Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin (PIONEER 8)

• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

This trial is conducted globally. The aim of the trial is to investigate the efficacy and safety of oral semaglutide versus placebo in subjects with Type 2 Diabetes Mellitus treated with insulin. All subjects should continue their pre-trial insulin therapy (basal, basal-bolus or premixed regimen including combinations of soluble insulins) throughout the trial. Subjects treated with metformin in addition to insulin treatment must continue their metformin treatment throughout the entire trial.

Condition or disease	Intervention/treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: semaglutide; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 731 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin. A 52-week, Randomised, Double-blind, Placebo-controlled Trial (PIONEER 8 - Insulin add-on)
• Actual Study Start Date: February 2, 2017
• Actual Primary Completion Date: January 18, 2018
• Actual Study Completion Date: August 22, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Semaglutide 3 mg	Drug: semaglutide; Oral semaglutide administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Experimental: Semaglutide 3 mg + 7 mg	Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Experimental: Semaglutide 3 mg + 7 mg + 14 mg	Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg and finally 14 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Placebo Comparator: Placebo	Drug: placebo; Oral semaglutide placebo administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c [ Time Frame: Week 0, week 26 ]
   Measured in %

Secondary Outcome Measures :

1. Change in body weight [ Time Frame: Week 0, week 26 ]
   Measured in kg
2. Change in HbA1c [ Time Frame: Week 0, week 52 ]
   Measured in %
3. Change in body weight [ Time Frame: Week 0, week 52 ]
   Measured in kg
4. Change in fasting plasma glucose (FPG) [ Time Frame: Week 0, week 26 ]
   Measured in mg/dl or other equivalent SI units
5. Change in fasting plasma glucose (FPG) [ Time Frame: Week 0, week 52 ]
   Measured in mg/dl or other equivalent SI units
6. Number of treatment-emergent adverse events (TEAEs) during exposure to trial product [ Time Frame: Assessed up to approximately 57 weeks ]
   Count and % of adverse events
7. Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trial product [ Time Frame: Assessed up to approximately 57 weeks ]
   Count of episodes
8. Change in 7-point self-measured plasma glucose (SMPG) profile - Mean 7-point profile [ Time Frame: Week 0, week 26 ]
   Mean daytime glucose value
9. Change in 7-point self-measured plasma glucose (SMPG) profile - Mean 7-point profile [ Time Frame: Week 0, week 52 ]
   Mean daytime glucose value
10. Change in 7-point self-measured plasma glucose (SMPG) profile - Mean postprandial increment (over all meals) [ Time Frame: Week 0, week 26 ]
    Mean glucose value over all meals
11. Change in 7-point self-measured plasma glucose (SMPG) profile - Mean postprandial increment (over all meals) [ Time Frame: Week 0, week 52 ]
    Mean glucose value over all meals
12. Change in body weight (%) [ Time Frame: Week 0, week 26 ]
    Measured in %
13. Change in body weight (%) [ Time Frame: Week 0, week 52 ]
    Measured in %
14. Change in body mass index (BMI) [ Time Frame: Week 0, week 26 ]
    Measured in kg/m^2
15. Change in body mass index (BMI) [ Time Frame: Week 0, week 52 ]
    Measured in kg/m^2
16. Change in waist circumference [ Time Frame: Week 0, week 26 ]
    Measured in cm
17. Change in waist circumference [ Time Frame: Week 0, week 52 ]
    Measured in cm
18. Change in fasting lipid profile - total cholesterol [ Time Frame: Week 0, week 26 ]
    Measured in mg/dl or other equivalent SI units
19. Change in fasting lipid profile - total cholesterol [ Time Frame: Week 0, week 52 ]
    Measured in mg/dl or other equivalent SI units
20. Change in fasting lipid profile - low density lipoprotein [LDL] [ Time Frame: Week 0, week 26 ]
    Measured in mg/dl or other equivalent SI units
21. Change in fasting lipid profile - low density lipoprotein [LDL] [ Time Frame: Week 0, week 52 ]
    Measured in mg/dl or other equivalent SI units
22. Change in fasting lipid profile - high density lipoprotein [HDL] [ Time Frame: Week 0, week 26 ]
    Measured in mg/dl or other equivalent SI units
23. Change in fasting lipid profile - high density lipoprotein [HDL] [ Time Frame: Week 0, week 52 ]
    Measured in mg/dl or other equivalent SI units
24. Change in fasting lipid profile - triglycerides [ Time Frame: Week 0, week 26 ]
    Measured in mg/dl or other equivalent SI units
25. Change in fasting lipid profile - triglycerides [ Time Frame: Week 0, week 52 ]
    Measured in mg/dl or other equivalent SI units
26. Change in patient-reported outcome (PRO) - Short Form (SF)-36v2(TM) (acute version) health survey [ Time Frame: Week 0, week 26 ]
    Short Form 36 v2.0 acute (SF-36) is a 36-item, patient-reported survey of patient health. SF-36 measures the subject's overall Health Related Quality of Life on 8 domains: physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role emotional and mental health
27. Change in patient-reported outcome (PRO) - Short Form (SF)-36v2(TM) (acute version) health survey [ Time Frame: Week 0, week 52 ]
    Short Form 36 v2.0 acute (SF-36) is a 36-item, patient-reported survey of patient health. SF-36 measures the subject's overall Health Related Quality of Life on 8 domains: physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role emotional and mental health
28. Change in patient-reported outcome (PRO) - Impact of Weight on Quality of Life (IWQOL) [ Time Frame: Week 0, week 26 ]
    The Impact of Weight on Quality of Life Lite for Clinical Trials Version (IWQoL-Lite for CT) questionnaire is a 22-item modified version of an instrument designed to assess weight-related quality of life.
29. Change in patient-reported outcome (PRO) - Impact of Weight on Quality of Life (IWQOL) [ Time Frame: Week 0, week 52 ]
    The Impact of Weight on Quality of Life Lite for Clinical Trials Version (IWQoL-Lite for CT) questionnaire is a 22-item modified version of an instrument designed to assess weight-related quality of life.
30. Change in patient-reported outcome (PRO) - Diabetes Treatment Satisfaction Questionnaire (DTSQs) [ Time Frame: Week 0, week 26 ]
    The DTSQs questionnaire will be used to assess subject's treatment satisfaction. This instrumentcontains 8 items and measures the treatment for your diabetes (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding treatment.
31. Change in patient-reported outcome (PRO) - Diabetes Treatment Satisfaction Questionnaire (DTSQs) [ Time Frame: Week 0, week 52 ]
    The DTSQs questionnaire will be used to assess subject's treatment satisfaction. This instrumentcontains 8 items and measures the treatment for your diabetes (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding treatment.
32. Achievement of HbA1c less than 7.0% (53 mmol/mol) (American Diabetes Association (ADA) target) (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
33. Achievement of HbA1c less than 7.0% (53 mmol/mol) (American Diabetes Association (ADA) target) (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
34. Achievement of HbA1c less than or equal to 6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target) (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
35. Achievement of HbA1c less than or equal to 6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target) (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
36. Achievement of HbA1c reduction greater than or equal to 1%-point (10.9 mmol/mol) (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
37. Achievement of HbA1c reduction greater than or equal to 1%-point (10.9 mmol/mol) (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
38. Achievement of weight loss greater than or equal to 3% (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
39. Achievement of weight loss greater than or equal to 3% (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
40. Achievement of weight loss greater than or equal to 5% (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
41. Achievement of weight loss greater than or equal to 5% (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
42. Achievement of weight loss greater than or equal to 10% (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects
43. Achievement of weight loss greater than or equal to 10% (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects
44. Achievement of HbA1c below 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemia) and no weight gain (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects fullfilling the criteria
45. Achievement of HbA1c below 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemia) and no weight gain (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects fullfilling the criteria
46. Achievement of HbA1c reduction greater than or equal to 1.0%-point (10.9 mmol/mol) and weight loss greater than or equal to 3% (yes/no) [ Time Frame: Week 26 ]
    Proportion of subjects fullfilling the criteria
47. Achievement of HbA1c reduction greater than or equal to 1.0%-point (10.9 mmol/mol) and weight loss greater than or equal to 3% (yes/no) [ Time Frame: Week 52 ]
    Proportion of subjects fullfilling the criteria
48. Time to rescue medication [ Time Frame: Week 0 - week 57 ]
    Measured in days/weeks/months/years
49. Change in total daily insulin dose (IU) [ Time Frame: Week 0, week 26 ]
    Measured in IU
50. Change in total daily insulin dose (IU) [ Time Frame: Week 0, week 52 ]
    Measured in IU
51. Number of treatment-emergent adverse events (TEAEs) during exposure to trial product [ Time Frame: Assessed up to approximately 26 weeks ]
    Count and % of adverse events
52. Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trial product [ Time Frame: Assessed up to approximately 26 weeks ]
    Count of episodes

