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Clinical Trial Results:
A Randomised, Open, Parallel-group Phase III Biosimilarity Study to Assess the Long-term Safety, Focusing on Immunogenicity, of Rechon Insulin Human Soluble in Type 1 Diabetic Patients.

Summary
EudraCT number	2016-004691-22
Trial protocol	DE PL
Global end of trial date	17 Dec 2019

Results information
Results version number	v1(current)
This version publication date	27 Nov 2020
First version publication date	27 Nov 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RCT-004

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Rechon Life Science AB

Sponsor organisation address

Soldattorpsvägen 5, Limhamn, Sweden, SE-216 10

Public contact

Clinical Development, Rechon Life Science AB, info@rechon.se

Scientific contact

Clinical Development, Rechon Life Science AB, info@rechon.se

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

17 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Dec 2019

Global end of trial reached?

Yes

Global end of trial date

17 Dec 2019

Was the trial ended prematurely?

Main objective of the trial

To asses the long-term safety of Rechon Human Insulin Soluble as compared to Humulin® Regular in terms of immunogenicity and insulin tolerance.

Protection of trial subjects

All patients received written and verbal information regarding the study. The given information emphasised that participation in the study was voluntary and that the patient could withdraw from the study at any time and for any reason. All patients were given the opportunity to ask questions about the study and were given sufficient time to decide whether they would participate in the study. Before any study-related procedures, the informed consent form (ICF) was signed and personally dated by the patient and by the person who conducted the informed consent discussion. Participation in the study was not judged to pose any risk for the patients. The individual patients participating in the study gained benefit from regular health checkups during the study. Additionally, by their participation they supported the development of new insulins to be put on the market. Rechon Insulin Human Soluble has been developed to compete with the innovator product on the market, thereby increasing the availability of insulin products for diabetic patients. Europe’s healthcare systems will benefit from the cost relief and the increased patient access to the life enhancing treatments that biosimilar products will bring.

Background therapy

N/A

Evidence for comparator

The insulin substance used in Humulin® Regular, the reference product, is a recombinant human insulin with a molecular weight of 5,808 kDa. The molecule consists of two chains interconnected by two disulfide bonds. The insulin substance is synthesised in a non-disease producing strain of E.coli that has been genetically altered by the addition of the human gene for insulin production. The insulin is produced by Eli Lilly and Company. Humulin® Regular is a fast acting solution. The IMP was manufactured by Eli Lilly and Company. Humulin® Regular was provided in 3 mL cartridges to be used in the insulin pen Humapen Savvio. The pen was intended for use with the Humulin® products. The Sponsor (Rechon Life Science AB) is developing the fast-acting insulin Rechon Insulin Human Soluble as a biosimilar to the fast-acting insulin Humulin® Regular and the intermediate-acting insulin Rechon Insulin Human Isophane as a biosimilar to Humulin® NPH. At the initiation of this clinical study, RCT-004, both pre-clinical studies and three clinical trials had been performed on the Rechon drug substance and on these two formulations of Rechon insulin, which were compared to their respective Humulin® reference products.

Actual start date of recruitment

20 Dec 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 323

Country: Number of subjects enrolled

Germany: 8

Worldwide total number of subjects

331

EEA total number of subjects

331

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

303

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In this study, 370 patients were screened for participation, and as 39 patients (10.5%) were screening failures, 331 patients (89.5%) were randomized to treatment with either Rechon Insulin (164 patients) or Humulin Regular (167 patients).

Screening details

Male or female patients 18-75 years, with BMI 18.0-32.0 kg/m2 and diagnosed with type 1 diabetes mellitus (T1DM) for at least two years. They should have ongoing daily treatment with insulin for at least 12 months, below or equal to 1.2 U/kg/day and HbA1c below or equal to 94 mmol/mol.

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Patients and Investigators were not blinded to study treatment in this study. It was not possible to completely blind the study since the cartridges differed in colour of the plunger, lined-seal and metal cap of the cartridges. The primary variable in the study was anti-insulin antibody, which was analysed by Wieslab AB, Malmö, Sweden. Laboratory staff doing the laboratory analyses were blinded to treatment.

Are arms mutually exclusive

Yes

Rechon Insulin Human Soluble

Arm description

Arm type

Experimental

Investigational medicinal product name

Rechon Insulin Human Soluble

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients received either Rechon Insulin Human Soluble or Humulin® Regular in a randomised way. The IMPs were administered at home by the patients themselves. Dosing was individualised and adjusted based on blood glucose levels for each patient. Rechon Insulin Human Soluble was provided in 3 mL cartridges to be used in the insulin pen (YpsoPen Twist) manufactured by Ypsomed AG, Switzerland. The pen is documented for use with Rechon insulin products and is CE marked. Before a meal, fast acting insulins (e.g. Rechon Insulin Human Soluble or) are taken to be able to utilise the carbohydrates in the food and prevent blood glucose levels to rise. The more carbohydrates the food contains, the more insulin is needed. Many fast acting insulins reach the blood after approximately 15 minutes and are effective for 3-4 hours.

Humulin® Regular

Arm description

Arm type

Reference product

Investigational medicinal product name

Humulin® Regular

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients received either Rechon Insulin Human Soluble or Humulin® Regular in a randomised way. The IMPs were administered at home by the patients themselves. Dosing was individualised and adjusted based on blood glucose levels for each patient. Before a meal, fast acting insulins (e.g. Rechon Insulin Human Soluble or) are taken to be able to utilise the carbohydrates in the food and prevent blood glucose levels to rise. The more carbohydrates the food contains, the more insulin is needed. Many fast acting insulins reach the blood after approximately 15 minutes and are effective for 3-4 hours. Humulin® Regular has a somewhat slower onset of the effect and is effective for a longer time. Humulin® Regular is taken around 30 minutes before each meal.

