A Research Study to Compare a New Weekly Insulin, Insulin Icodec, and an Available Daily Insulin, Insulin Degludec, Both in Combination With Mealtime Insulin in People With Type 1 Diabetes (ONWARDS 6) (ONWARDS 6)

• ClinicalTrials.gov Identifier: NCT04848480
• Recruitment Status: Completed
• First Posted: April 19, 2021
• Last Update Posted: September 14, 2023
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: April 16, 2021
• First Posted Date: April 19, 2021
• Last Update Posted Date: September 14, 2023
• Actual Study Start Date: April 30, 2021
• Actual Primary Completion Date: April 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 12, 2023)

Change in Glycosylated Haemoglobin (HbA1c) at Week 26 [ Time Frame: Baseline (week 0), week 26 ]

Change in HbA1c from baseline to week 26 is presented. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.

Original Primary Outcome Measures (submitted: April 16, 2021)

Change in HbA1c (glycated haemoglobin) [ Time Frame: From baseline (week 0) to week 26 ]

%-point

Current Secondary Outcome Measures (submitted: September 12, 2023)

• Change in Glycosylated Haemoglobin (HbA1c) at Week 52 [ Time Frame: Baseline (week 0), week 52 ]
  Change in HbA1c from baseline to week 52 is presented. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Change in Fasting Plasma Glucose (FPG) [ Time Frame: Baseline (week 0), week 26 ]
  Change in FPG from baseline to week 26 is presented. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Percentage of Time in Range 3.9-10.0 mmol/L (70-180 Milligrams Per Deciliter [mg/dL]) Using Continuous Glucose Monitoring (CGM) System [ Time Frame: From week 22 to week 26 ]
  Percentage of time in range 3.9-10.0 mmol/L (70-180 mg/dL) using CGM system from week 22 to week 26 is presented. Time in range is defined as 100 times the number of recorded measurements in glycaemic range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Total Treatment Satisfaction [ Time Frame: Baseline (week 0), week 26 ]
  Change in DTSQs in total treatment satisfaction from baseline to week 26 is presented. The sum score for DTSQ in total treatment satisfaction was calculated by adding the six item scores of items 1, 4, 5, 6, 7 and 8. The sum score for DTSQ can range from 0 to 36, with 0 being the lowest and 36 being the highest score in total treatment satisfaction. Higher scores on the DTSQ total score indicate higher treatment satisfaction. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [ Time Frame: From baseline (week 0) to week 26 ]
  Number of severe hypoglycaemic episodes (level 3) from baseline to week 26 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the electronic case report form (eCRF), and ended at the first date of any of the following: the end date of the on-treatment period; week 26. On-treatment: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit, the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [ Time Frame: From baseline (week 0) to week 57 ]
  Number of severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose [BG] Meter): From Baseline (Week 0) to Week 26 [ Time Frame: From baseline (week 0) to week 26 ]
  Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 26 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by BG Meter): From Baseline (Week 0) to Week 57 [ Time Frame: From baseline (week 0) to week 57 ]
  Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 57 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [ Time Frame: From baseline (week 0) to week 26 ]
  Number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 26 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [ Time Frame: From baseline (week 0) to week 57 ]
  Number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [ Time Frame: From baseline (week 0) to week 26 ]
  Number of nocturnal clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 26 are presented. Nocturnal: The period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. On-treatment period: Onset date on or after first dose of trial product and no later than first date of either follow-up visit, last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for in-trial period.
• Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [ Time Frame: From baseline (week 0) to week 57 ]
  Number of nocturnal clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Nocturnal: The period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Percentage of Time spent Less Than (<) 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System [ Time Frame: From week 22 to week 26 ]
  Percentage of time spent < 3.0 mmol/L using CGM system from week 22 to week 26 is presented. Time spent below threshold (< 3.0 mmol/L [54 mg/dL]) was defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Percentage of Time spent Greater Than (>) 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System [ Time Frame: From week 22 to week 26 ]
  Percentage of time spent > 10 mmol/L using CGM system from week 22 to week 26 is presented. Time spent above threshold (> 10 mmol/L [180 mg/dL]) was defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.
• Mean Total Weekly Insulin Dose: From Week 24 to Week 26 [ Time Frame: From week 24 to week 26 ]
  Mean total weekly insulin dose from week 24 to week 26 is presented. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Mean Total Weekly Insulin Dose: From Week 50 to Week 52 [ Time Frame: From week 50 to week 52 ]
  Mean total weekly insulin dose from week 50 to week 52 is presented. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
• Change in Body Weight [ Time Frame: Baseline (week 0), week 26 ]
  Change in body weight from baseline to week 26 is presented. Data is reported for 'in-trial' period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for participants who withdrew their informed consent; the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above.

