A Clinical Proof-of-principle Trial in Adult Subjects With Newly Diagnosed Type 1 Diabetes Mellitus Investigating the Effect of NNC0114-0006 and Liraglutide on Preservation of Beta-cell Function

Area under the concentration-time curve, from 0 to 4 hours (AUC0-4h) of a mixed meal tolerance test (MMTT) stimulated C-peptide at week 54 is presented as ratio to baseline. AUC of C-peptide was measured as Nano moles*hour per liter (nmol*h/L).

Area under the concentration-time curve, from 0 to 2 hours (AUC0-2h) of a MMTT stimulated C-peptide at week 54 is presented as ratio to baseline. AUC of C-peptide was measured as 'nmol*h/L'.

Maximum observed concentration (Cmax) of a MMTT stimulated C-peptide at week 54 is presented as ratio to baseline. Cmax of C-peptide was measured as nanomoles per liter (nmol/L).

Area under the concentration-time curve, from 0 to 4 hours (AUC0-4h) of a MMTT stimulated glucose at week 54 is presented as ratio to baseline. AUC of glucose was measured as Milli moles*hour per liter (mmol*h/L).

Area under the concentration-time curve, from 0 to 2 hours (AUC0-2h) of a MMTT stimulated glucose at week 54 is presented as ratio to baseline. AUC of glucose is measured as 'mmol*h/L'.

Maximum observed concentration (Cmax) of a MMTT stimulated glucose at week 54 is presented as ratio to baseline. Cmax of C-peptide was measured as 'mmol/L'.

An adverse event was any untoward medical occurrence in a participants administered a product, and which did not necessarily have a causal relationship with this treatment. An adverse event was defined as treatment emergent if the onset of the adverse event occurs on or after the first day of trial product administration. Number of treatment emergent adverse events from first dose of trial product to week 54 and week 80 are presented. Results are based on the on-treatment and on-observation period.

On-treatment period: From the day of first trial product administration to the day of the visit at week 54. On-observation: From the day after the visit at week 54 to the day of the last visit.

Hyperglycaemic episodes were defined as treatment-emergent if the onset occurred on or after the first day of trial product administration. Number of treatment emergent episodes of hyperglycaemic episodes from first dose of trial product to week 54 and from week 54 to week 80 are presented. Results are based on the on-treatment and on-observation period.

On-treatment period: From the day of first trial product administration to the day of the visit at week 54. On-observation: From the day after the visit at week 54 to the day of the last visit.

Diabetic ketoacidosis episodes were defined as treatment-emergent if the onset occurred on or after the first day of trial product administration. Number of treatment emergent episodes of hyperglycaemic episodes from first dose of trial product to week 54 and from week 54 to week 80 are presented. Results are based on the on-treatment and on-observation period.

On-treatment period: From the day of first trial product administration to the day of the visit at week 54. On-observation: From the day after the visit at week 54 to the day of the last visit.

Injection/infusion site reactions episodes were defined as treatment-emergent if the onset occurred on or after the first day of trial product administration. Number of participants experiencing treatment emergent episodes of injection/infusion site reactions episodes from first dose of trial product to week 54 (treatment period) is presented.

Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 1 day after the date of last contact. Number of treatment-emergent hypoglycaemic episodes according to American Diabetes Association (ADA) classification from first dose of trial product to week 54 and from week 54 to week 80 are presented.

Results presented hypoglycaemia episodes were recorded as per ADA definition: Severe hypoglycaemia, Documented symptomatic hypoglycaemia, Asymptomatic hypoglycaemia, Probable symptomatic hypoglycaemia and Pseudo-hypoglycaemia.

Hypoglycaemia episodes were recorded as per Novo Nordisk definition: Symptomatic BG-confirmed: An episode that is blood glucose (BG) confirmed by plasma glucose (PG) value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Asymptomatic BG-confirmed: An episode that is BG-confirmed by PG value <3.1 mmol/L without symptoms consistent with hypoglycaemia. Severe or BG-confirmed symptomatic: An episode that is severe according to the ISPAD classification or BG-confirmed by a PG value <3.1 mmol/L with symptoms consistent with hypoglycaemia. BG-confirmed: An episode that is BG-confirmed by a PG value <3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Severe or BG-confirmed: An episode that is severe according to the International Society for Pediatric and Adolescent Diabetes (ISPAD) classification or BG-confirmed by a PG value <3.1 mmol/L with or without symptoms consistent with hypoglycaemia.