Number of subjects in period 1	Rechon Insulin Human Soluble	Humulin® Regular
Started	164	167
Completed	152	152
Not completed	12	15
Consent withdrawn by subject	8	9
Physician decision	2	-
Adverse event, non-fatal	2	3
Pregnancy	-	1
Lost to follow-up	-	1
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Rechon Insulin Human Soluble

Reporting group description

Reporting group title

Humulin® Regular

Reporting group description

Reporting group values	Rechon Insulin Human Soluble	Humulin® Regular	Total
Number of subjects	164	167	331
Age categorical
Patients 18-75 years, both inclusively, could be included in the study.
Units: Subjects
Adults (18-64 years)	149	154	303
From 65-84 years	15	13	28
Age continuous
In the safety set, the mean age was similar in both treatment groups, 46.2 years in the Rechon Insulin group and 45.5 years in the Humulin Regular group. The demographic characteristics in the PPS were similar to those in the safety set, where the overall mean age in the PPS was 45.9 years. Baseline characteristics have only been summarized for the safety set for respective reporting group and total, wherefore the Humulin reporting group is based on 164 patients, i.e. not 167.
Units: years
arithmetic mean (standard deviation)	46.2 ± 13.8	45.5 ± 13.2	-
Gender categorical
Both male and female patients were included in the study. The demographics were similar in the treatment groups, both in the safety set and the PPS, apart from a skewed gender distribution in the Humulin Regular group where only approximately 40% of the patients were female.
Units: Subjects
Female	86	67	153
Male	78	100	178
Race
Information of race (White, Black, Asian, Other) were collected at screening. The vast majority of patients were White in both treatment groups, 99.4% of the patients (n=163) in the Rechon Insulin group and 100% of the patients (n=164) in the Humulin Regular group.
Units: Subjects
White	163	167	330
White, Other	1	0	1

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All randomised patients who took at least 1 dose of the study drug. In total, 0.9% of the patients (n=3), all randomised to treatment with Humulin Regular, were excluded from the safety set.

Subject analysis set title

Per protocol set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PPS was defined for each study visit to consist of all randomised patients who completed the study up to the specific visit and were deemed to have no major protocol deviations that could interfere with the objectives of this study. The visit-specific PPS are sub-sets of the safety set. 3.3% of the patients (n=11) had at least some data that was excluded from the PPS on a per-visit basis. For the primary endpoint, PPS was the primary analysis population.

Subject analysis sets values	Safety set	Per protocol set
Number of subjects	328	320
Age categorical
Patients 18-75 years, both inclusively, could be included in the study.
Units: Subjects
Adults (18-64 years)	300	293
From 65-84 years	28	27
Age continuous
In the safety set, the mean age was similar in both treatment groups, 46.2 years in the Rechon Insulin group and 45.5 years in the Humulin Regular group. The demographic characteristics in the PPS were similar to those in the safety set, where the overall mean age in the PPS was 45.9 years. Baseline characteristics have only been summarized for the safety set for respective reporting group and total, wherefore the Humulin reporting group is based on 164 patients, i.e. not 167.
Units: years
arithmetic mean (standard deviation)	45.9 ± 13.0	±
Gender categorical
Both male and female patients were included in the study. The demographics were similar in the treatment groups, both in the safety set and the PPS, apart from a skewed gender distribution in the Humulin Regular group where only approximately 40% of the patients were female.
Units: Subjects
Female	151	149
Male	177	171
Race
Information of race (White, Black, Asian, Other) were collected at screening. The vast majority of patients were White in both treatment groups, 99.4% of the patients (n=163) in the Rechon Insulin group and 100% of the patients (n=164) in the Humulin Regular group.
Units: Subjects
White	328	320
White, Other	0	0

End points

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Reporting group title

Rechon Insulin Human Soluble

Reporting group description

Reporting group title

Humulin® Regular

Reporting group description

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All randomised patients who took at least 1 dose of the study drug. In total, 0.9% of the patients (n=3), all randomised to treatment with Humulin Regular, were excluded from the safety set.

Subject analysis set title

Per protocol set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Anti-Insulin Binding Antibodies (PPS)

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End point title

Anti-Insulin Binding Antibodies (PPS)

End point description

The primary endpoint of this study was to evaluate the proportion of patients having binding antibodies against human insulin. Since it was expected that a large proportion of patients would have anti-insulin antibodies already at baseline, the primary analysis assessed shift from negative at baseline to positive at subsequent visits. For the primary endpoint, PPS was the primary analysis population. In the PPS, fewer patients were positive for anti-insulin antibodies at baseline in the Rechon Insulin group (4.3% of the patients [n=7]) as compared to the Humulin Regular group (7.4% of the patients [n=12]) with only small changes over time. At Visit 5, the difference between the groups was 8.0 percent units more positive patients in the Humulin Regular group than in the Rechon Insulin group (95% CI: -13.3, -2.7).

End point type

Primary

End point timeframe

From Visit 2, Day 1 to Visit 5, Day 180.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[1]	164 ^[2]
Units: Number of patients with non-missing data
Visit 2 - Positive	7	12
Visit 2 - Negative	156	151
Visit 3 - Positive	6	12
Visit 3 - Negative	152	146
Visit 4 - Positive	5	11
Visit 4 - Negative	149	143
Visit 5 - Positive	3	15
Visit 5 - Negative	147	135

Notes
[1] - Visit 2, n=163 Visit 3, n=158 Visit 4, n=154 Visit 5, n=150
[2] - Visit 2, n=163 Visit 3, n=158 Visit 4, n=154 Visit 5, n=150

Odds Ratio for Testing Positive for Anti-Insulin A

Statistical analysis description

A sensitivity analysis using logistic regression in the safety set shows a trend for patients in the Humulin Regular group to have a higher probability of being positive for anti-insulin binding antibodies at Visit 3 and Visit 4, compared to patients treated with Rechon Insulin. At Visit 5, the difference in probability of being positive for anti-insulin antibodies was statistically significant (p-value 0.0152) in favour of the Rechon Insulin treatment.

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.6434 ^[3]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Confidence interval

Notes
[3] - Visit 3, P=0.6434 Visit 4, P=0.4903 Visit 5, P=0.0152

Primary: Testing Positive for Anti-Insulin Antibodies (Safety Set)

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End point title

Testing Positive for Anti-Insulin Antibodies (Safety Set) ^[4]

End point description

End point type

Primary

End point timeframe

Visit 3 - Visit 5.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Presented under the primary end point Anti-Insulin Binding Antibodies.

