. The censoring 
time will be the last administration date (e-CRF “Treatment Status Library” page), or the end date 
of the study (e-CRF “Completion of End of Study/Follow-up” page) if the last administration date 
is not available, or the last contact date  if the last administration date and end date of the study are 
not available. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group, for both the overall 
population and separately for each ethnic/race subgroup, for the 26-week randomized treatment 
period, unless specified otherwise.  
All safety analyses will be performed on the safety population using the following common rules: 
The “observation period” defined in Section 2.1.4 is applicable in all safety analyses for the 
classification of AEs, determination of treatment-emergent Potentially Clinically Significant 
Abnormality (PCSA) values and the last on-treatment value for the laboratory, vital sign and ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (e.g., exposed but not 
randomized) will be listed separately 
• 
The baseline value is defined as the last available value before the first dose of IMP 
• 
PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG.  PCSA criteria will 
determine which patients had at least 1 PCSA during the treatment-emergent adverse event 
period, taking into account all evaluations performed during the treatment-emergent 
adverse event period, including nonscheduled or repeated evaluations.  The number of all 
such patients will be the numerator for the treatment emergent PCSA percentage 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
• 
For laboratory parameters cited in the protocol as efficacy endpoints (including HbA1c and 
plasma glucose etc.), PCSA summaries will not be provided. These parameters will be 
summarized in Section 2.4.4. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group for the entire 26-week treatment period only.  Summaries will 
include the last on-treatment value. The last on-treatment value is commonly defined as 
the value collected at the same day/time of the last administration of IMP. If this value is 
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missing, this last on-treatment value will be the closet value prior to the last dose 
administration of IMP during the entire 26-week treatment period. 
• 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned.  Relative risks versus Lantus and their 95% confidence intervals may be 
provided, if relevant 
 
2.4.5.1 Hypoglycemia 
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4. 
Hypoglycemia will be classified as severe hypoglycemia, documented hypoglycemia (blood 
glucose ≤70 mg/dL and <54 mg/dL), probable symptomatic hypoglycemia or pseudo 
hypoglycemia.  
The number (%) of patients with at least 1hypoglycemia, severe hypoglycemia and documented 
hypoglycemia (blood glucose ≤70 mg/dL and <54 mg/dL), probable symptomatic hypoglycemia or 
pseudo hypoglycemia will be summarized respectively by treatment group during the TEAE 
period, as well as the incidence rate in patient years. Two types of incidence rates will be 
presented: the number of patients with at least 1 event per patient-year (calculated as the number 
of patients with at least 1 event / total exposure in patient-year), and the number of events per 
patient-year (calculated as the total number of events / total exposure in patient-years). Note: here 
exposure (in days) is the duration of TEAE period, i.e., duration of IMP treatment in days +1 (see 
Section 2.1.4). 
A KM curve will also be provided by treatment group for the time to first severe hypoglycemia or 
documented hypoglycemia during the TEAE period for the entire 26-week treatment period only. 
A listing of patients for all events reported on the dedicated e-CRF “Hypoglycemic event 
information” page will be provided with each category flagged (i.e., severe hypoglycemia, 
documented hypoglycemia, probable symptomatic hypoglycemia and pseudo hypoglycemia). 
2.4.5.2 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  Pre-
treatment andpost-treatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pre-treatment or post-treatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
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Adverse event incidence tables will be presented by SOC, HLGT, HLT, and PT, sorted by the 
internationally agreed order for SOCs and alphabetic order for HLGT, HLT and PT within a SOC, 
the number (n) and percentage (%) of patients experiencing an adverse event.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase.  The denominator for computation of percentages is the safety population within 
each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent, and post-treatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the Soliqua 
100/33 group) will define the presentation order for all other similar tables unless otherwise 
specified. In case of equal frequency regarding PTs, alphabetical order will be used. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated during the 26-week 
randomized treatment period for the safety population. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
• 
All treatment-emergent adverse events by primary SOC, showing number (%) of patients 
with at least 1 treatment-emergent adverse event, sorted by internationally agreed order of 
primary system organ class  
• 
All adverse events for the whole on-study period (on-treatment and post-treatment periods) 
by primary SOC, showing number (%) of patients with at least 1 adverse event during the 
on-study period, sorted by internationally agreed order of primary system organ class  
• 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the SOC 
internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
• 
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the Soliqua 100/33 group 
• 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC in the Soliqua 
100/33 group.  This sorting order will be applied to all other similar tables, unless 
otherwise specified 
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• 
All treatment-emergent adverse events regardless of relationship and related to IMP by 
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 
treatment-emergent adverse event, sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• 
All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (i.e., mild, moderate, or severe), sorted by the sorting order defined above 
• 
Common TEAEs (PTs with an incidence ≥1% in any treatment group) by primary SOC, 
HLGT, HLT, and PT, sorted by internationally agreed order of SOCs. The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order.  
• 
Common TEAEs (PTs with an incidence ≥1% in any treatment group) will be provided as 
appropriate by primary SOC, HLGT, HLT, and PT and by demographic factors including 
gender (Male, Female), age group (<50, ≥50 to <65, ≥65 years of age), race (White, Black 
or African American, Asian, other). SOC will be sorted by internationally agreed order and 
the other levels (HLGT, HLT, PT) in alphabetic order. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order 
• 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
Analysis of adverse events of special interest 
• 
Serious allergic/hypersensitivity reactions, pregnancy and overdose for the combined on-
treatment and post-treatment period will be included in overall AE summaries if any are 
reported. ALT increase >3 x ULN for the TEAE period is included in laboratory PCSA 
summary and listed in the PCSA listing which will include both the on-treatment and post-
treatment periods. 
 