Change in body weight is measured at week 54 and week 80 respective to baseline. Body weight was measured in unit 'Kg'.

Number of participants evaluated for diabetic retinopathy at baseline (Day -28 to -14), week 54 and week 80 are presented as 'yes', 'no' or 'unknown'.

The eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Change in eGFR (measured in milliliters per minute per 1.73 square meters) from baseline (week 0) at week 54 and week 80 is presented as ratio to baseline.

Change in erythrocytes (measured in 10^12 cells per liter) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in haematocrit (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in haemoglobin (measured in millimoles per liter 'mmol/L') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in leukocytes (measured in 10^9 cells/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in mean Corpuscular hemoglobin (measured in femtomole 'fmol') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in mean corpuscular hemoglobin concentration (MCHC) (measured in gram per liter 'g/L') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Mean Corpuscular volume (measured in femtoliter 'fL') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in thrombocytes (measured in 10^9 cells per liter) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in eosinophil (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in neutrophils (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in basophils (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in lymphocytes (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in monocytes (measured in percentage '%') from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in ALAT (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in albumin (measured in gram per deciliter [g/dL]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in amylase (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in ALP (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in ASAT (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Total bilirubin (measured in micromole per liter [umol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in calcium corrected (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in chloride (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in creatine kinase (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in creatinine (measured in micromole per liter [umol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in GGT (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in C-reactive protein serum (measured in milligrams per liter [mg/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Lactate Dehydrogenase (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in lipase (measured in units per liter [U/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in magnesium (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in phosphate (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in potassium (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in sodium (measured in millimole per liter [mmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in total protein (measured in gram per liter [g/dL]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in blood urea nitrogen serum (measured in milligram per deciliter [mg/dL]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Uric Acid (measured in milligram per deciliter [mg/dL]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in INR (measured in ratio]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in D-Dimer (measured in mg/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in total cholesterol (measured in mmol/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in total free fatty acids (measured in mmol/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in HDL cholesterol (measured in mmol/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in LDL cholesterol (measured in mmol/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Triglycerides (measured in mmol/L) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in IgE (measured in kilo international units per liter [kIU/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Urinalysis was performed by urine dipsticks for protein, glucose, erythrocytes, ketones leukocytes, nitrite, pH and specific gravity and categorised as normal, abnormal not clinically significant (NCS) and abnormal clinially significant (CS). Number of participants in each category at baseline (week 0), week 54 and 80 are presented.

IL-6 levels at baseline (week 0), weeks 54 and 80 are evaluated and presented.

IL-10 levels at baseline (week 0), weeks 54 and 80 are evaluated and presented.

IL-17 levels at baseline (week 0), weeks 54 and 80 are evaluated and presented.

IFN gamma levels at baseline (week 0), weeks 54 and 80 are evaluated and presented.

TNF-alpha levels at baseline (week 0), weeks 54 and 80 are evaluated and presented.

Change in TSH (measured in milli international units per liter [mIU/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in Calcitonin (measured in nanogram per liter [ng/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) are evaluated from baseline (week 0) to weeks 54 and 80.

Change in pulse is evaluated from baseline (week 0) to weeks 54 and 80

Change in body temperature is evaluated from baseline (week 0) to weeks 54 and 80.

Change in respiratory rate is evaluated from baseline (week 0) to weeks 54 and 80.

The ECG was assessed by the investigator at baseline (week 0), week 54 and week 80 and categorised as normal, abnormal NCS or abnormal CS. Number of participants in each ECG category at baseline, week 54 and week 80 are presented.

Dilated fundoscopy or fundus photography was performed by the investigator at week 0, week 54 and week 80. The results of the examination were interpreted for each eye (left/right) are categorised as normal, abnormal NCS or abnormal CS. Number of participants in each category at week 0, week 54 and week 80 are presented.

Physical examination parameters are categorised as general appearance; head, ears, eyes, nose, throat, neck; respiratory system;cardiovascular system; gastrointestinal system including mouth; musculoskeletal system; central and peripheral nervous system; skin; lymph node palpation and thyroid gland. Investigator assessed the participants with normal, abnormal not clinically significant (NCS) and abnormal clinically significant (CS) findings at week 0, week 54 and week 80 are presented.

This outcome measure was applicable for NNC0114-0006 + Liraglutide treatment arm and NNC0114-0006 treatment arm. Participants was assessed for anti-NNC0114-0006 antibodies. Participant who reported anti-NNC0114-0006 antibodies were further analyzed for cross-reactivity. Number of participants who measured with anti-NNC0114-0006 antibodies at week 54 and week 80 are presented.