End point values	Safety set
Number of subjects analysed	328
Units: odds ratio
number (confidence interval 95%)
Visit 3	0.817 (0.347 to 1.922)
Visit 4	0.759 (0.344 to 1.671)
Visit 5	0.320 (0.128 to 0.803)

No statistical analyses for this end point

Secondary: Total Daily Insulin dose (Safety Set)

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End point title

Total Daily Insulin dose (Safety Set)

End point description

In the safety set, the median total daily insulin dose at baseline was 0.645 IU/kg in the Rechon Insulin group and 0.665 IU/kg in the Humulin Regular group. The median total daily dose changed from baseline by 0.026 IU/kg in the Rechon Insulin group and by 0.027 IU/kg in the Humulin Regular group at Visit 5.

End point type

Secondary

End point timeframe

Visit 2 to visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[5]	164 ^[6]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.685 ± 0.208	0.678 ± 0.198
Visit 3 - Change from baseline	0.035 ± 0.100	0.022 ± 0.086
Visit 4 - Change from baseline	0.035 ± 0.111	0.026 ± 0.099
Visit 5 - Change from baseline	0.035 ± 0.114	0.036 ± 0.108

Notes
[5] - Visit 2, n=148 Visit 3, n=143 Visit 4, n=137 Visit 5, n=134
[6] - Visit 2, n=156 Visit 3, n=152 Visit 4, n=144 Visit 5, n=139

No statistical analyses for this end point

Secondary: Daily Basal Insulin Dose (Safety Set)

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End point title

Daily Basal Insulin Dose (Safety Set)

End point description

In the safety set, the median basal insulin dose at baseline was 0.260 IU/kg in the Rechon Insulin group and 0.246 IU/kg in the Humulin Regular group. The change from baseline at Visit 5 was -0.002 IU/kg in the Rechon Insulin group and 0.001 IU/kg in the Humulin Regular group.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[7]	164 ^[8]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.267 ± 0.116	0.264 ± 0.104
Visit 5 - Change from baseline	-0.002 ± 0.046	0.007 ± 0.066

Notes
[7] - Visit 2, n=153 Visit 5, n=140
[8] - Visit 2, n=158 Visit 5, n=143

No statistical analyses for this end point

Secondary: Daily Bolus Insulin Dose (Safety Set)

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End point title

Daily Bolus Insulin Dose (Safety Set)

End point description

In the safety set, the median bolus insulin dose at baseline was 0.396 IU/kg in the Rechon Insulin group and 0.386 IU/kg in the Humulin Regular group and the change from baseline at Visit 5 was 0.032 IU/kg in the Rechon Insulin group and 0.023 IU/kg in the Humulin Regular group.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[9]	164 ^[10]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.425 ± 0.165	0.418 ± 0.163
Visit 5 - Change from baseline	0.035 ± 0.096	0.029 ± 0.105

Notes
[9] - Visit 2, n=157 Visit 5, n=141
[10] - Visit 2, n=160 Visit 5, n=143

No statistical analyses for this end point

Secondary: Total Daily Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

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End point title

Total Daily Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

End point description

In the safety set, there were approximately 10-times more patients that had long/ultralong-acting basal insulin at baseline compared to patients that had intermediate-acting insulin. For patients with intermediate-acting basal insulin at baseline, the median total daily insulin dose was 0.652 IU/kg in the Rechon Insulin group and 0.606 IU/kg in the humulin Regular group, which at Visit 5 had changed by 0.027 IU/kg and 0.029 IU/kg, respectively. For patients with long/ultralong-acting basal insulin at baseline, the median total daily insulin dose was 0.641 IU/kg in the Rechon Insulin group and 0.665 IU/kg in the Humulin Regular group, which at Visit 5 had changed by 0.023 IU/kg and 0.027 IU/kg, respectively.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[11]	164 ^[12]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.703 ± 0.191	0.656 ± 0.190
Visit 5 - Change from baseline	0.038 ± 0.094	0.007 ± 0.092

Notes
[11] - Visit 2, n=14 Visit 5, n=12
[12] - Visit 2, n=10 Visit 5, n=10

No statistical analyses for this end point

Secondary: Total Daily Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

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End point title

Total Daily Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

End point description

In the safety set, there were approximately 10-times more patients that had long/ultralongacting basal insulin at baseline compared to patients that had intermediate-acting insulin. For patients with intermediate-acting basal insulin at baseline, the median total daily insulin dose was 0.652 IU/kg in the Rechon Insulin group and 0.606 IU/kg in the Humulin Regular group, which at Visit 5 had changed by 0.027 IU/kg and 0.029 IU/kg, respectively. For patients with long/ultralong-acting basal insulin at baseline, the median total daily insulin dose was 0.641 IU/kg in the Rechon Insulin group and 0.665 IU/kg in the Humulin Regular group, which at Visit 5 had changed by 0.023 IU/kg and 0.027 IU/kg, respectively.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[13]	164 ^[14]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.682 ± 0.212	0.679 ± 0.202
Visit 5 - Change from baseline	0.031 ± 0.115	0.038 ± 0.111

Notes
[13] - Visit 2, n=131 Visit 5, n=119
[14] - Visit 2, n=142 Visit 5, n=126

No statistical analyses for this end point

Secondary: Daily Bolus Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

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End point title

Daily Bolus Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

End point description

For patients in the safety set with intermediate-acting basal insulin at baseline, the median daily bolus dose was 0.432 IU/kg in the Rechon Insulin group and 0.422 IU/kg in the Humulin Regular group, which at Visit 5 had changed by 0.031 IU/kg and 0.019 IU/kg, respectively. For patients with long/ultralong-acting basal insulin at baseline, the median daily bolus dose was 0.391 IU/kg in the Rechon Insulin group and 0.383 IU/kg in the Humulin Regular group, which at Visit 5 had changed by 0.032 IU/kg and 0.025 IU/kg, respectively.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[15]	164 ^[16]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.446 ± 0.153	0.422 ± 0.142
Visit 5 - Change from baseline	0.042 ± 0.098	0.006 ± 0.075

Notes
[15] - Visit 2, n=14 Visit 5, n=12
[16] - Visit 2, n=10 Visit 5, n=10

No statistical analyses for this end point

Secondary: Daily Bolus Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

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End point title

Daily Bolus Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

End point description

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[17]	164 ^[18]
Units: IU/kg
arithmetic mean (standard deviation)
Visit 2 - Derived value	0.420 ± 0.161	0.413 ± 0.156
Visit 5 - Change from baseline	0.034 ± 0.096	0.034 ± 0.105