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Gastrointestinal adverse events 
• 
The number (%) of patients with events reported on the AE form for gastrointestinal 
adverse events will be summarized by PT for each treatment group. 
 
Analysis of pre-treatment and post-treatment adverse events  
• 
All pre-treatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pre-treatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the Soliqua 100/33 group 
• 
All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the Soliqua 100/33 group 
Listings 
Supportive AE listings will be provided for all AEs, SAEs, AEs leading to treatment 
discontinuation and/or death, and EOSI as appropriate. Listing of all AEs, SAEs and AEs leading 
to treatment discontinuation and/or death, sorted by treatment, patient identification and onset 
date, will include at least the following information: treatment, patient identification, country, age, 
gender, race, BMI, primary SOC, PT, reported term, onset date, study day (relative day to the start 
date of IMP treatment), AE duration, duration of exposure, intensity, corrective treatment, action 
taken with IMP, date of treatment discontinuation (if relevant), relationship to IMP, outcome, date 
of death (if any), seriousness, seriousness criteria, and AE status ( “Pre” for a pre-treatment AE;  
“T” for a TEAE; and “Post” for an on-study post-treatment AE). 
2.4.5.3 Deaths 
The following summaries of deaths will be generated. 
• 
Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
• 
Deaths in nonrandomized patients or randomized but not treated patients 
• 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC. 
2.4.5.4 Analyses of laboratory variables  
Laboratory parameters will be taken at baseline and summarized as part of baseline characteristics. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables) will be calculated by treatment group.   
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The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by biological function and treatment group whatever the baseline level and/or 
according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the TEAE period. When a PCSA 
definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least 1 post-baseline PCSA during the on-treatment and post-treatment 
period (or out of normal range when no PCSA criterion is defined) will be provided which will 
display the entire patients’ profile across time for all parameters belonging to the corresponding 
biological function. Individual data listings will include the following flags when applicable: 
• 
Baseline values will be flagged “B”. 
• 
Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, last on-treatment value, and individual data will be flagged “L” if 
the value is below the LLN and will be flagged “H” if it is above the ULN. 
• 
Laboratory PCSA criteria will be used for the corresponding laboratory parameters. Values 
reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction and 
level of the abnormality). Flags for WBC and differential counts will be determined using 
data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  The 
proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group (only if a tabulation summary is necessary).  
Listing of possible Hy’s law cases identified by treatment group (e.g., patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters (if available):  
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase, 
serum creatinine, complete blood count. 
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2.4.5.5 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of heart rate, temperature and respiratory rate (observed values, or mean of 
observed values, and changes from baseline) will be calculated for each visit or study assessment 
(baseline, each post-baseline time point, last on-treatment value) by treatment group.  
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for SBP, DBP and HR. All measurements collected during the TEAE period, including 
values from unscheduled visits, will be considered for the PCSA summaries. The summaries will 
include patients in the safety population who have at least 1 assessment performed during the 
TEAE period. When a PCSA definition involves a change from baseline value, patients must also 
have a baseline value to be included in the summaries. 
A listing of patients with at least 1 post-baseline PCSA will be provided and will display the 
patient’s profile over time of all vital sign parameters. Individual data listings will include the 
following flags: 
• 
Baseline values will be flagged “B”, 
• 
Parameter values reaching a PCSA limit will be flagged (+, or - depending of the 
direction). 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
N/A. 
2.4.7 Analyses of patient reported outcome variables 
The data originally planned were no longer considered to be critical and evaluations will not be 
performed. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
HbA1c 
The formula to convert HbA1c from Diabetes Control and Complications Trial (DCCT) aligned 
