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Effect of semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and chronic kidney disease (FLOW)

Effect of semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and chronic kidney disease (FLOW)

3533

The mean age at baseline was 66.6 years (and 63.6% of subjects were >=65 years and 18.6% of subjects were >=75 years). Overall, 69.7% of subjects were male. The distribution of subjects with mild, moderate and severe kidney impairment at baseline was comparable across treatment groups. In total, 0.9% had normal kidney function, 19.5% had mild kidney impairment, 68.3% had moderate kidney impairment and 11.3% had severe kidney impairment. The distribution of subjects with normo-albuminuria (UACR < 30 mg/g), micro-albuminuria (30mg/g<=UACR < 300 mg/g) and macro-albuminuria (UACR>=300 mg/g) at baseline was comparable across treatment groups. In total, 3.1% had normo-albuminuria, 28.4% had micro albuminuria and 68.5% had macro-albuminuria. In total, 3.6% had a history at baseline of acute kidney failure and 0.6% had been treated with dialysis. Almost all had a history of chronic kidney disease. At screening, subjects were required to be treated with a stable maximum labelled or tolerated dose of a RAAS blocking agent (an ACE inhibitor or an ARB) as standard-of-care treatment for CKD in T2D, unless such treatment was contraindicated or not tolerated. Approximately 95% of the subjects in each treatment group were treated with a RAAS blocking agent at screening. The remaining approximately 5% were not treated with a RAAS blocking agent at screening, with the primary reason being hyperkalemia followed by unacceptable kidney function deterioration and hypotension.

A total of 5581 subjects were screened for this trial, of which 2042 (36.6% of all screened) were screening failures (including those subjects who did not return for randomisation or who withdrew consent prior to randomisation). A total of 3539 eligible subjects were randomised (1:1) to treatment with semaglutide 1 mg (1770 subjects) or placebo (1769 subjects). Five (5) randomisations were removed due to subjects being randomised more than once in the trial, and one (1) subject was not included in FAS due to GCP issues at site. Thus, the FAS comprised 3533 subjects (1767 subjects in the semaglutide 1 mg group and 1766 subjects in the placebo group). A small proportion of randomised subjects in the FAS were not exposed to trial product (<0.1% in the semaglutide 1 mg group and 0.1% in the placebo group). In total, 97.1% of subjects in the FAS completed the trial (attended the follow-up visit or died while considered active in the trial). The proportions of subjects who withdrew consent, or were lost to follow up, were comparable across treatment groups. A total of 48 subjects (1.4%) withdrew from the trial, of which 14 withdrawals were by sponsor decision, following closure of 2 sites in Russia related to sanctioned entities. A total of 53 subjects (1.5%) were lost to follow-up.

The overall safety profile of semaglutide s.c. 1 mg once weekly, added to standard of care, in subjects with T2D and CKD was similar to that observed in previous clinical trials with semaglutide. Semaglutide 1 mg was overall safe and well tolerated. The key safety results are summarised below: Deaths: - The proportion of subjects having SAEs with a fatal outcome and the corresponding event rate were lower with semaglutide 1 mg (12.79% of subjects and 5.55 events per 100 patient-years of observation [PYO] than with placebo (15.86% of subjects and 6.98 events per 100 PYO). - Most of the events with a fatal outcome were assessed as unlikely to be related to the trial product by the investigator. - The most frequent fatal events across both treatment groups by SOC were Infections and infestations (primarily PTs of COVID-19 pneumonia and COVID-19), Cardiac disorders (primarily PTs of cardiac failure acute, acute myocardial infarction and cardiac arrest) and General disorders and administration site conditions (primarily PTs of death, sudden death and multiple organ dysfunction syndrome). Serious adverse events: - The proportion of subjects reporting SAEs and the corresponding event rate were lower with semaglutide 1 mg (49.63% of subjects and 43.92 events per 100 PYO) than with placebo (53.79% of subjects and 49.00 events per 100 PYO). - Most of the reported SAEs were of severe or moderate severity, most were assessed as unlikely to be related to the trial product by the investigator and most had an outcome of recovered at the end of the trial. - The most frequent SAEs across both treatment groups by SOC were Infections and infestations (primarily PTs of COVID-19 pneumonia, pneumonia and COVID-19), Cardiac disorders (primarily PTs of acute myocardial infarction, cardiac failure and cardiac failure congestive) and Renal and urinary disorders (primarily PTs of acute kidney injury and chronic kidney disease). Safety focus areas: - The proportion of subjects reporting cardiovascular disorder SAEs and the corresponding event rate were lower with semaglutide 1 mg than with placebo. - The proportion of subjects reporting COVID-19 AEs and the corresponding event rate were lower with semaglutide 1 mg than with placebo. - Within the remaining evaluated safety focus areas, no relevant differences between the treatment groups were observed. Clinical laboratory evaluation: - Overall, no noteworthy changes from a safety perspective in clinical laboratory parameters were observed. Safety in special groups and situations: - The safety profile of semaglutide 1 mg was not markedly affected by baseline intrinsic factors (sex, age, body mass index [BMI], race, ethnicity, HbA1c level, duration of diabetes, kidney function, albuminuria status, prior myocardial infarction or stroke, chronic heart failure status, and use of metformin, insulin and SGLT-2 inhibitors) or extrinsic factors (region).