Notes
[17] - Visit 2, n=131 Visit 5, n=119
[18] - Visit 2, n=142 Visit 5, n=126

No statistical analyses for this end point

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

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End point title

Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

End point description

For clinical chemistry and haematology parameters, there were no apparent trends for the assessed values to change over time from Visit 2 to Visit 5. The assessed values and absolute change from baseline were similar between the treatment groups.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[19]
Units: U/L
arithmetic mean (standard deviation)
Alkaline phosphatase - Visit 2	82.1 ± 22.7	81.1 ± 25.2
Alkaline phosphatase - Change at Visit 5	2.06 ± 17.3	1.32 ± 17.6
Alanine aminotransferase - Visit 2	28.8 ± 12.5	28.8 ± 15.0
Alanine aminotransferase - Change at Visit 5	0.0993 ± 12.1	2.66 ± 19.3
Aspartate aminotransferase - Visit 2	24.4 ± 20.2	24.1 ± 9.96
Aspartate aminotransferase - Change at Visit 5	0.828 ± 15.0	1.89 ± 13.2
Gamma glutamyltransferase - Visit 2	23.1 ± 19.3	31.8 ± 37.3
Gamma glutamyltransferase - Change at Visit 5	2.25 ± 14.6	2.06 ± 31.7

Notes
[19] - Safety set

No statistical analyses for this end point

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

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End point title

Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

End point description

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[20]
Units: mg/dl
arithmetic mean (standard deviation)
Total bilirubin - Visit 2	0.633 ± 0.311	0.667 ± 0.302
Total bilirubin - Change at Visit 5	0.0100 ± 0.244	0.0161 ± 0.245
Creatinine - Visit 2	0.859 ± 0.149	0.910 ± 0.286
Creatinine - Change at Visit 5	0.0168 ± 0.106	-0.0001 ± 0.147
C-reactive protein - Visit 2	0.286 ± 0.416	0.386 ± 0.820
C-reactive protein - Change at Visit 5	0.0564 ± 0.543	-0.0793 ± 0.761
Glucose in NaF blood - Visit 2	183 ± 74.7	186 ± 86.1
Glucose in NaF blood - Change at Visit 5	24.3 ± 92.1	5.73 ± 105

Notes
[20] - Safety set

No statistical analyses for this end point

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

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End point title

Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

End point description

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[21]
Units: mmol/L
arithmetic mean (standard deviation)
Potassium - Visit 2	4.46 ± 0.434	4.41 ± 0.418
Potassium - Change at Visit 5	0.0000 ± 0.436	0.0171 ± 0.450
Sodium - Visit 2	140 ± 3.76	139 ± 3.04
Sodium - Change at Visit 5	-0.809 ± 3.96	-0.368 ± 5.44

Notes
[21] - Safety set

No statistical analyses for this end point

Secondary: Haematology Assessments at Baseline and Absolute Change at Visit 5

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End point title

Haematology Assessments at Baseline and Absolute Change at Visit 5

End point description

End point type

Secondary

End point timeframe

From visit 2 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[22]
Units: various
arithmetic mean (standard deviation)
Haematocrit (%) - Visit 2	43.9 ± 3.94	44.1 ± 4.69
Haematocrit (%) - Change at Visit 5	0.513 ± 3.30	0.899 ± 4.36
Haemoglobin (g/dL) - Visit 2	14.1 ± 1.37	14.3 ± 1.63
Haemoglobin (g/dL) - Change at Visit 5	-0.146 ± 0.621	0.0457 ± 1.23
Platelets (10^3/uL) - Visit 2	259 ± 66.6	250 ± 70.7
Platelets (10^3/uL) - Change at Visit 5	9.20 ± 53.7	15.1 ± 52.6
Erythrocytes (/pL) - Visit 2	4.76 ± 0.466	4.76 ± 0.510
Erythrocytes (/pL) - Change at Visit 5	-0.0285 ± 0.214	0.0351 ± 0.382
Leukocytes (/nL) - Visit 2	6.14 ± 1.73	6.13 ± 1.97
Leukocytes (/nL) - Change at Visit 5	0.0695 ± 1.49	0.212 ± 1.44
Haemoglobin A1c (mmol/mol Hb) - Visit 2	62.6 ± 12.7	63.8 ± 13.4
Haemoglobin A1c (mmol/mol Hb) - Change at Visit 5	1.44 ± 6.99	0.739 ± 9.37

Notes
[22] - Safety set

No statistical analyses for this end point

Secondary: Level of circulating Antibodies

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End point title

Level of circulating Antibodies

End point description

Blood samples for analysing levels of total circulating immunoglobulin E (IgE) antibodies were taken at Visit 2, Visit 3, Visit 4 and Visit 5. The analysis was performed by Synlab, Munich. At baseline, the IgE levels were 35.0 kU/I in the Rechon Insulin group and 37.8 kU/I in the Humulin Regular group, with a change of 0.1 kU/I and 0.8 kU/I compared to the IgE levels at Visit 5 for the treatment groups, respectively.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[23]	164 ^[24]
Units: kU/l
median (inter-quartile range (Q1-Q3))
Visit 2	35.0 (13.8 to 95.6)	37.8 (17.2 to 95.8)
Visit 3	34.8 (12.4 to 102)	36.1 (17.1 to 94.2)
Vsiit 3 - Change from baseline	0.00 (-2.40 to 2.60)	-0.700 (-4.50 to 3.35)
Visit 4	37.3 (12.0 to 98.8)	43.2 (18.0 to 96.3)
Visit 4 - Change from baseline	-0.450 (-4.20 to 4.50)	0.800 (-4.60 to 5.80)
Visit 5	36.6 (12.8 to 98.6)	44.9 (18.4 to 103)
Visit 5 - Change from baseline	0.100 (-3.55 to 8.35)	0.800 (-5.30 to 8.75)

Notes
[23] - Visit 2, n=164 Visit 3, n=159 Visit 4, n=154 Visit 5, n=152
[24] - Safety set Visit 2, n=164 Visit 3, n=160 Visit 4, n=155 Visit 5, n=152

Circulating IgE Antibodies (ANCOVA) (Safety Set)

Statistical analysis description

An ANCOVA assessment did not detect a statistically significant difference between the treatment groups in change from baseline (p-value 0.745 at Visit 5).

