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Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes (PIONEER 9)

Primary Purpose

Diabetes, Diabetes Mellitus, Type 2

Status

Completed

Phase

Phase 3

Locations

Japan

Study Type

Interventional

Intervention

Semaglutide

Placebo

Liraglutide

About this trial

This is an interventional treatment trial for Diabetes

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
Japanese male or female, age above or equal to 20 years at the time of signing informed consent
Diagnosed with type 2 diabetes mellitus for at least 30 days prior to day of screening
HbA1c 6.5%-9.5% (48-80 mmol/mol) (both inclusive) for subjects treated with oral antidiabetic drug as monotherapy and 7.0%-10.0% (53-86 mmol/mol) (both inclusive) for subjects treated with diet and exercise therapy alone
Treatment for at least 30 days prior to day of screening with;- stable daily dose of oral anti-diabetic drug as monotherapy (allowed oral anti-diabetic drugs are: metformin, sulphonylurea, glinide, α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter-2 inhibitor) at a half-maximum approved dose or below according to Japanese labelling in addition to diet and exercise therapy. or - diet and exercise therapy alone

Exclusion Criteria:

Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method. Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives
Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol
Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC)
History of pancreatitis (acute or chronic)
History of major surgical procedures involving the stomach and potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation
Subject presently classified as being in New York Heart Association (NYHA) Class IV
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
Subjects with alanine aminotransferase (ALT) above 2.5 x upper normal limit (UNL)
Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)
Treatment with once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor or thiazolidinedione in a period of 90 days before the day of screening
Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 60 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days
Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation
History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in-situ carcinomas)
Initiation of anti-diabetic medication between the day of screening and the day of randomisation

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Placebo Comparator

Active Comparator

Arm Label

Oral semaglutide 3 mg

Oral semaglutide 7 mg

Oral semaglutide 14 mg

Oral placebo

Liraglutide 0.9 mg

Arm Description

Outcomes

Primary Outcome Measures

Change in HbA1c (Week 26)

Change from baseline (week 0) to week 26 in glycosylated haemoglobin (HbA1c). The endpoint was analysed based on data from the on-treatment without rescue medication observation period. On-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication. The endpoint was also evaluated based on data from the in-trial observation period. In-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Secondary Outcome Measures

Change in HbA1c (Week 52)

Change from baseline (week 0) to week 52 in HbA1c. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Body Weight (kg)

Change from baseline (week 0) in body weight. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting Plasma Glucose

Change from baseline (week 0) in fasting plasma glucose. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Self-measured Plasma Glucose 7-point Profile (SMPG) - Mean 7-point Profile

Change from baseline (week 0) in mean 7-point self-measured plasma glucose (SMPG) profile. SMPG was recorded at the following 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after dinner and at bedtime. Mean 7-point profile was defined as the area under the profile, calculated using the trapezoidal method, divided by the measurement time. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Mean Postprandial Increment Over All Meals in SMPG

Change from baseline (week 0) in the average of the post-prandial increments over all meals. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Body Weight (%)

Relative change (%) from baseline (week 0) in body weight (kg). Data based on on-treatment without resue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Body Mass Index

Change from baseline (week 0) in body mass index (BMI). BMI was calculated based on body weight and height based on the formulae: BMI kg/m^2 = body weight (kg)/(Height (m) x Height (m)). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Waist Circumference

Change from baseline (week 0) in waist circumference. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Total Cholesterol (Ratio to Baseline)

Change from baseline (week 0) in total cholesterol (measured as mmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in HDL Cholesterol (Ratio to Baseline)

Change from baseline (week 0) in high density lipoprotein (HDL) cholesterol (measured as mmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in LDL Cholesterol (Ratio to Baseline)

Change from baseline (week 0) in low density lipoprotein (LDL) cholesterol (measured as mmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in VLDL Cholesterol (Ratio to Baseline)

Change from baseline (week 0) in very low density lipoprotein (VLDL) cholesterol (measured as mmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Triglycerides (Ratio to Baseline)

Change from baseline (week 0) in triglycerides (measured as mmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting Insulin (Ratio to Baseline)

Change from baseline (week 0) in fasting insulin (measured as picomoles per liter [pmol/L]) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting C-peptide (Ratio to Baseline)

Change from baseline (week 0) in fasting C-peptide (measured as nanomoles per liter [nmol/L]) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting Glucagon (Ratio to Baseline)

Change from baseline (week 0) in fasting glucagon (measured as picograms per milliliter [pg/mL]) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting Pro-insulin (Ratio to Baseline)