value to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 
standardized value is, 
IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] x 10.929. 
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Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4] -1.154 x Age 
(year) -0.203 x 1.212 (if Black) x 0.742 (if Female) 
Conventional unit: eGFR (mL/min/1.73 m2) = 175 x Serum Creatinine (mg/dL) -1.154 x Age (year) 
-0.203 x 1.212 (if Black) x 0.742 (if Female) 
2.5.2 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Derived variables will be considered missing if any of the original variables required to calculate 
them are missing. For example, if either a baseline assessment or an endpoint assessment is 
missing for a particular patient, then change from baseline at endpoint will be missing. Depending 
upon the assessment, analyses may not include all patients in the analysis population, because 
certain patients in the intended population may have missing data. 
Incomplete date of first administration of IMP 
Date/time of first administration is the first non-missing start date/time of IMP. 
For patients who are randomized and dispensed a treatment kit but who are lost to follow-up just 
after Visit 2, the date of first administration will be imputed using the date of randomization. 
When a patient is randomized but not exposed, “Not taken” should be ticked in the e-CRF “First 
dose IMP” module.  
Handling of computation of treatment duration if IMP end of treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the e-CRF “Treatment status library” page.  If this date is missing, 
the exposure duration should be left as missing.  
The last dose administration should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
In the case of subjects being exposed to more than 1 IMPs, the missing end of treatment date for 
one IMP could be imputed as the day before the non-missing first administration date of the next 
IMP date. 
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Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial adverse event/hypoglycemia onset dates and times will be imputed so that if the 
partial adverse event/hypoglycemia onset date/time information does not indicate that the adverse 
event/hypoglycemia started prior to treatment or after the treatment-emergent adverse event 
period, the adverse event/hypoglycemia will be classified as treatment-emergent.  No imputation 
of adverse event end dates/times will be performed.  These data imputations are for categorization 
purpose only and will not be used in listings.  No imputation is planned for date/time of adverse 
event resolution. 
Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first IMP administration is missing, the day of randomization 
should be considered as the start date of TEAE period (see Section 2.1.4).  The exposure duration 
should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of IMP is equal to the 
date of the last administration reported on the eCRF “Treatment Status Library” page.  
If the date of last administration reported on the eCRF “Treatment Status Library” page is  
• 
Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on eCRF “Completion of End of Study/Follow-up”.  
• 
Completely missing, it will be imputed with the date of last available information on eCRF 
“Completion of End of Study/Follow-up” page.  
If the date of last available information on eCRF “Completion of End of Study/Follow-up” page is  
• 
Partially missing, it will be imputed with a date as late as possible. 
• 
Completely missing, all adverse events occurred on or after the first administration of IMP 
will be considered as treatment emergent adverse events.  
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, the relationship to IMP has to be assumed 
and the adverse event considered as such in the frequency tables of possibly related adverse 
events, but no imputation should be done at the data level. 
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Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with an AE identification number that links the new record to the original record. An 
AE that worsened or became serious will be considered a new recurring AE in the summary of 
recurrent events or in the summary of events by time intervals. 
Handling of missing data for continuous efficacy endpoints 
Please see Section 2.4.4.1 and Section 2.5.3. 
2.5.3 Windows for time points 
The following steps will decide how the scheduled and/or unscheduled visits will be used in the 
analyses on efficacy variables and the by-visit summaries for safety variables. 
Step 1 A scheduled measurement will be used if it is available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it happens to be on the same date as the date of the scheduled visit. 
Step 2 After Step 1, if there are still no measurement for a given parameter at a scheduled visit, the 
analysis window below (Table 4) will be applied to re-allocate a post-baseline unscheduled 
measurement to a scheduled measurement. 
 