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.492 ^[25]

Method

ANCOVA

Confidence interval

Notes
[25] - Visit 3, P= 0.492 Visit 4, P= 0.394 Visit 5, P= 0.745

Secondary: Partial Correlation Analysis of Circulating IgE Antibodies (Safety Set)

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End point title

Partial Correlation Analysis of Circulating IgE Antibodies (Safety Set)

End point description

Partial Spearman correlations were performed where the change in anti-insulin antibody levels was compared to: - change from baseline in HbA1c; - change from baseline in body weight; - level of fasting glucose; and - total insulin dose. At Visit 3, there was a moderate, statistically significant correlation in change from baseline in HbA1c in the Humulin Regular group (0.3630, p-value <0.0001) and a weak positive correlation in total insulin dose in the Rechon Insulin group (0.1980, p-value 0.0186). In addition, there was a statistically significant weak negative correlation in change from baseline in body weight at Visit 5 in the Rechon Insulin group (-0.1970, p-value 0.0220).

End point type

Secondary

End point timeframe

From Baseline to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[26]
Units: various
number (not applicable)
Change from baseline in HbA1c (mmol/mol Hb) - V3	0.0857	0.3630
Change from baseline in HbA1c (mmol/mol Hb) - V4	0.689	0.0849
Change from baseline in HbA1c (mmol/mol Hb) - V5	0.987	0.0574
Change from baseline in body weight (kg) - V3	-0.0212	-0.0330
Change from baseline in body weight (kg) - V4	-0.1105	-0.1329
Change from baseline in body weight (kg) - V5	-0.1970	-0.0033
Fasting glucose (mg/dL) - V3	-0.0546	-0.0404
Fasting glucose (mg/dL) - V4	-0.0327	0.0637
Fasting glucose (mg/dL) - V5	0.0545	0.0989
Total insulin dose (IU/kg) - V3	0.1980	0.0089
Total insulin dose (IU/kg) - V4	0.1592	0.0124
Total insulin dose (IU/kg) - V5	0.1167	-0.0654

Notes
[26] - Safety set

Partial Correlation Analysis - HbA1c

Statistical analysis description

At Visit 3, there was a moderate, statistically significant correlation in change from baseline in HbA1c in the Humulin Regular group (0.3630, p-value <0.0001) and a weak positive correlation in total insulin dose in the Rechon Insulin group (0.1980, p-value 0.0186).

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.3125 ^[28]

Method

Spearman correlation

Confidence interval

Notes
[27] - Correlation
[28] - Rechon insulin, Visit 3, P=0.3125 Humulin Regular, Visit 3, P=0.3630 Rechon insulin, Visit 4, P=0.4239 Humulin Regular, Visit 4, P=0.3118 Rechon insulin, Visit 5, P=0.2548 Humulin Regular, Visit 5, P=0.5040

Partial Correlation Analysis - Body weight

Statistical analysis description

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.8033 ^[30]

Method

Spearman correlation

Confidence interval

Notes
[29] - Correlation
[30] - Rechon insulin, Visit 3, P=0.8033 Humulin Regular, Visit 3, P=0.6925 Rechon insulin, Visit 4, P=0.1987 Humulin Regular, Visit 4, P=0.1124 Rechon insulin, Visit 5, P=0.0220 Humulin Regular, Visit 5, P=0.9690

Partial Correlation Analysis - Fasting glucose

Statistical analysis description

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.5201 ^[32]

Method

Spearman correlation

Confidence interval

Notes
[31] - Correlation
[32] - Rechon insulin, Visit 3, P=0.5201 Humulin Regular, Visit 3, P=0.6279 Rechon insulin, Visit 4, P=0.7043 Humulin Regular, Visit 4, P=0.4483 Rechon insulin, Visit 5, P=0.5303 Humulin Regular, Visit 5, P=0.2483

Partial Correlation Analysis - Total insulin dose

Statistical analysis description

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.0186 ^[34]

Method

Spearman correlation

Confidence interval

Notes
[33] - Correlation
[34] - Rechon insulin, Visit 3, P=0.0186 Humulin Regular, Visit 3, P=0.9147 Rechon insulin, Visit 4, P=0.0631 Humulin Regular, Visit 4, P=0.8832 Rechon insulin, Visit 5, P=0.1776 Humulin Regular, Visit 5, P=0.4461

Secondary: Spearman Correlation of Circulating IgE Antibodies versus Body Weight, Fasting Blood Glucose, HbA1c, and Insulin Dose at Visit 5 (Safety Set)

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End point title

Spearman Correlation of Circulating IgE Antibodies versus Body Weight, Fasting Blood Glucose, HbA1c, and Insulin Dose at Visit 5 (Safety Set)

End point description

The clinical relevance of antibody formation was evaluated using Spearman correlations between change from baseline in anti-insulin antibody levels and change from baseline in glucose response as HbA1c, fasting plasma glucose, insulin dose and weight change. Based on the results from the Spearman correlation analyses, it is not possible to conclude if there is any specific relationship between antibody formation and change from baseline in HbA1c, change from baseline in body weight, fasting glucose or total insulin dose.

End point type

Secondary

End point timeframe

Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[35]
Units: correlation rank
number (not applicable)
Body weight	-0.1539	-0.0322
Fasting blood glucose	0.0092	0.0960
Glycosylated A1c	0.1141	0.0752
Insulin dose	0.1004	-0.0747

Notes
[35] - Safety set

No statistical analyses for this end point

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

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End point title

Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

End point description

All hypoglycaemic episodes were summarised by severity according to ADA-defined categories 1-5 and in total. All hypoglycaemic episodes were presented, including number of and percent of patients with at least one episode, number of episodes and rate (as number of events per patient year of exposure). Hypoglycaemic episodes occurred overall at a significantly higher rate (1.20 [1.14-1.27], p-value <0.0001) in the Rechon Insulin group (2700 episodes) than in the Humulin Regular group (2217 episodes). With the exception of the overall rate ratio for hypoglycaemic episodes, that was slightly higher in the Rechon Insulin group, no clinically meaningful changes were detected compared to treatment with Humulin Regular.