Change from baseline (week 0) in fasting pro-insulin (measured as pmol/L) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Fasting Pro-insulin/Insulin Ratio (Ratio to Baseline)

Change from baseline (week 0) in fasting pro-insulin/insulin ratio is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Insulin Resistance (HOMA-IR) (Ratio to Baseline)

Change from baseline (week 0) in insulin resistance (measured as percentage of insulin resistance) by homeostatic model assessment index of insulin resistance (HOMA-IR) is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Change in Beta-cell Function (HOMA-B) (Ratio to Baseline)

Change from baseline (week 0) in beta-cell function (measured as percentage of beta-cell function) by homeostatic model assessment index of beta-cell function is presented as ratio to baseline. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved HbA1c < 7.0% (53 mmol/Mol) ADA Target (Yes/no)

Participants who achieved HbA1c <7.0% (53 millimoles per mole [mmol/mol]) according to American Diabetes Association (ADA) target, at week 26 and week 52. Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol), AACE Target (Yes/No)

Participants who achieved HbA1c below or equal to 6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target (Yes/No). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain (Yes/No)

Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 milligrams per deciliter [mg/dL]) with symptoms consistent with hypoglycaemia. Number of participants who achieved HbA1c below 7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic hypoglycaemia episodes and no weight gain (Yes/No). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved HbA1c Reduction Above or Equal to 1% (10.9 mmol/Mol) and Weight Loss Above or Equal to 3%

Participants who achieved above or equal to 1% (10.9 mmol/mol) reduction in HbA1c and losing 3% or more of baseline body weight (Yes/No). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved Weight Loss Above or Equal to 5% (Yes/No)

Participants losing 5% or more of baseline body weight (Yes/No). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Participants Who Achieved Weight Loss Above or Equal to 10% (Yes/No)

Participants losing 10% or more of baseline body weight (Yes/No). Data based on on-treatment without rescue medication observation period is presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Time to Additional Anti-diabetic Medication

Presented results are the number of participants who had taken additional anti-diabetic medication anytime from week 0 to week 52. 'Additional anti-diabetic medication': use of new anti-diabetic medication for more than 21 days with the initiation at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time to Rescue Medication

Presented results are the number of participants who had taken rescue medication anytime from week 0 to week 52. 'Rescue medication': use of new anti-diabetic medication as add-on to trial product and used for more than 21 days with the initiation at or after randomisation and before last day on trial product. Time to rescue medication was estimated based on data from on-treatment without rescue medication observation period.

Number of Treatment-emergent Adverse Events (TEAEs)

A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) with onset in the on-treatment observation period (time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any, and excluding any period after premature trial product discontinuation) assessed up to approximately 57 weeks (52 weeks treatment period + 5 weeks follow-up period).

Change in Amylase (Ratio to Baseine)

Change in amylase (measured as units per liter [U/L]) is presented as ratio to baseline. Data based on on-treatment observation period is presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Change in Lipase (Ratio to Baseine)

Change in lipase (measured as U/L) is presented as ratio to baseline. Data based on on-treatment observation period is presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Change in Pulse Rate

Change from baseline in pulse rate. Data based on on-treatment observation period is presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Change in Blood Pressure

Change from baseline in blood pressure (systolic [sBP] and diastolic [dBP]). Data based on on-treatment observation period is presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Change in ECG Evaluation

Electrocardiogram (ECG) was evaluated and interpreted by the investigator and categorised as normal, abnormal not clinically significant (NCS) or abnormal clinically significant (CS). The number of participants who had shifted from normal, abnormal NCS or abnormal CS ECG results from baseline (week 0) to week 26, week 52 is presented. Data based on in-trial observation period is presented. In-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Change in Physical Examination

Physical examination included examination of cardiovascular system, nervous system (central and peripheral), gastrointestinal system including mouth, general appearence, head and neck (head, ears, eyes, nose, throat, neck), lymph node palpation, musculoskeletal system, respiratory system, skin and thyroid gland. Physical examination was performed by the investigator and categorised as normal, abnormal NCS or abnormal CS. Data based on in-trial observation period is presented. In-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Change in Eye Examination Category

Eye examination was performed by the investigator and categorised as normal, abnormal not clinically significant (NCS) or abnormal clinically significant (CS). Data based on in-trial observation period is presented. In-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Anti-semaglutide Binding Antibodies (Yes/no)