 
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Table 4 - Analyses window definition 
Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Week 6 (Visit 6) 
42 
1 to 83 
Week 12 (Visit 14) 
84 
84 to 104 
Week 18 (Visit 16) 
126 
105 to 153 
Week 26 (Visit 19) 
182 
154 to 195 
Study days are calculated from the day of first administration of IMP; the day of first administration of IMP (or the day of randomization if not 
exposed) is Day 1. 
After applying the above time windows, if multiple assessments are associated to the same time 
point, the closest from the targeted study day will be used. In case of equality, the last 
measurement will be used. Re-allocated scheduled visits (i.e., visit numbers) should be sequential 
if ordered by the date of measurement. 
After Step 2, if there are still no measurement for a given parameter at a scheduled visit, data is 
considered missing for efficacy analyses, where multiple imputation would be applied as 
appropriately as described in Section 2.4.4.  
For endpoints where measurements were only taken at baseline and Week 26, post-baseline 
measurement that is closest to the Week 26 target day will be used for Week 26. 
Reference day 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of IMP or the day of randomization if not exposed to IMP, 
denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement including unscheduled assessments, assessed prior to the first administration of IMP. 
For the efficacy analyses, the baseline for a given parameter is defined as the last available 
measurement including unscheduled assessments, assessed prior to the first administration of IMP 
or the last available value before randomization if not treated with IMP. 
Summary statistics by visit for continuous efficacy endpoints 
Summary statistics (number, mean, SD, SE, minimum, median, maximum) of continuous efficacy 
endpoints (observed data and change from baseline) will be provided at scheduled visits as per 
protocol. Summaries showing data by visit will be presented according to the visit number (or re-
allocated visit number) and labeled with the targeted approximate day/week.  
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Last on-treatment value for laboratory variables and vital signs 
The last on-treatment value is the final measurement assessed during the treatment epoch, 
regardless of the introduction of rescue therapy, including measurements at unscheduled visits.  
Display of safety data by visit (laboratory variables and vital signs)  
Descriptive statistics (number, mean, SD, minimum, median, maximum) of quantitative 
laboratory variables and vital signs (observed data and change from baseline) during the TEAE 
period will be provided at scheduled visits. In addition, these summaries will also include a row 
for the ‘last value on-treatment’ to describe the last available on-treatment value (see above). 
Summaries showing data by visit will be presented according to the visit number (or re-allocated 
visit number) and labeled with the targeted approximate day/week. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories. The local results will not be used in the efficacy analyses or in the definition of 
baseline for both safety and efficacy analyses. In the safety analyses, local results will only be used 
in the PCSA summary if they are accompanied by a local laboratory normal range. 
When a patient has more than 1 measurement from the central laboratory for the same laboratory 
parameter on the same date, the average of the measurements will be used. For the same 
laboratory parameter, if a patient has more than 1 measurement on different dates for the same 
scheduled visit, the value closest to the date of the visit will be used for the scheduled visit. When 
the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit. Similar rules will be applicable to a patient who has more than 1 set of 
measurements for the same vital sign parameter (i.e., SBP, DBP, or HR) on the same date. 
26-week randomized treatment period  
The 26-week randomized treatment period is the time from first administration of IMP to the last 
administration of IMP on or before Visit 19/Week 26 (or Day 182 if Visit 19/Week 26 date is 
missing). This is for defining EOT status at Week 26 and analyzing selected efficacy parameters 
during the 26-week randomized core treatment period.  
TEAE period for the 26-week randomized treatment period  
The TEAE period for 26-week randomized treatment period is (1) the time from the first 
administration of the IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
IMP if the patient discontinued treatment on or before Visit 19/Week 26 (or Day 182 if Visit 
19/Week 26 date is missing), or (2) the time from the first administration of the IMP to the 
administration at Visit 19/Week 26 (or Day 182 if Visit 19/Week 26 date is missing) if the patient 
remained treated beyond Visit 19/Week 26. This is for the purpose of safety analyses during the 
26-week randomized treatment period. 
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2.5.4 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and etc. but will be used for 
computation of baseline, the last on-treatment value, PCSAs, and the shift summaries for safety or 
efficacy. They will be included in the by-visit summaries if they are re-allocated to scheduled 
visits. 
2.5.5 Pooling of centers for statistical analyses 
Center or pooling of centers is not planned and will not be included in the statistical models for 
efficacy analyses.  
2.5.6 Statistical technical issues 
N/A. 
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3 
INTERIM ANALYSIS 
No formal interim analysis is planned for this study.  
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4 
DATABASE LOCK 
The database is planned to be locked approximately 8 weeks after the last patient last visit. 
 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS® version 9.2 or higher. 
 