Original Secondary Outcome Measures (submitted: April 16, 2021)

• Change in fasting plasma glucose (FPG) [ Time Frame: From baseline (week 0) to week 26 ]
  mmol/L
• Time in range 3.9-10.0 mmol/L (70-180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6 [ Time Frame: From week 22 to week 26 ]
  % of readings
• Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment satisfaction [ Time Frame: From baseline (week 0) to week 26 ]
  Score 0-36 6 items scored on a scale of 0 to 6. The higher the score the greater the satisfaction with treatment
• Change in HbA1c [ Time Frame: From baseline (week 0) to week 52 ]
  %-point
• Number of severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 26 ]
  Number of episodes
• Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) [ Time Frame: From baseline (week 0) to week 26 ]
  Number of episodes
• Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 26 ]
  Number of episodes
• Number of severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 57 ]
  Number of episodes
• Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) [ Time Frame: From baseline (week 0) to week 57 ]
  Number of episodes
• Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 57 ]
  Number of episodes
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 26 ]
  Number of episodes
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) [ Time Frame: From baseline (week 0) to week 57 ]
  Number of episodes
• Time spent below 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6 [ Time Frame: From week 22 to week 26 ]
  % of readings
• Time spent greater than 10 mmol/L (180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6 [ Time Frame: From week 22 to week 26 ]
  % of readings
• Mean total weekly insulin dose [ Time Frame: From week 24 to week 26 ]
  U
• Mean total weekly insulin dose [ Time Frame: From week 50 to week 52 ]
  U
• Change in body weight [ Time Frame: From baseline (week 0) to week 26 ]
  kg

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Research Study to Compare a New Weekly Insulin, Insulin Icodec, and an Available Daily Insulin, Insulin Degludec, Both in Combination With Mealtime Insulin in People With Type 1 Diabetes (ONWARDS 6)
• Official Title: Efficacy and Safety of Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec 100 Units/mL, Both in Combination With Insulin Aspart, in Adults With Type 1 Diabetes. A 26-week, Randomised, Multicentre, Open-label, Active-controlled, Parallel Group, Two Armed, Treat-to-target Trial Investigating the Effect on Glycaemic Control and Safety of Treatment With Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec, Both in Combination With Insulin Aspart in Adults With Type 1 Diabetes, With a 26-week Extension Investigating Long Term Safety

Brief Summary

This study compares insulin icodec (a new insulin) to insulin degludec (an insulin already available on the market) in people with type 1 diabetes.

The study will look at how well insulin icodec taken weekly controls blood sugar compared to insulin degludec taken daily.

Participants will either get insulin icodec that participants will have to inject once a week on the same day of the week, or insulin degludec that participants will have to inject once a day at the same time every day. Which treatment participants get is decided at random. Participants will also get a mealtime insulin.

The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach.

The study will last for about 1 year and 2 months. Participants will have 28 clinic visits and 28 phone calls with the study doctor. At 11 clinic visits participants will have blood samples taken.

At 6 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit.

Participants will be asked to wear a sensor that measures your blood sugar all the time. Participants will be asked to wear it for a total of 57 weeks (around 1 year).

Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diabetes Mellitus, Type 1

Intervention

• Drug: insulin icodec
  insulin icodec 700 units/mL, subcutaneously (under the skin), solution for injection once weekly
• Drug: insulin degludec
  insulin degludec 100 units/mL, subcutaneously (under the skin), solution for injection once daily
• Drug: insulin aspart
  insulin aspart 100 units/mL, subcutaneously (under the skin), solution for injection daily

Study Arms

• Experimental: Insulin icodec + insulin aspart
  insulin icodec once a week in combination with 2-4 times daily injections of insulin aspart at meal times.
  Interventions:

  • Drug: insulin icodec
  • Drug: insulin aspart
• Active Comparator: Insulin degludec + insulin aspart
  insulin degludec once a day in combination with 2-4 times daily injections of insulin aspart at meal times.
  Interventions:

  • Drug: insulin degludec
  • Drug: insulin aspart

• Publications *: Philis-Tsimikas A, Bajaj HS, Begtrup K, Cailleteau R, Gowda A, Lingvay I, Mathieu C, Russell-Jones D, Rosenstock J. Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes. Diabetes Obes Metab. 2023 Feb;25(2):331-341. doi: 10.1111/dom.14871. Epub 2022 Oct 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 12, 2023): 582
• Original Estimated Enrollment (submitted: April 16, 2021): 580
• Actual Study Completion Date: December 2, 2022
• Actual Primary Completion Date: April 28, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female aged greater than or equal to 18 years at the time of signing informed consent.
• Diagnosed with type 1 diabetes mellitus greater than or equal to 1 year prior to the day of screening.
• Treated with multiple daily insulin injections (basal and bolus insulin analogue regimes) greater than or equal to 1 year prior to the day of screening.
• HbA1c below10% at screening visit based on analysis from central laboratory.

Exclusion Criteria:

• Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening.
• Chronic heart failure classified as New York Heart Association (NYHA) Class IV at screening.
• Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or corticosteroids).
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Canada, Germany, India, Italy, Japan, Netherlands, Russian Federation, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04848480
• Other Study ID Numbers: NN1436-4625; U1111-1251-7315 ( Other Identifier: World Health Organization (WHO) ); 2020-002374-27 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

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

• Current Responsible Party: Novo Nordisk A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Novo Nordisk A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Transparency (1452); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: September 2023