End point type

Secondary

End point timeframe

After first exposure of randomised treatment and no later than 1 day after last exposure to randomised treatment.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[36]
Units: Numbers of events
All hypoglycaemic events	2700	2217
1. Severe hypoglycaemia	3	3
2. Documented symptomatic hypoglycaemia	2003	1764
3. Asymptomatic hypoglycaemia	582	401
4. Probable symptomatic hypoglycaemia	11	5
5. Relative hypoglycaemia	101	41

Notes
[36] - Safety set

Hypoglycaemic Episodes: Gen. Linear Regression

Statistical analysis description

A generalised linear regression model with number of episodes as response (using a log-link function in accordance with a Poisson regression) and including treatment group and country as factors and exposure time as offset was applied to estimate the treatment rate ratio with a 95% CI.

Comparison groups

Rechon Insulin Human Soluble v Humulin® Regular

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Rate ratio

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

1.14

upper limit

1.27

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

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End point title

Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

End point description

End point type

Secondary

End point timeframe

After first exposure of randomised treatment and no later than 1 day after last exposure to randomised treatment.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164
Units: No of patients with at least one event
All hypoglycaemic events	109	117
1. Severe hypoglycaemia	3	3
2. Documented symptomatic hypoglycaemia	101	110
3. Asymptomatic hypoglycaemia	40	40
4. Probable symptomatic hypoglycaemia	3	2
5. Relative hypoglycaemia	23	14

No statistical analyses for this end point

Secondary: Hypersensitivity (Safety Set)

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End point title

Hypersensitivity (Safety Set)

End point description

The patients were asked to complete a paper diary with doses of administered insulin during one week after Visit 2 and during one week before Visit 3, 4 and 5 and to register local and systemic hypersensitivity reactions and hypoglycaemic episodes daily. Local and systemic hypersensitivity reactions were reported by 3.7% of patients (n=6) in each of the treatment groups. The 13 incidents in the Rechon Insulin and the 6 incidents in the Humulin Regular group that were recorded by the patients in the diary and judged by the Investigators either as not an AESI, an AESI not related to treatment or an AESI related to treatment

End point type

Secondary

End point timeframe

Visit 2 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[37]
Units: Numbers of events and patients
Number of hypersensitivity events	13	6
Number of patients with at least one event	6	6

Notes
[37] - Safety set

No statistical analyses for this end point

Secondary: Systolic Blood Pressure

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End point title

Systolic Blood Pressure

End point description

Supine systolic and diastolic blood pressure (mmHg) were taken after 5 minutes lying down. Assessments of blood pressure and pulse showed similar results in both treatment groups and over time.

End point type

Secondary

End point timeframe

Visit 1 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[38]	164 ^[39]
Units: mmHg
arithmetic mean (standard deviation)
Visit 1	129.6 ± 15.4	129.8 ± 17.9
Visit 5 - Change from baseline	-1.1 ± 12.7	-0.5 ± 12.4

Notes
[38] - Visit 1, n=164 Visit 5, n=152
[39] - Visit 1, n=164 (Safety set) Visit 5, n=152

No statistical analyses for this end point

Secondary: Diastolic Blood Pressure

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End point title

Diastolic Blood Pressure

End point description

Supine systolic and diastolic blood pressure (mmHg) were taken after 5 minutes lying down. Assessments of blood pressure and pulse showed similar results in both treatment groups and over time.

End point type

Secondary

End point timeframe

Visit 1 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[40]	164 ^[41]
Units: mmHg
arithmetic mean (standard deviation)
Visit 1	78.6 ± 9.2	78.1 ± 8.4
Visit 5 - Change from baseline	-0.6 ± 8.8	-0.2 ± 7.4

Notes
[40] - Visit 1, n=164 Visit 5, n=152
[41] - Visit 1, n=164 (Safety set) Visit 5, n=152

No statistical analyses for this end point

Secondary: Pulse

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End point title

Pulse

End point description

Supine systolic and diastolic blood pressure (mmHg) were taken after 5 minutes lying down. Assessments of blood pressure and pulse showed similar results in both treatment groups and over time.

End point type

Secondary

End point timeframe

Visit 1 to Visit 5

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[42]	164 ^[43]
Units: beats/min
arithmetic mean (standard deviation)
Visit 1	74.0 ± 9.9	73.6 ± 8.8
Visit 5 - Change from baseline	0.1 ± 8.9	1.5 ± 9.1

Notes
[42] - Visit 1, n=164 Visit 5, n=152
[43] - Visit 1, n=164 (Safety set) Visit 5, n=152

No statistical analyses for this end point

Secondary: Physical examination

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End point title

Physical examination

End point description

Standard physical examinations included assessments of the general condition, heart, lungs and abdomen. The physical examinations showed similar results between groups, with only 3 cases of CS abnormal findings that were noted at baseline, which all were due to the patients’ general condition and not related to the study treatment.

End point type

Secondary

End point timeframe

From Visit 1 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[44]	164 ^[45]
Units: Number of patients
V1, General Condition - Normal	160	160
V1, General Condition - Abnormal NCS	4	4
V2, General Condition - Normal	158	160
V2, General Condition - Abnormal NCS	6	4
V3, General Condition - Normal	155	155
V3, General Condition - Abnormal NCS	5	5
V3, General Condition - Abnormal CS	1	0
V4, General Condition - Normal	153	151
V4, General Condition - Abnormal NCS	2	3
V4, General Condition - Abnormal CS	0	1
V5, General Condition - Normal	145	149
V5, General Condition - Abnormal NCS	6	3
V5, General Condition - Abnormal CS	1	0
V1, Abdomen - Normal	156	160
V1, Abdomen - Abnormal NCS	8	4
V2, Abdomen - Normal	158	160
V2, Abdomen - Abnormal NCS	6	4
V3, Abdomen - Normal	154	156
V3, Abdomen - Abnormal NCS	7	4
V4, Abdomen - Normal	150	152
V4, Abdomen - Abnormal NCS	5	3
V5, Abdomen - Normal	145	149
V5, Abdomen - Abnormal NCS	7	3
V1, Lungs - Normal	163	163
V1, Lungs - Abnormal NCS	1	1
V2, Lungs - Normal	162	163
V2, Lungs - Abnormal NCS	2	1
V3, Lungs - Normal	159	160
V3, Lungs - Abnormal NCS	2	0
V4, Lungs - Normal	154	155
V4, Lungs - Abnormal NCS	1	0
V5, Lungs - Normal	149	151
V5, Lungs - Abnormal NCS	3	1
V1, Heart - Normal	163	161
V1, Heart - Abnormal NCS	1	3
V2, Heart - Normal	164	163
V2, Heart - Abnormal NCS	0	1
V3, Heart - Normal	161	160
V3, Heart - Abnormal NCS	0	0
V4, Heart - Normal	154	155
V4, Heart - Abnormal NCS	1	0
V5, Heart - Normal	150	152
V5, Heart - Abnormal NCS	2	0

Notes
[44] - Visit 1, n=164 Visit 2, n=164 Visit 3, n=161 Visit 4, n=155 Visit 5, n=152
[45] - Visit 1, n=164 (Safety set) Visit 2, n=164 Visit 3, n=160 Visit 4, n=155 Visit 5, n=152

No statistical analyses for this end point

Secondary: Injection site reactions (Safety Set)

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End point title

Injection site reactions (Safety Set)

End point description

There were only a few cases of AESI of injection site reactions and thus no trends were seen for a different distribution between treatment groups for injection site erythema, injection site pain, injection site pruritus and injection site rash.