Number of participants with the presence or absence (yes/no) of anti-semaglutide binding antibodies in blood anytime post-baseline (week 0) and up to week 57. This endpoint is applicable only to the reporting groups "Oral semaglutide 3 mg, Oral semaglutide 7 mg and Oral semaglutide 14 mg". Data based on the in-trial observation period was presented. The in-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Anti-semaglutide Neutralising Antibodies (Yes/no)

Number of participants with the presence or absence (yes/no) of anti-semaglutide neutralising antibodies in blood anytime post-baseline (week 0) and up to week 57. This endpoint is applicable only to the reporting groups "Oral semaglutide 3 mg, Oral semaglutide 7 mg and Oral semaglutide 14 mg". Data based on the in-trial observation period is presented. The in-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Number of participants with the presence or absence (yes/no) of anti-semaglutide binding antibodies cross reacting with native GLP-1 in blood anytime post-baseline (week 0) and up to week 57. This endpoint is applicable only to the reporting groups "Oral semaglutide 3 mg, Oral semaglutide 7 mg and Oral semaglutide 14 mg". Data based on the in-trial observation period was presented. The in-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Number of participants with the presence or absence (yes/no) of anti-semaglutide neutralising antibodies cross reacting with native GLP-1 in blood anytime post-baseline (week 0) and up to week 57. This endpoint is applicable only to the reporting groups "Oral semaglutide 3 mg, Oral semaglutide 7 mg and Oral semaglutide 14 mg". Data based on the in-trial observation period was presented. The in-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Anti-semaglutide Binding Antibody Levels

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (weeks 0-57). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). Results are based on the data from the in-trial observation period. The in-trial observation period - time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Data based on on-treatment observation period was presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Number of participants with treatment emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes. Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Data based on on-treatment observation period was presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Semaglutide Plasma Concentration

Semaglutide plasma concentration is presented. Samples for pharmacokinetic (PK) analysis were drawn at any time during the visit except for the visit at week 26 where samples were taken both pre-dose and 60-90 minutes post dosing. This endpoint is applicable only to the reporting groups, "Oral semaglutide 3 mg, Oral semaglutide 7 mg and Oral semaglutide 14 mg". Data based on on-treatment observation period was presented. The on-treatment observation period - time period when a participant was on treatment with trial product, including the period after initiation of rescue medication, if any and excluding any period after premature trial product discontinuation.

Change in SF-36: Sub-domains

SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured the HRQoL on 8 domains 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. 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. Change from baseline in the sub-domain scores is presented. A positive change score indicates an improvement since baseline. Data based on on-treatment without rescue medication observation period is presented.

Change in SF-36: Physical Component Summary (PCS)

Change in short form 36 v2.0 acute domain PCS from baseline (week 0) to week 56. SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. It consists of 2 component summary measures that further summarize 8 health domain scales. The PCS measure is derived from domain scales of physical functioning, role-physical, bodily pain, and general health. 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. 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 indicates an improvement since baseline. Data based on on-treatment without rescue medication observation period is presented.

Change in SF-36: Mental Component Summary (MCS)

Change in short form 36 v2.0 acute domain MCS from baseline (week 0) to week 56. SF- 36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The MCS measure is derived from domain scales of vitality, social functioning, role emotional and mental health. 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. 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 indicates an improvement since baseline. Data based on on-treatment without rescue medication observation period is presented.

Change From Baseline in DTR-QOL: Total Score

Diabetes Therapy-Related QOL (DTR-QOL) questionnaire is a 29-item patient-reported survey of patient health that measures the influence of diabetes treatment on HRQoL on 4 domains on individual scale ranges: "Burden on social activities and daily activities", "Anxiety and dissatisfaction with treatment", "Hypoglycemia" and "Satisfaction with treatment" on a 7-point graded response scale. Higher item scores indicate a higher level of HRQoL for items 1-25. For items 26-29 a higher score indicates a lower level of HRQoL. The domain score is calculated from the mean score of the attribute items, and the scoring range is converted to 0 - 100. The total score, after simple addition of the item scores, is converted to 0 - 100 (best-case response = 100; worstcase response = 0). Data based on on-treatment without rescue medication observation period is presented.

