NCT02827708: PIONEER 5

Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes and Moderate Renal Impairment

Completed Phase 3 Results posted Last updated 17 February 2020

What this trial tests

Phase 3 trial testing semaglutide in Diabetes in 324 participants. Completed in 15 May 2018.

Timeline

20 September 2016

Primary endpoint
10 April 2018

15 May 2018

Quick facts

Lead sponsor	Novo Nordisk A/S
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	324
Start date	20 September 2016
Primary completion	10 April 2018
Estimated completion	15 May 2018
Sites	117 locations across Denmark, Finland, Russia, Sweden, United Kingdom, Israel, Poland, United States

Drugs / interventions tested

• semaglutide (semaglutide) — full drug profile →
• placebo

Conditions studied

• Diabetes — all drugs for Diabetes →
• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

Novo Nordisk A/S — full company profile →

Who can join

18 and older, any sex, with Diabetes or Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in HbA1c Primary · Week 0, week 26

Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated 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 and/or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any per

In-trial

Group	Value	95% CI
Oral Semaglutide 14 mg	-1.1	± 1.0
Placebo	-0.2	± 0.9

On-treatment without rescue medication

Group	Value	95% CI
Oral Semaglutide 14 mg	-1.2	± 0.9
Placebo	-0.1	± 0.9

Change in Body Weight (kg) Secondary · Week 0, week 26

Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated 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 and/or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation

In-trial

Group	Value	95% CI
Oral Semaglutide 14 mg	-3.5	± 3.8
Placebo	-0.9	± 2.9

On-treatment without rescue medication

Group	Value	95% CI
Oral Semaglutide 14 mg	-3.9	± 3.6
Placebo	-0.9	± 2.9

Change in FPG Secondary · Week 0, week 26

Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Group	Value	95% CI
Oral Semaglutide 14 mg	-1.58	± 2.96
Placebo	-0.34	± 3.03

Change in Body Weight (%) Secondary · Week 0, week 26

Relative change from baseline (week 0) in body weight (kg) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Group	Value	95% CI
Oral Semaglutide 14 mg	-3.75	± 4.10
Placebo	-0.92	± 3.13

Change in BMI Secondary · Week 0, week 26

Change from baseline (week 0) in body mass index (BMI) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Group	Value	95% CI
Oral Semaglutide 14 mg	-1.2	± 1.3
Placebo	-0.3	± 1.0

Change in Waist Circumference Secondary · Week 0, week 26

Change from baseline (week 0) in waist circumference was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Group	Value	95% CI
Oral Semaglutide 14 mg	-2.8	± 4.9
Placebo	-0.7	± 3.8

Participants Who Achieve HbA1c <7.0% (53 mmol/Mol), ADA Target (Yes/no) Secondary · Week 26

Participants who achieved HbA1c \<7.0% (American Diabetes Association (ADA) target) (yes/no), was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	89
Placebo	35

No

Group	Value	95% CI
Oral Semaglutide 14 mg	65
Placebo	120

Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol), AACE Target (Yes/no) Secondary · Week 26

Participants who achieved HbA1c ≤6.5% (American Association of Clinical Endocrinologists (AACE) target) (yes/no), was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	60
Placebo	12

No

Group	Value	95% CI
Oral Semaglutide 14 mg	94
Placebo	143

Participants Who Achieve Weight Loss ≥5% (Yes/no) Secondary · Week 26

Participants who achieved weight loss ≥5% of their baseline body weight (yes/no) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	55
Placebo	15

No

Group	Value	95% CI
Oral Semaglutide 14 mg	99
Placebo	140

Participants Who Achieve Weight Loss ≥10% (Yes/no) Secondary · Week 26

Participants who achieved weight loss of ≥10% of their baseline body weight (yes/no) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	13
Placebo	0

No

Group	Value	95% CI
Oral Semaglutide 14 mg	141
Placebo	155

Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no) Secondary · Week 26

Participants who achieved HbA1c \<7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) was evaluated at week 26. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value \<3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a part

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	78
Placebo	27

No

Group	Value	95% CI
Oral Semaglutide 14 mg	76
Placebo	128

Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no) Secondary · Week 26

Participants who achieved HbA1c reduction ≥1% and weight loss of ≥3% (yes/no) was evaluated at week 26. 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 and/or premature discontinuation of trial product.