 
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6 
REFERENCES 
 
1. 
Savre I, Mapi Research Trust. TRIM-D Treatment Related Impact Measure-Diabetes. 
Infomation booklet. 1st ed. Hojbjerre L, Novo Nordisk. France. Mapi Research Trust;c2013. 41p. 
  
  
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7 
LIST OF APPENDICES 
 
Appendix A  
Potentially clinically significant abnormalities criteria 
Appendix B 
Summary of statistical analyses  
Appendix C 
Study flow chart 
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Appendix A 
Potentially clinically significant abnormalities criteria 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
Clinical Chemistry 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurements. 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
 
>408 µmol/L 
<120 µmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
≥17 mmol/L 
 
<80 mmol/L 
>115 mmol/L 
 
≤129 mmol/L 
≥160 mmol/L 
 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
≥3 ULN 
 
≥3 ULN 
 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
>8% 
 
≤25 g/L 
 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
>4.0 Giga/L 
 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
>0.7 Giga/L 
 
>0.1 Giga/L 
 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
≤4.6 
≥8 
 
Vital signs 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
PCSA 
Comments 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings. 
 
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Appendix B 
Summary of statistical analyses 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
HbA1c: Change from 
baseline at Week 26, 
(Soliqua 100/33 vs. Lantus)  
 
ITT 
Summary statistics only 
  
   
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
 
Secondary endpoints 
 
 
 
 
 
Proportion of patients with 
HbA1c target of <7% at 
Week 26; 
2-hour PPG, daily insulin 
glargine dose and body 
weight: Change from 
Baseline to Week 26;  
ITT 
 
 
. 
Summary statistics for observed values and 
changes from baseline by visit.  
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
 
 
Summary statistics only 
 
 
 
Other endpoints 
 
HbA1c change from 
baseline to Week 12; 
 
Proportion of patients 
requiring rescue treatment 
by Week 26 
 
ITT 
 
 
 
ITT 
Summary statistics only  
 
 
 
No 
Summary statistics for observed values and 
changes from baseline by visit. . 
For patients requiring rescue treatment: KM plot; 
List of patients rescued 
 
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SAFETY ANALYSES 
Endpoint 
Analysis 
Population 
Primary 
analysis 
Supportive 
Analysis 
Subgroup 
analysis 
Other 
analyses 
Hypoglycemia 
Safety 
Follow safety guidelines 
Number (%) of patients with any 
hypoglycemia, severe 
hypoglycemia, documented 
hypoglycemia, pseudo 
hypoglycemia and probable 
symptomatic hypoglycemia during 
TEAE period, and summary of 
frequency and incidence rates in 
100 patient-years. 
No 
No 
KM plot time to first event of severe hypoglycemia 
or documented hypoglycemia 
 