Change From Baseline in DTR-QOL: Sub-domains

DTR-QOL questionnaire is a 29-item patient-reported survey of patient health that measures the the influence of diabetes treatment on HRQoL. DTR-QOL questionnaire measured the HRQoL on 4 domains on individual scale ranges: "Burden on social activities and daily activities", "Anxiety and dissatisfaction with treatment", "Hypoglycemia" and "Satisfaction with treatment" on a 7-point graded response scale. Higher item scores indicate a higher level of HRQoL for items 1-25. For items 26-29 a higher score indicates a lower level of HRQoL. The domain score is calculated from the mean score of the attribute items, and the scoring range is converted to 0 - 100. W26 and W52 refer to week 26 and week 52 respectively. Data based on on-treatment without rescue medication observation period was presented. The on-treatment without rescue medication observation period - time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.

Full Information

NCT ID

NCT03018028

First Posted

January 6, 2017

Last Updated

January 14, 2021

Sponsor

Novo Nordisk A/S

1. Study Identification

Unique Protocol Identification Number

NCT03018028

Brief Title

Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes

Acronym

PIONEER 9

Official Title

Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Completed

Study Start Date

January 10, 2017 (Actual)

Primary Completion Date

January 9, 2018 (Actual)

Study Completion Date

August 15, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This trial is conducted in Asia. The aim of this trial is to investigate the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese subjects with type 2 diabetes mellitus

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes, Diabetes Mellitus, Type 2

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

243 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Oral semaglutide 3 mg

Arm Type

Experimental

Arm Title

Oral semaglutide 7 mg

Arm Type

Experimental

Arm Title

Oral semaglutide 14 mg

Arm Type

Experimental

Arm Title

Oral placebo

Arm Type

Placebo Comparator

Arm Title

Liraglutide 0.9 mg

Arm Type

Active Comparator

Intervention Type

Drug

Intervention Name(s)

Semaglutide

Intervention Description

Oral administration once daily

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Oral administration once daily

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Intervention Description

Subcutaneous (s.c., under the skin) injection once daily

Primary Outcome Measure Information:

Title

Change in HbA1c (Week 26)

Description

Time Frame

Week 0, week 26

Secondary Outcome Measure Information:

Title

Change in HbA1c (Week 52)

Description

Time Frame

Week 0, week 52

Title

Change in Body Weight (kg)

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Fasting Plasma Glucose

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Self-measured Plasma Glucose 7-point Profile (SMPG) - Mean 7-point Profile

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Mean Postprandial Increment Over All Meals in SMPG

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Body Weight (%)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Body Mass Index

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Waist Circumference

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Total Cholesterol (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in HDL Cholesterol (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in LDL Cholesterol (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in VLDL Cholesterol (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Triglycerides (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Fasting Insulin (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Fasting C-peptide (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Fasting Glucagon (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Fasting Pro-insulin (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Fasting Pro-insulin/Insulin Ratio (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Insulin Resistance (HOMA-IR) (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Change in Beta-cell Function (HOMA-B) (Ratio to Baseline)

Description

Time Frame

Week 0, week 26 and week 52

Title

Participants Who Achieved HbA1c < 7.0% (53 mmol/Mol) ADA Target (Yes/no)

Description

Time Frame

Week 26 and week 52

Title

Participants Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol), AACE Target (Yes/No)

Description

Time Frame

Week 26 and week 52

Title

Participants Who Achieved HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain (Yes/No)

Description

Time Frame

Week 26 and week 52

Title

Participants Who Achieved HbA1c Reduction Above or Equal to 1% (10.9 mmol/Mol) and Weight Loss Above or Equal to 3%

Description

Time Frame

Week 26 and week 52

Title

Participants Who Achieved Weight Loss Above or Equal to 5% (Yes/No)

Description

Time Frame

Week 26 and week 52

Title

Participants Who Achieved Weight Loss Above or Equal to 10% (Yes/No)

Description

Time Frame

Week 26 and week 52

Title

Time to Additional Anti-diabetic Medication

Description

Time Frame

Weeks 0 - 52

Title

Time to Rescue Medication

Description

Time Frame

Weeks 0 - 52

Title

Number of Treatment-emergent Adverse Events (TEAEs)

Description

Time Frame

Weeks 0 - 57

Title

Change in Amylase (Ratio to Baseine)

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Lipase (Ratio to Baseine)

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Pulse Rate

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Blood Pressure

Description

Time Frame

Week 0, week 26, week 52

Title

Change in ECG Evaluation

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Physical Examination

Description

Time Frame

Baseline (Week -8), week 26, week 52

Title

Change in Eye Examination Category

Description

Time Frame

Week -8, Week 52

Title

Anti-semaglutide Binding Antibodies (Yes/no)