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. - Male or female, age above or equal to 18 years at the time of signing informed consent. For Japan only: Male or female, age above or equal to 20 years at the time of signing informed consent. - Diagnosed with type 2 diabetes mellitus 90 days or more prior to the day of screening. - HbA1c (glycosylated haemoglobin) of 7.0-9.5% (53-80 mmol/mol) (both inclusive). - Stable treatment with one of the following insulin regimens (minimum 10 IU/day) 90 or more days prior to the day of screening. Maximum 20% change in total daily dose is acceptable: (1) Basal insulin alone or (2) Basal and bolus insulin in any combination or (3) Premixed insulin including combinations of soluble insulins 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 measure as required by local regulation or practice). For Greece only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence. For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives. For Canada only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence - 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 (MI), stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation. - Classified as being in New York Heart Association (NYHA) Class IV. - Planned coronary, carotid or peripheral artery revascularisation known on the day of screening. - Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) less than 60 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI). - Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening. An exception is short-term change of insulin treatment for acute illness for a total of 14 days or less. - Known hypoglycaemic unawareness according to Clarke's questionnaire. - 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 carcinoma in situ). - Subjects with alanine aminotransferase (ALT) more than 2.5 x upper normal limit (UNL).

Contacts and Locations

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Sponsors and Collaborators

Novo Nordisk A/S

More Information

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT03021187 History of Changes
• Other Study ID Numbers: NN9924-4280; 2016-000988-16 ( EudraCT Number ); U1111-1180-3637 ( Other Identifier: World Health Organization (WHO) ); JapicCTI-173508 ( Other Identifier: JAPIC )
• First Posted: January 13, 2017
• Last Update Posted: December 20, 2018
• Last Verified: December 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin; Insulin, Globin Zinc; Hypoglycemic Agents; Physiological Effects of Drugs