The superiority of semaglutide 1 mg to placebo was confirmed for the primary endpoint of time to first occurrence of the composite kidney event (comprising onset of persistent >=50% reduction in eGFR, onset of persistent eGFR<15 mL/min/1.73 m2, initiation of chronic kidney replacement therapy, kidney death and CV death [including undetermined cause of death]): -The primary analysis of time to first composite kidney event resulted in an estimated HR of 0.76 [0.66; 0.88] 95%CI, (p=0.0001) for semaglutide 1 mg versus placebo.

The superiority of semaglutide 1 mg to placebo was confirmed for the confirmatory secondary endpoint of annual rate of change in eGFR (total eGFR slope): - There was a decline from baseline in eGFR in both treatment groups, which included a greater decline in the semaglutide 1 mg group at Week 4 and 12, returning near to the baseline value at Week 26 and a slower rate of decline throughout the in-trial period. The estimated mean difference in slopes was in favour of semaglutide 1 mg with an ETD of 1.16 [0.86; 1.47]95%CI, (p < 0.0001); for semaglutide 1 mg versus placebo. The superiority of semaglutide 1 mg to placebo was confirmed for the confirmatory secondary endpoint of time to first occurrence of MACE (comprising CV death, non-fatal myocardial infarction, non-fatal stroke): - The confirmatory analysis of time to first EAC-confirmed MACE resulted in an estimated HR of 0.82 [0.68; 0.98]95%CI, (p = 0.0145); for semaglutide 1 mg versus placebo, corresponding to an 18% lower risk of a first MACE with semaglutide 1 mg. The superiority of semaglutide 1 mg to placebo was confirmed for the confirmatory secondary endpoint of time to occurrence of all-cause death: - The confirmatory analysis of time from randomisation to all-cause death resulted in an estimated HR of 0.80 [0.67; 0.95]95%CI, (p = 0.0052); for semaglutide 1 mg versus placebo, corresponding to a 20% lower risk of all-cause death with semaglutide 1 mg.

This trial demonstrated the superiority of semaglutide 1 mg versus placebo with a clinically relevant reduction of 24% in the risk of a first occurrence of a composite kidney event in subjects with T2D and CKD. The results from this trial support the use of semaglutide 1 mg for reducing the risk of CKD progression in a population of patients with T2D and CKD.

May. 24, 2024

https://www.nejm.org/doi/10.1056/NEJMoa2403347

Yes

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com https://www.novonordisk-trials.com

Kinoshita Kazunori

Novo Nordisk Pharma Ltd.

2-1-1, Marunouchi, Chiyodaku, Tokyo

JPHC_clinical_trials@novonordisk.com

clinical trial information registration administrator

Novo Nordisk Pharma Ltd.

2-1-1, Marunouchi, Chiyodaku, Tokyo

+81-3-6266-1000

JPHC_clinical_trials@novonordisk.com

completed

July. 01, 2019

Interventional

randomized controlled trial, double blind, placebo control, parallel assignment

treatment purpose

3

1. 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, except for protocol described pre-screening activities which require a separate informed consent.
2. Male or female, age above or equal to 20 years at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus.
4. HbA1c <=10% (<= 86 mmol/mol).
5. Renal impairment defined either by:
a. serum creatinine-based eGFR >= 50 and <= 75mL/min/1.73 m2(CKD-EPI), and UACR > 300 and < 5000 mg/g.
or
b. serum creatinine-based eGFR >= 25 and < 50 mL/min/1.73 m2(CKD-EPI)* and UACR > 100 and < 5000 mg/g.
6. Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment is contraindicated or not tolerated. Treatment dose must be stable for at least 4 weeks prior to the date of the laboratory assessments used for determination of inclusion criterion 5 and kept stable until screening.

1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as randomisation.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method.
4. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening. Brazil: For country specific requirements.
5. Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol.
6. Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations.
7. Use of any GLP-1 receptor agonist within 30 days prior to screening.
8. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid carcinoma (MTC).
9. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 60 days prior to the day of screening.
10. Presently classified as being in New York Heart Association (NYHA) Class IV heart failure.
11. Planned coronary, carotid or peripheral artery revascularisation.
12. Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis.
13. 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.
14. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
15. A prior solid organ transplant or awaiting solid organ transplant.
16. Combination use of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB).

Both

Type 2 diabetes with chronic kidney disease

Semaglutide 1.0 mg or placebo (subcutaneous once weekly) added to standard treatment

Time to first occurrence of a composite endpoint consisting of:
- Onset of persistent >= 50% reduction in eGFR (CKD-EPI) compared with baseline
- Onset of persistent eGFR (CKD-EPI) <15 mL/min/1.73 m2
- Initiation of chronic renal replacement therapy (dialysis or kidney transplantation)
- Renal death
-CV death

April. 11, 2019