End point type

Secondary

End point timeframe

From first dose of IMP to completion of Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular	Safety set
Number of subjects analysed	164	164 ^[46]	328
Units: Number of patients and events
Injection site erythema - No of events	1	1	2
Inj. site erythema - No of patients with event	1	1	2
Injection site pain - No of events	0	1	1
Injection site pain - No of patients with event	0	1	1
Injection site pruritus - No of events	1	1	2
Inj. site pruritus - No of patients with event	1	1	2
Injection site rash - No of events	2	0	2
Injection site rash - No of patients with event	2	0	2

Notes
[46] - Safety set

No statistical analyses for this end point

Secondary: Creatinine Assessments (Safety Set)

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End point title

Creatinine Assessments (Safety Set)

End point description

Overall, the laboratory assessments showed similar results between the treatment groups without clear tendencies to change over time, including creatinine, indicating a stable diabetic condition over time irrespective of treatment. The creatinine level at baseline was 0.859 mg/dL in the Rechon Insulin group and 0.910 mg/dL in the Humulin Regular group, which at Visit 5 had changed by 0.0168 mg/dL and -0.0001 mg/dL, respectively.

End point type

Secondary

End point timeframe

Visit 2 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164 ^[47]	164 ^[48]
Units: mg/dL
arithmetic mean (standard deviation)
Visit 2	0.859 ± 0.149	0.910 ± 0.286
Visit 3	0.876 ± 0.172	0.0214 ± 0.100
Visit 3 - Change from baseline	0.892 ± 0.247	-0.0134 ± 0.123
Visit 4	0.875 ± 0.168	0.0213 ± 0.101
Visit 4 - Change from baseline	0.915 ± 0.266	0.0066 ± 0.131
Visit 5	0.870 ± 0.164	0.0168 ± 0.106
Visit 5 - Change from baseline	0.911 ± 0.284	-0.0001 ± 0.147

Notes
[47] - Visit 2, n=163 Visit 3, n=159 Visit 4, n=154 Visit 5, n=152
[48] - Visit 2, n=164 (Safety set) Visit 3, n=158 Visit 4, n=153 Visit 5, n=152

No statistical analyses for this end point

Secondary: Clinically Significant Laboratory Values: Urinalysis (Safety Set)

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End point title

Clinically Significant Laboratory Values: Urinalysis (Safety Set)

End point description

As expected from the patient population, the urinalysis parameter most commonly assessed as CS abnormal was glucose in urine. This was reported for slightly more patients in the Rechon Insulin group than in the Humulin Regular group; for 7 patients on 10 occasions in the Rechon Insulin group and by 3 patients on 5 occasions in the Humulin Regular group. Out of these in total 15 cases of CS abnormal glucose in urine, 1 case was reported as an AE which was unrelated to treatment with Humulin Regular. All other cases were reported as medical history.

End point type

Secondary

End point timeframe

From Visit 1 to Visit 5.

End point values	Rechon Insulin Human Soluble	Humulin® Regular
Number of subjects analysed	164	164 ^[49]
Units: Number of patients with CS values
Visit 1 - Glucose in urine	4	1
Visit 2 - Glucose in urine	3	2
Visit 3 - Glucose in urine	1	1
Visit 4 - Glucose in urine	1	1
Visit 5 - Glucose in urine	1	0
Visit 1 - Protein in urine	1	0
Visit 2 - Protein in urine	0	0
Visit 3 - Protein in urine	0	0
Visit 4 - Protein in urine	0	0
Visit 5 - Protein in urine	0	0
Visit 1 - Erythrocytes in urine	1	0
Visit 2 - Erythrocytes in urine	0	0
Visit 3 - Erythrocytes in urine	0	0
Visit 4 - Erythrocytes in urine	1	0
Visit 5 - Erythrocytes in urine	0	0
Visit 1 - Leukocytes in urine	1	0
Visit 2 - Leukocytes in urine	0	1
Visit 3 - Leukocytes in urine	0	0
Visit 4 - Leukocytes in urine	0	0
Visit 5 - Leukocytes in urine	0	0

Notes
[49] - Safety set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of IMP until the completion of Visit 5.

Adverse event reporting additional description

Detailed information on each AE was recorded in the eCRF. Any AE that was ongoing at the time when the patient left the study was to be followed up until the AE was resolved or the Investigator decided that the AE was stable and did not need further follow-up.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Rechon Insulin Human Soluble

Reporting group description

Patients received either Rechon Insulin Human Soluble or Humulin® Regular in a randomised way. The IMP was administered at home by the patients themselves. Dosing was individualised and adjusted based on blood glucose levels for each patient. In total, 0.9% of the patients (n=3), all randomised to treatment with Humulin Regular, were excluded from the safety set.