This outcome measure is applicable for NNC0114-0006 + Liraglutide treatment arm and Liraglutide treatment arm. Participants was assessed for anti-liraglutide antibodies. Participant who reported anti-liraglutide antibodies were further analyzed for cross-reactivity. Number of participants who measured with anti-liraglutide antibodies at week 54 and week 80 are presented.

The total daily insulin dose was derived as the average of the doses reported on the three days prior to the visit. Change in daily total insulin dose from baseline (week 0) after 54 weeks of treatment and week 80 are presented.

The number of insulin injections was derived as the average of the reported number on the three days prior to the visit. The change in number of insulin injections per day (count) from baseline (week 0) after 54 weeks of treatment and week 80 are presented.

The number of weeks off bolus insulin after 54 weeks of treatment and week 80 are presented.

Change in glycosylated haemoglobin (HbA1c) is evaluated from baseline (week 0) to weeks 54 and 80.

Change in fasting plasma glucose is evaluated from baseline (week 0) to weeks 54 and 80.

Change in fasting C-peptide (measured in nanomole per liter [nmol/L]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Change in fasting glucagon (measured in picogram per milliliter [pg/mL]) from baseline (week 0) to weeks 54 and 80 is presented as ratio to baseline.

Participants measured plasma glucose values using the blood glucose meter at 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime. 7-point SMPG profile values are presented for week 54 and week 80.

Participants measured plasma glucose values using the blood glucose meter at 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Change from baseline (week 0) to week 54 and week 80 in 7-point SMPG postprandial glucose /prandial increment (breakfast, lunch and dinner) value are presented.

Participants measured plasma glucose values using the blood glucose meter at 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime. Change from baseline (week 0) to week 54 and week 80 in 7-point self-measured plasma glucose (SMPG) postprandial glucose /prandial increment (average over the three meals) value is presented.

Participants measured plasma glucose values using the blood glucose meter at 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime. Change from baseline (week 0) to week 54 and week 80 in mean of 7-point profiles value is presented.

Participants measured plasma glucose values using the blood glucose meter at 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Before breakfast 7-point self-measured plasma glucose (SMPG) profile values are presented at week 54 and week 80.

AUCtau, NNC0114-0006 was derived as the area under the concentration-time curve using the linear trapezoidal technique based on observed values and actual measurement times between 0 and 6 weeks (after the last dose). This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

Terminal half life was calculated as log(2)/λz. The terminal rate constant λz was determined through linear regression with the logarithm to concentration as the response variable and actual measurement time as the explanatory variable. Valid observations from the terminal part of the curve, which is approximately linear, were used for the determination. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

The apparent volume of distribution of NNC0114-0006 at steady-state was calculated as mean residence time of (MRT) of NNC0114-0006 multiplied by clearance of NNC0114-0006 at steady state. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

Clearance of NNC0114-0006 at steady state was calculated as dose/AUCtau, NNC0114-0006. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms. Mean residence time of NNC0114-0006 is presented.

Accumulation ratio of NNC114-0006 was defined as AUC48-54 weeks/AUC0-6 weeks. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

Ctrough of NNC0114-0006 was defined as concentration prior to dosing of NNC0114-0006 at steady state. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

C1h, NNC0114-0006 was defined as concentration of NNC0114-0006 at 1 hour after dosing of NNC0114-0006 at steady state. This outcome measure was applicable for NNC0114-0006 + Liraglutide and NNC0114-0006 treatment arms.

C liraglutide was defined as the liraglutide concentration at steady state. This outcome measure was applicable for NNC0114-0006 + Liraglutide and Liraglutide treatment arms.

B cell panel is evaluated by Immune phenotyping of peripheral blood mononuclear cells (PBMC) at baseline (week 0), week 54 and week 80.

In below table CD refer to Cluster of Differentiation; IgMNeg refers to Immunoglobulin M negative; IgDNeg refers to Immunoglobulin D negative.

NK cell panel is evaluated by Immune phenotyping of peripheral blood mononuclear cells (PBMC) at baseline (week 0), week 54 and week 80.

In below table ADCC refer to Antibody-dependent cellular cytotoxicity; CD refer to Cluster of Differentiation.

T cell panel is evaluated by Immune phenotyping of peripheral blood mononuclear cells (PBMC) at baseline (week 0), week 54 and week 80.

In below table CD refer to Cluster of Differentiation; TEMRA refers to terminally differentiated effector memory cells re-expressing CD45RA; CCR refers to C-C chemokine receptor; TREG refers to Regulatory T cells.