Yes

Group	Value	95% CI
Oral Semaglutide 14 mg	60
Placebo	12

No

Group	Value	95% CI
Oral Semaglutide 14 mg	94
Placebo	143

Adverse events — posted to ClinicalTrials.gov

Time frame: Week 0 to week 31 (26 weeks treatment period + 5 weeks follow-up period). Results are based on the safety analysis set (SAS), which comprised all randomised participants who received at least one dose of trial product.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Oral Semaglutide 14 mg

Serious: 17/163 (10%)

Deaths: 1/163

Placebo

Serious: 17/161 (11%)

Deaths: 2/161

Serious adverse events (48 terms)

Reaction	System	Oral Semaglutide 14 mg	Placebo
Acute myocardial infarction	Cardiac disorders	—	—
Angina unstable	Cardiac disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Animal bite	Injury, poisoning and procedural complications	—	—
Arteriosclerotic gangrene	Infections and infestations	—	—
Atrial fibrillation	Cardiac disorders	—	—
Biliary sepsis	Infections and infestations	—	—
Bladder transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Confusional state	Psychiatric disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Device related infection	Infections and infestations	—	—
Dysarthria	Nervous system disorders	—	—
Escherichia urinary tract infection	Infections and infestations	—	—
Eyelid ptosis	Eye disorders	—	—
Flank pain	Musculoskeletal and connective tissue disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Gastroenteritis bacterial	Infections and infestations	—	—
Gout	Metabolism and nutrition disorders	—	—
Haemorrhagic stroke	Nervous system disorders	—	—
Hypertensive crisis	Vascular disorders	—	—
Infected bite	Infections and infestations	—	—
Injection site abscess	Infections and infestations	—	—
Invasive ductal breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Ischaemic stroke	Nervous system disorders	—	—
Limb crushing injury	Injury, poisoning and procedural complications	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	Oral Semaglutide 14 mg	Placebo
Nausea	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Acute myocardial infarction, Angina unstable, Acute kidney injury, Animal bite, Arteriosclerotic gangrene, Atrial fibrillation, Biliary sepsis, Bladder transitional cell carcinoma.

Data from ClinicalTrials.gov NCT02827708 adverse events section.

Sponsor's own description

This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes and moderate renal impairment.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.
   Li Y, Liu Y, Liu S, Gao M, et al · · 2023 · cited 392× · PMID 37037849 · DOI 10.1038/s41392-023-01400-z
2. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
   Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, et al · · 2019 · cited 250× · PMID 31189517 · DOI 10.1016/s2213-8587(19)30192-5
3. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.
   Husain M, Bain SC, Jeppesen OK, Lingvay I, et al · · 2020 · cited 144× · PMID 31903692 · DOI 10.1111/dom.13955
4. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes.
   Mahapatra MK, Karuppasamy M, Sahoo BM. · · 2022 · cited 92× · PMID 34993760 · DOI 10.1007/s11154-021-09699-1
5. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.
   Thethi TK, Pratley R, Meier JJ. · · 2020 · cited 90× · PMID 32267058 · DOI 10.1111/dom.14054
6. Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review.
   Mahapatra MK, Karuppasamy M, Sahoo BM. · · 2022 · cited 84× · PMID 35650449 · DOI 10.1007/s11095-022-03302-1
7. Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment.
   Granhall C, Søndergaard FL, Thomsen M, Anderson TW. · · 2018 · cited 80× · PMID 29623579 · DOI 10.1007/s40262-018-0649-2
8. Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.
   Overgaard RV, Hertz CL, Ingwersen SH, Navarria A, et al · · 2021 · cited 65× · PMID 34622228 · DOI 10.1016/j.xcrm.2021.100387