Description

Time Frame

Week 0 - 57

Title

Anti-semaglutide Neutralising Antibodies (Yes/no)

Description

Time Frame

Week 0 - 57

Title

Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Description

Time Frame

Week 0 - 57

Title

Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Description

Time Frame

Week 0 - 57

Title

Anti-semaglutide Binding Antibody Levels

Description

Time Frame

Weeks 0-57

Title

Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Description

Time Frame

Week 0 - 57

Title

Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Description

Time Frame

Weeks 0 - 57

Title

Semaglutide Plasma Concentration

Description

Time Frame

Week 26 and week 52

Title

Change in SF-36: Sub-domains

Description

Time Frame

Week 0, week 26, week 52

Title

Change in SF-36: Physical Component Summary (PCS)

Description

Time Frame

Week 0, week 26, week 52

Title

Change in SF-36: Mental Component Summary (MCS)

Description

Time Frame

Week 0, week 26, week 52

Title

Change From Baseline in DTR-QOL: Total Score

Description

Time Frame

Week 0, week 26, week 52

Title

Change From Baseline in DTR-QOL: Sub-domains

Description

Time Frame

Week 0, week 26, week 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial Japanese male or female, age above or equal to 20 years at the time of signing informed consent Diagnosed with type 2 diabetes mellitus for at least 30 days prior to day of screening HbA1c 6.5%-9.5% (48-80 mmol/mol) (both inclusive) for subjects treated with oral antidiabetic drug as monotherapy and 7.0%-10.0% (53-86 mmol/mol) (both inclusive) for subjects treated with diet and exercise therapy alone Treatment for at least 30 days prior to day of screening with;- stable daily dose of oral anti-diabetic drug as monotherapy (allowed oral anti-diabetic drugs are: metformin, sulphonylurea, glinide, α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter-2 inhibitor) at a half-maximum approved dose or below according to Japanese labelling in addition to diet and exercise therapy. or - diet and exercise therapy alone Exclusion Criteria: Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method. Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC) History of pancreatitis (acute or chronic) History of major surgical procedures involving the stomach and potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation Subject presently classified as being in New York Heart Association (NYHA) Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Subjects with alanine aminotransferase (ALT) above 2.5 x upper normal limit (UNL) Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) Treatment with once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor or thiazolidinedione in a period of 90 days before the day of screening Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 60 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in-situ carcinomas) Initiation of anti-diabetic medication between the day of screening and the day of randomisation

Facility Information:

Facility Name

Novo Nordisk Investigational Site

City

Akita-shi, Akita

ZIP/Postal Code

010-8543

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Arakawa-ku, Tokyo

ZIP/Postal Code

116-0012

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Ebina-shi, Kanagawa

ZIP/Postal Code

243-0432

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Gunma

ZIP/Postal Code

373-0036

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Kanagawa

ZIP/Postal Code

232-0064

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Minato-ku, Tokyo

ZIP/Postal Code

108-0075

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Naka-shi

ZIP/Postal Code

311 0113

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Osaka-shi, Osaka

ZIP/Postal Code

553-0003

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Ota-ku, Tokyo

ZIP/Postal Code

144-0051

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Saga-shi, Saga

ZIP/Postal Code

849-0937

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Sendai-shi, Miyagi

ZIP/Postal Code

980-8574

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Suita-shi, Osaka

ZIP/Postal Code

565-0853

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Tokyo

ZIP/Postal Code

103-0027

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Tokyo

ZIP/Postal Code

103-0028

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Tokyo

ZIP/Postal Code

104-0031

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Tokyo

ZIP/Postal Code

160-0008

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Citations:

PubMed Identifier

32998732

Citation

Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020 Sep 30;19(1):156. doi: 10.1186/s12933-020-01106-4.

Results Reference

derived

PubMed Identifier

32333875

Citation

Yamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, Seino Y; PIONEER 9 investigators. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020 May;8(5):377-391. doi: 10.1016/S2213-8587(20)30075-9.

Results Reference

derived

PubMed Identifier

32267058

Citation

Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes Metab. 2020 Aug;22(8):1263-1277. doi: 10.1111/dom.14054. Epub 2020 May 13.

Results Reference

derived

PubMed Identifier

31903692

Citation

Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, Vilsboll T. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020 Mar;22(3):442-451. doi: 10.1111/dom.13955. Epub 2020 Feb 5.

Results Reference

derived

Learn more about this trial

Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes

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Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes (PIONEER 9)

Diabetes, Diabetes Mellitus, Type 2

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial