The Rationale, Design and Baseline Data of FLOW, a Kidney Outcomes Trial With Once-Weekly Semaglutide in People With Type 2 Diabetes and Chronic Kidney Disease

Peter Rossing; Florian M.M. Baeres; George Bakris; Heidrun Bosch-Traberg; Mette Gislum; Stephen C.L. Gough; Thomas Idorn; Jack Lawson; Kenneth W. Mahaffey; Johannes F.E. Mann; Henriette Mersebach; Vlado Perkovic; Katherine Tuttle; Richard Pratley

Disclosures

Nephrol Dial Transplant. 2023;38(9):2041-2051.

Abstract and Introduction

Abstract

Background: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.

Methods: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50−≤75 ml/min/1.73 m² and urine albumin:creatinine ratio (UACR) >300−<5000 mg/g or eGFR ≥25−<50 ml/min/1.73 m² and UACR >100−<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin–angiotensin–aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m² or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.

Results: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A_1cof 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m

Table 1. Inclusion and exclusion criteria for the FLOW trial.
Inclusion criteria	Exclusion criteria
• Informed consent • Male or female • Age ≥18 years (except for Japan where participants must be ≥20 years) • Diagnosis of T2D • HbA_1c ≤10% (≤86 mmol/mol) • Renal impairment, defined as either: eGFR^a ≥50 and ≤75 ml/min/1.73 m² and UACR >300 and <5000 mg/g^b,c or eGFR^a ≥25 and <50 ml/min/1.73 m² and UACR >100 and <5000 mg/g^b • Stable treatment with maximum labelled or tolerated dose of a RAAS blocking agent^d	• Known or suspected hypersensitivity to trial product(s) or related products • Pregnancy, breastfeeding or intention to become pregnant; child-bearing potential and not using a highly effective contraceptive method • Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening • Any disorder which, in the investigator's opinion, might jeopardise a subject's safety or compliance with the protocol • Congenital or hereditary kidney diseases^e or autoimmune kidney diseases^f • MI, stroke, hospitalisation for unstable angina or TIA within 60 days prior to the day of screening; NYHA class IV; or planned coronary, carotid or peripheral artery revascularisation • Use of any GLP-1RA within 30 days prior to screening • Personal or first-degree relative(s) with a history of MEN2 or MTC • Chronic or intermittent haemodialysis or peritoneal dialysis within ≤90 days • Uncontrolled and potentially unstable diabetic retinopathy or maculopathy^g • Presence or history of malignant neoplasm within 5 years prior to the day of screening^h • Prior solid organ transplant or awaiting solid organ transplant • Combination use of ACE inhibitor and ARB

^aBased on the CKD-EPI formula.
^bMeasurements taken ≤90 days before screening with subject in usual health condition.
^cNumber of participants with eGFR ≥60 ml/min/1.73 m² capped at 20% of randomised participants.
^dACE inhibitor or ARB, unless such treatment is contraindicated or not tolerated.
^eIncluding PKD.
^fIncluding glomerulonephritis or congenital urinary tract malformations.
^gVerified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation; eye examination performed by a suitably qualified healthcare provider (e.g. optometrist or ophthalmologist).
^hBasal and squamous cell skin cancer and any carcinoma in situ were allowed.
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; MEN2, multiple endocrine neoplasia type 2; MI, myocardial infarction; MTC, medullary thyroid carcinoma; NYHA, New York Heart Association; PKD, polycystic kidney disease; TIA, transient ischaemic attack.

Table 2. FLOW trial endpoints.
Study endpoints	Time frame
Primary endpoint
Time to first occurrence of a composite endpoint consisting of • Onset of kidney failure, defined as initiation of chronic kidney replacement therapy (dialysis or kidney transplantation) or persistent eGFR <15 ml/min/1.73 m² for at least 4 weeks • Death from kidney failure • CV death • Onset of persistent ≥50% reduction in eGFR (CKD-EPI) versus baseline	Randomisation to EOT
Confirmatory secondary endpoints
Annual rate of change in eGFR (CKD-EPI) (total eGFR slope)	Randomisation to EOT
Time to first occurrence of a composite CV MACE endpoint consisting of: • Non-fatal myocardial infarction • Non-fatal stroke • CV death	Randomisation to EOT
Time to occurrence of all-cause death	Randomisation to EOT
Supportive secondary endpoints
Time to occurrence of each of the individual components of the primary composite endpoint and of the confirmatory secondary MACE endpoint	Randomisation to EOT
Time to first occurrence of MALE, a composite endpoint consisting of: • Acute limb ischaemia hospitalisation • Chronic limb ischaemia hospitalisation	Randomisation to EOT
Annual rate of change in eGFR (CKD-EPI) (chronic eGFR slope)	Week 12 to EOT
Change in eGFR (CKD-EPI)	Randomisation to week 12
Change in eGFR (cystatin C CKD-EPI)	Randomisation to year 3
Relative change in UACR	Randomisation to year 3
Change in body weight	Randomisation to year 3
Change in HbA_1c	Randomisation to year 3
Change in systolic blood pressure	Randomisation to year 3
Change in diastolic blood pressure	Randomisation to year 3
Number of severe hypoglycaemic episodes	Randomisation to EOT
Exploratory endpoints
Change in EQ-5D-5L index score	Randomisation to year 3
Change in EQ-5D-5L visual analogue scale score	Randomisation to year 3

Randomisation = week 0; end of trial = a period expected to be ≥61 months for the individual participant; persistent = two consecutive central laboratory assessments that meet criteria, at least 4 weeks apart. Events including deaths, those leading to kidney replacement therapy, acute coronary syndrome, stroke or transient ischaemic attack, and MALE are reviewed by an independent external EAC in a blinded manner.
EOT, end of trial; EQ-5D-5L, EuroQol five-dimension, five-level questionnaire; MALE, major adverse limb events.

Table 3. Baseline characteristics and demographics.
Characteristics	Values
Total randomised population, N	3534
Age (years)	66.6 (9.0)
Male, n (%)	2464 (69.7)
Race, n (%)
White Black or African American Asian American Indian or Alaska Native Hawaiian or other Pacific Islander Other Not reported	2323 (65.7) 160 (4.5) 846 (23.9) 25 (0.7) 5 (0.1) 96 (2.7) 79 (2.2)
Ethnicity, n (%)
Hispanic or Latino Not Hispanic or Latino Not reported	556 (15.7) 2833 (80.2) 145 (4.1)
Region, n (%)
Europe Asia North America South America Africa Other	962 (27.2) 913 (25.8) 865 (24.5) 252 (7.1) 101 (2.9) 441 (12.5)
Systolic BP (mmHg)	138.6 (15.8)
Diastolic BP (mmHg)	76.4 (10.0)
Pulse (bpm)	73.1 (11.3)
Body mass index (kg/m²)	32.0 (6.3)
Body weight (kg)	89.6 (20.5)
HbA_1c (%)	7.8 (1.3)
HbA_1c (mmol)	61.5 (14.1)
HbA_1c >7%, n (%)	2424 (68.6)
T2D duration, years	17.4 (9.3)
eGFR (ml/min/1.73 m²)^a	47.0 (15.2)
eGFR <60 ml/min/1.73 m², n (%)	2814 (79.6)
UACR (mg/g), median (range)	568 (2–11 852)
Macroalbuminuria (UACR ≥300 mg/g), n (%)	2419 (68.4)
Diabetic neuropathy, n (%)^b	1521 (43.0)
Diabetic retinopathy in worst eye, n (%)^c	1585 (44.9)
Mild non-proliferative Moderate–severe non-proliferative Proliferative	943 (26.7) 436 (12.3) 204 (5.8)
Diabetic macular oedema in worst eye, n (%)^c	240 (6.8)
Previous cardiovascular disease^c Previous MI Previous stroke Heart failure	1838 (52.0) 513 (14.5) 367 (10.4) 675 (19.1)
Very high CKD progression risk (KDIGO criteria), n (%)^d	2413 (68.2)
Oral anti-diabetes drugs at baseline, n (%)
Metformin^e Sulphonylurea DPP-4i SGLT2i Thiazolidinedione Alpha-glucosidase inhibitors	1825 (51.6) 879 (24.9) 898 (25.4) 548 (15.5) 147 (4.2) 109 (3.1)
Insulin at baseline, n (%)	2172 (61.5)
Long acting Short acting Premixed	1616 (45.7) 1293 (36.6) 224 (6.3)
RAAS inhibitors, n (%)	3368 (95.3)
Cardiovascular medications, n (%)	3511 (99.3)
Beta blockers ACE inhibitors Angiotensin receptor blockers Calcium channel blockers Angiotensin receptor–neprilysin inhibitor	1823 (51.6) 1242 (35.1) 2127 (60.2) 1992 (56.4) 24 (0.68)
Lipid-lowering drugs, n (%)	2799 (79.2)
Statins Bile acid sequestrants Fibrates Ezetimibe PCSK-9 inhibitors Eicosapentaenoic acid ethyl ester Omega-3-acid ethyl ester Other omega 3-triglycerides	2655 (75.1) 1 (0.03) 302 (8.5) 248 (7.0) 9 (0.3) 22 (0.6) 12 (0.3) 64 (1.8)