Adverse Events 
Safety 
Follow safety guidelines 
No 
Common TEAEs by 
demographic factors including 
gender (Male, Female), age 
group (<50, ≥50 to <65, ≥65 
years of age), race (White, 
Black or African American, 
Asian, other) 
No 
Clinical laboratory 
data 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
 
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Statistical Analysis Plan  
28-Feb-2019 
AVE0010-LPS14860 - Soliqua™100/33 
Version number: 3 
 
Property of the Sanofi Group - strictly confidential 
Page 54 
 
Appendix C 
Study flow chart 
STUDY FLOW CHART 
  
Study Period 
Screening 
Open-label Randomized Treatment 
Follow-Up Visit 
1 
1.2b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19c 
19 + 3 
VISITa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEK 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
15 
18 
21 
24 
26 
26+3 days 
Inclusion criteria including Informed Consentd 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history (including diabetes) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and BMIe 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Vital signsf 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Diet and lifestyle counselingg 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
IRT contacth 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of IMP (as appropriate)  
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
 
 
Pen-injector and self-injection training and re-
trainingi 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
(electronic 
 
 
3.0)


Statistical Analysis Plan  
28-Feb-2019 
AVE0010-LPS14860 - Soliqua™100/33 
Version number: 3 
 
Property of the Sanofi Group - strictly confidential 
Page 55 
 
Study Period 
Screening 
Open-label Randomized Treatment 
Follow-Up Visit 
1 
1.2b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19c 
19 + 3 
VISITa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEK 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
15 
18 
21 
24 
26 
26+3 days 
Review and evaluation/adjustment of IMP doses 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Collection of used and unused IMP pens; 
compliance check 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Glucometer/supplies/diary dispensation 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucometers, SMPG, hypoglycemia, insulin dose 
titration, diary training and re-trainingi  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
SMPGj 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Two-hour standardized meal test (a sub-set of 
patients only) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
HbA1c (central laboratory) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
FPG (central laboratory) (A 1-time repeat 
measurement before Visit 2 is permitted) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
PRO questionnairesk  
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
Hematologyl 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistrym 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisn 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRo 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum calcitonin 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testp 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
Concomitant medications 
Continuously assessed and recorded throughout the study 
(electronic 
 
 
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Statistical Analysis Plan  
28-Feb-2019 
AVE0010-LPS14860 - Soliqua™100/33 
Version number: 3 
 
Property of the Sanofi Group - strictly confidential 
Page 56 
 
Study Period 
Screening 
Open-label Randomized Treatment 
Follow-Up Visit 
1 
1.2b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19c 
19 + 3 
VISITa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEK 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
15 
18 
21 
24 
26 
26+3 days 
AEs/SAEs/AESIs/hypoglycemia collection 
Continuously assessed and recorded throughout the study 
 