TfH cell panel is evaluated by Immune phenotyping of peripheral blood mononuclear cells (PBMC) at baseline (week 0), week 54 and week 80.

In below table CTFH refer to Circulating T follicular helper; ICOS refers to inducible T-cell co-stimulator; PD refers to Programmed cell death protein; CCR refers to C-C chemokine receptor; CXCR refers to C-X-C chemokine receptor; CD refer to Cluster of Differentiation; CM refers to central memory; EM refers to effector memory, TIGIT refers to T cell immunoreceptor with Ig and ITIM domains.

Myeloid panel is evaluated by Immune phenotyping of peripheral blood mononuclear cells (PBMC) at baseline (week 0), week 54 and week 80.

In below table HLA refers to Human Leukocyte Antigen; MDSC refers to myeloid-derived suppressor cell; DC refers to Dendritic cells; MYDC refers to Myeloid Dendritic Cells; IMMYE_MDSC refers to Immature myeloid cells & a subset of myeloid suppressor cells within the CD14-HLA class II- myeloid cell population.

Participants were analyzed for autoantibodies against Glutamic acid decarboxylase (GAD) and were categorized as negative and positive.

Participants were analyzed for autoantibodies against Zinc-transporter 8 (ZnT8) and were categorized as negative and positive.

Participants were analyzed for autoantibodies against Islet antigen-2 (IA2) and were categorized as negative and positive.

Participants were analyzed for autoantibodies against Insulin autoantibodies (IAA) and were categorized as negative and positive.

IL-21 is evaluated at baseline (week 0), week 54 and week 80.

Serum vitamin D is evaluated at baseline (week 0), week 54 and week 80.

SF-36v2™ questionnaire measured the HRQoL on 8 domains (Bodily Pain, General Health, Mental Health, Physical Functioning, Role Emotion, Physical Health, Social Functioning and Vitality) on individual scale ranges. The scores 0-100 (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. Change from baseline (week 0) to week 54 and week 80 in SF-36 score is presented.The MCS measure is derived from domain scales of vitality, social functioning, role emotional and mental health. The PCS measure is derived from domain scales of physical functioning, role-physical, bodily pain, and general health. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. A positive change score indicate an improvement since baseline.

Treatment Benefits and Barriers (ETBB) questionnaire measured diabetes-specific health beliefs on 2 categories: Total Score for Perceived Barriers and Perceived Benefits. The measurement of perceived benefits of, and barriers to, treatment was achieved by creating a pool 28 statements each with a 7-point scale ranging from strongly agree (6) to strongly disagree (0). ETBB benefits score was calculated using the responses from questions 1, 4, 7, 8, 10, and 12 and ETBB barriers score was calculated using the responses from questions 2, 3, 5, 6, 9, and 11. Both was calculated as the sum of responses divided by number of responses received multiplied by the maximum number of responses. Based on the responses used the maximum responses available was 6. The higher score indicates more perceived benefits or more perceived barrier.

Change from baseline (week 0) in DTSQ is evaluated at week 54 and 80. The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher score indicates a higher level of glycaemia/treatment satisfaction.

Area under the concentration-time curve, from 0 to 4 hours (AUC0-4h) of a mixed meal tolerance test (MMTT) stimulated C-peptide at week 80 is presented as ratio to baseline. AUC of C-peptide was measured as Nano moles*hour per liter (nmol*h/L).

Area under the concentration-time curve, from 0 to 2 hours (AUC0-2h) of a MMTT stimulated C-peptide at week 80 is presented as ratio to baseline. AUC of C-peptide was measured as 'nmol*h/L'.

Maximum observed concentration (Cmax) of a MMTT stimulated C-peptide at week 80 is presented as ratio to baseline. Cmax of C-peptide was measured as nanomoles per liter (nmol/L).

Area under the concentration-time curve, from 0 to 4 hours (AUC0-4h) of a MMTT stimulated glucose at week 80 is presented as ratio to baseline. AUC of glucose was measured as Milli moles*hour per liter (mmol*h/L).

Area under the concentration-time curve, from 0 to 2 hours (AUC0-2h) of a MMTT stimulated glucose at week 80 is presented as ratio to baseline. AUC of glucose was measured as 'mmol*h/L'.

Maximum observed concentration (Cmax) of a MMTT stimulated glucose at week 80 is presented as ratio to baseline. Cmax of C-peptide was measured as 'mmol/L'.