Reporting group title

Humulin® Regular

Reporting group description

Serious adverse events	Rechon Insulin Human Soluble	Humulin® Regular
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 164 (5.49%)	9 / 164 (5.49%)
number of deaths (all causes)	0	2
number of deaths resulting from adverse events	0	2
Injury, poisoning and procedural complications
Muscle rupture
subjects affected / exposed	1 / 164 (0.61%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Iliac artery occlusion
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastric haemorrhage
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 164 (0.61%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	0 / 164 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 164 (0.61%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 164 (0.61%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	5 / 164 (3.05%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	3 / 5	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	1 / 164 (0.61%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1.2%

Non-serious adverse events	Rechon Insulin Human Soluble	Humulin® Regular
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 164 (19.51%)	12 / 164 (7.32%)
Nervous system disorders
Headache
subjects affected / exposed	3 / 164 (1.83%)	1 / 164 (0.61%)
occurrences all number	3	1
General disorders and administration site conditions
Injection site rash
subjects affected / exposed	2 / 164 (1.22%)	0 / 164 (0.00%)
occurrences all number	2	0
Peripheral swelling
subjects affected / exposed	2 / 164 (1.22%)	0 / 164 (0.00%)
occurrences all number	2	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 164 (0.00%)	2 / 164 (1.22%)
occurrences all number	0	2
Nausea
subjects affected / exposed	2 / 164 (1.22%)	1 / 164 (0.61%)
occurrences all number	2	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 164 (1.83%)	0 / 164 (0.00%)
occurrences all number	3	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 164 (1.22%)	1 / 164 (0.61%)
occurrences all number	2	1
Nasopharyngitis
subjects affected / exposed	2 / 164 (1.22%)	2 / 164 (1.22%)
occurrences all number	2	2
Rhinitis
subjects affected / exposed	2 / 164 (1.22%)	0 / 164 (0.00%)
occurrences all number	2	0
Sinusitis
subjects affected / exposed	2 / 164 (1.22%)	0 / 164 (0.00%)
occurrences all number	2	0
Urinary tract infection
subjects affected / exposed	4 / 164 (2.44%)	2 / 164 (1.22%)
occurrences all number	4	2
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	3 / 164 (1.83%)	0 / 164 (0.00%)
occurrences all number	3	0
Hypoglycaemia
subjects affected / exposed	5 / 164 (3.05%)	3 / 164 (1.83%)
occurrences all number	5	3

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Were there any global substantial amendments to the protocol? Yes

05 Dec 2017

Prior to this amendment, there were two local versions of the CSP; version 3.0 that was approved only in Poland and version 4.0 that was approved only in Germany. This substantial amendment was made to combine information in the two local CSP versions into a single global version of the CSP. This substantial amendment included: - Addition of a withdrawal criterion regarding pregnancy - Updated information on origin of source data and medical records - Correction to the list of references This substantial amendment rendered the global CSP version 5.0.

25 Jun 2018

The analysis method for the primary variable was changed to a 3-tiered approach with a new method of analysis and procedure for the detection of antibodies against insulin. A clarification was made for the re-check of eligibility criteria, where laboratory safety assessments were to be performed. Exclusion criteria regarding definition of hypoglycaemic episodes and patient life expectancy were updated. Definition and reporting procedure for suspected unexpected serious adverse reactions (SUSARs), as well as clarification of follow-up of patients with ongoing AEs at database lock was added. In addition, clarification of when hypoglycaemic events should be reported as an AE was made. A sample size adjustment was added to avoid a decrease in sample size due to dropout and the planned study start and end dates were updated. Information regarding data protection was updated in light of new GDPR legislation. Minor administrative and editorial changes were made. This substantial amendment rendered the CSP version 6.0.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

N/A

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Clinical trials

Clinical Trial Results: A Randomised, Open, Parallel-group Phase III Biosimilarity Study to Assess the Long-term Safety, Focusing on Immunogenicity, of Rechon Insulin Human Soluble in Type 1 Diabetic Patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Anti-Insulin Binding Antibodies (PPS)

Primary: Anti-Insulin Binding Antibodies (PPS)

Primary: Testing Positive for Anti-Insulin Antibodies (Safety Set)

Primary: Testing Positive for Anti-Insulin Antibodies (Safety Set)

Secondary: Total Daily Insulin dose (Safety Set)

Secondary: Total Daily Insulin dose (Safety Set)

Secondary: Daily Basal Insulin Dose (Safety Set)

Secondary: Daily Basal Insulin Dose (Safety Set)

Secondary: Daily Bolus Insulin Dose (Safety Set)

Secondary: Daily Bolus Insulin Dose (Safety Set)

Secondary: Total Daily Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

Secondary: Total Daily Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

Secondary: Total Daily Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

Secondary: Total Daily Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

Secondary: Daily Bolus Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

Secondary: Daily Bolus Insulin Dose at Baseline - Intermediate-acting insulin (Safety Set)

Secondary: Daily Bolus Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

Secondary: Daily Bolus Insulin Dose at Baseline - Long/ultralong-acting insulin (Safety Set)

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Clinical Chemistry Assessments at Baseline and Absolute Change at Visit 5

Secondary: Haematology Assessments at Baseline and Absolute Change at Visit 5

Secondary: Haematology Assessments at Baseline and Absolute Change at Visit 5

Secondary: Level of circulating Antibodies

Secondary: Level of circulating Antibodies

Secondary: Partial Correlation Analysis of Circulating IgE Antibodies (Safety Set)

Secondary: Partial Correlation Analysis of Circulating IgE Antibodies (Safety Set)

Secondary: Spearman Correlation of Circulating IgE Antibodies versus Body Weight, Fasting Blood Glucose, HbA1c, and Insulin Dose at Visit 5 (Safety Set)

Secondary: Spearman Correlation of Circulating IgE Antibodies versus Body Weight, Fasting Blood Glucose, HbA1c, and Insulin Dose at Visit 5 (Safety Set)

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

Secondary: Assessment of Hypoglycaemic Episodes According to ADA Criteria (Safety Set)

Secondary: Hypersensitivity (Safety Set)

Secondary: Hypersensitivity (Safety Set)

Secondary: Systolic Blood Pressure

Secondary: Systolic Blood Pressure

Secondary: Diastolic Blood Pressure

Secondary: Diastolic Blood Pressure

Secondary: Pulse

Secondary: Pulse

Secondary: Physical examination

Secondary: Physical examination

Secondary: Injection site reactions (Safety Set)

Secondary: Injection site reactions (Safety Set)

Secondary: Creatinine Assessments (Safety Set)

Secondary: Creatinine Assessments (Safety Set)

Secondary: Clinically Significant Laboratory Values: Urinalysis (Safety Set)

Secondary: Clinically Significant Laboratory Values: Urinalysis (Safety Set)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomised, Open, Parallel-group Phase III Biosimilarity Study to Assess the Long-term Safety, Focusing on Immunogenicity, of Rechon Insulin Human Soluble in Type 1 Diabetic Patients.