 = Remote visit (telephone or videoconference); all other visits will be performed in person, at the site location, except for the patients that will be enrolled through the virtual site model, who will complete all study visits in a 
remote setting 
a. Screening period duration is of up to 2 weeks (i.e., it can be less than 2 weeks if all required procedures have been performed and patient’s eligibility has been confirmed). Starting with Visit 3 through (and including) Visit 
14, a ±2-day window, calculated relative to the Randomization Visit (Visit 2) is permitted; for Visits 15 through 18, a ±3-day window is permitted, while for Visit 19 a +3-day window is permitted. If a study visit is performed 
outside of the permitted window, the subsequent visits must be scheduled according to the original schedule (i.e., relative to the date of Visit 2, Randomization Visit). The date of the follow-up visit must be determined 
relative to the date of Visit 19. Additional remote visits should be scheduled as often as deemed necessary by the Investigator. 
b. Mandatory for all patients until at least 75 randomized patients per treatment/ethnicity/race group completed the test during the screening period; the visit can be performed any time prior to Visit 2, once the patient’s 
eligibility based on Visit 1 criteria has been confirmed. Sponsor or designee will communicate when/if this evaluation is no longer required for study patients. 
c. In case of rescue therapy initiation or if IMP is being permanently discontinued, Week 26 (Visit 19) procedures should be performed before starting rescue therapy/IMP discontinuation; subsequently, patients should 
continue study treatment and all visits/procedures should be performed per protocol. 
d. Informed consent should be collected at Visit 1 only, before any other study procedures are performed (or when amendments to the consent are created by the Sponsor or designee). 
e. BMI will be calculated by the site at Visit 1 only using the following formula: BMI=weight (kg)/(height in m)2. 
f. Blood pressure and heart rate will be measured after 5 minutes rest in seated position. 
g. Additional counseling will be performed as appropriate throughout the study. 
h. IRT will be contacted by the site at the pre-specified timepoints, as well as any other time when the patient needs re-dispensation of the IMP. 
i. Repeated as often as necessary, including during remote visits. 
j. SMPG monitoring is to be performed to guide insulin titration and for hypoglycemia evaluation, as appropriate, by study patients after Visit 2  and throughout the study duration 
1. 
Fasting (prebreakfast/preinjection) SMPG should be performed daily until the FPG target has been achieved. Thereafter, the number of fasting SMPG measurements could be reduced, according to the Investigator’s 
judgment, however at least 3 fasting SMPG measurements per week must be done. 
Note: After randomization the fasting SMPG will follow the window for the preinjection SMPG 
2. 
Preinjection SMPG (within 30 minutes prior to the injection of Soliqua 100/33 or Lantus - if the latter is administered in the morning) during the randomized treatment period. 
k. PROs will be assessed per the following schedule: 
1. 
TRIM-D – to be done at Baseline, W12 and W26 
2. 
Patient/Physician assessments: W26. 
l. Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. 
m. Serum chemistry: AST, ALT, ALP, total bilirubin (if >ULN, then the direct and indirect sub-fractions must be measured), creatinine, uric acid, sodium, potassium 
n. Urinalysis: pH, glucose, ketones, leukocytes, blood/hemoglobin, protein. 
o. Using the Modification of Diet in Renal Disease (MDRD) equation. 
(electronic 
 
 
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Statistical Analysis Plan  
28-Feb-2019 
AVE0010-LPS14860 - Soliqua™100/33 
Version number: 3 
 
Property of the Sanofi Group - strictly confidential 
Page 57 
 
p. Women of childbearing potential only; serum pregnancy test at Visit 1; urine pregnancy test at all subsequent visits for patients at traditional sites (if needed, a confirmatory serum pregnancy test can be performed). 
Investigators may conduct additional locally analyzed urine pregnancy tests as per their judgment. For patients participating at the designated site for the virtual study model, all pregnancy tests will be serum and for Visit 2, 
this may be done up to 1 week prior to the Visit 2 date (i.e., it may be done at Visit 1.2, if patient performs this visit; the results must be obtained prior to patient randomization).  
AE=adverse event; AL=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BMI=body mass index; eGFR=estimated glomerular filtration rate; FP=fasting plasma glucose; HbA1c 
=hemoglobin A1c; IMP=investigational medicinal product; IRT=interactive response technology; PRO=patient reported outcome; SAE=serious adverse event; SMPG=self-monitoring of plasma glucose; ULN=upper limit of 
normal.   
 = Remote visit (telephone or videoconference); all other visits will be performed in person, at the site location, except for the patients that will be enrolled through the virtual (telemedicine) site model, who will 
complete all study visits in a remote setting.  
 
(electronic 
 
 
3.0)


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LPS14860 16.1.9 Statistical Analysis Plan
Clinical Approval
28-Feb-2019 16:38 GMT+0100
Clinical Approval
09-Apr-2019 03:53 GMT+0200
Clinical Approval
09-Apr-2019 23:39 GMT+0200