All values are mean (SD) unless stated otherwise.
As the trial is ongoing, data may be subject to minor changes until database lock.
^aeGFR was estimated using the CKD-EPI equation.
^bBased on medical history.
^cBased on eye examination at baseline, verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation; eye examination performed by a suitably qualified healthcare provider (e.g. optometrist or ophthalmologist).
^dDefined as (i) UACR (mg/g) <30 and eGFR (mL/min/1.73 m²) ≤15 to <30, (ii) UACR (mg/g) ≤30 to <300 and eGFR (mL/min/1.73 m²) ≤30 to <45, (iii) UACR (mg/g) ≤30 to <300 and eGFR (mL/min/1.73 m²) ≤15 to <30, (iv) UACR (mg/g) ≤300 and eGFR (mL/min/1.73 m²) ≤45 to <60, (v) UACR (mg/g) ≤300 and eGFR (mL/min/1.73 m²) ≤30 to <45 or (vi) UACR (mg/g) ≤300 and eGFR (mL/min/1.73 m²): ≤15 to <30.
^eRelatively low proportion of patients due to metformin being contraindicated in participants with a low eGFR.
ACE, angiotensin-converting enzyme; BP, blood pressure; bpm, beats per minute; DPP-4i, dipeptidyl peptidase-4 inhibitor; MI, myocardial infarction; n, number of participants; PCSK-9, proprotein convertase subtilisin/kexin type 9.

Authors and Disclosures

Peter Rossing^1,2, Florian M.M. Baeres³, George Bakris⁴, Heidrun Bosch-Traberg³, Mette Gislum³, Stephen C.L. Gough³, Thomas Idorn³, Jack Lawson³, Kenneth W. Mahaffey⁵, Johannes F.E. Mann⁶, Henriette Mersebach³, Vlado Perkovic⁷, Katherine Tuttle⁸ and Richard Pratley⁹, and on behalf of the FLOW Steering Committee and FLOW Trial Investigators

¹Complication Research, Steno Diabetes Center Copenhagen, Herlev, Denmark, ²Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark, ³Novo Nordisk A/S, Søborg, Denmark, ⁴Department of Medicine, AHA Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL, USA, ⁵Department of Medicine, Stanford Center for Clinical Research, Stanford School of Medicine, Palo Alto, CA, USA, ⁶Outpatients Clinic, KfH Kidney Center, München, Germany, ⁷Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia, ⁸Division of Nephrology, University of Washington/Providence Health Care, Spokane, WA, USA and ⁹Translational Research Institute, AdventHealth, Orlando, FL, USA

Correspondence to
Peter Rossing; E-mail: peter.rossing@regionh.dk

Authors' Contributions
All authors were involved in the conceptualisation of the article and its development and critical revision and have read and agreed to the published version. M.G. provided data analysis.

Conflict of Interest Statement
P.R. has received grants from Bayer, AstraZeneca and Novo Nordisk; received honoraria to the Steno Diabetes Centre Copenhagen from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi and Bayer; and consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi and Bayer. M.G., F.M.M.B., H.B.-T., H.M., J.L., S.G. and T.I. are employees of Novo Nordisk A/S. F.M.M.B., H.B.-T., H.M., S.G. and T.I. also hold stock in Novo Nordisk A/S. G.B. reports consulting fees from Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Novo Nordisk and Dia Medica Therapeutics. K.W.M. has received consulting fees from Amgen, Applied Therapeutics, AstraZeneca, Bayer, CSL Behring, Elsevier Fibrogen, Inova, Johnson & Johnson, Lexicon Myokardia, Novartis, Novo Nordisk, Otsuka Phasebio, Portola Sanofi and Theravance. J.M. reports grants from Novo Nordisk, the European Union and McMaster University Hamilton, Canada; consulting fees from Novo Nordisk, AstraZeneca, Bayer and Boehringer Ingelheim; honoraria from Novo Nordisk, AstraZeneca, Bayer, Fresenius and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi and Boehringer Ingelheim as well as a leadership role in the KDIGO group. V.P. has received honoraria for steering committee, data monitoring committee or advisory board roles or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Dimerix, GlaxoSmithKline, Janssen, Medimmune, Mitsubishi Tanabe, Mundipharma, Novo Nordisk, Novartis, Otsuka, Travere, Tricida and Vifor Pharma; is a Board Director for George Clinical, St. Vincents Health Australia and several independent medical research institutes. K.T. reports grants/contracts from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH), National Heart, Lung, and Blood Institute/NIH, National Center for Advancing Translational Sciences/NIH, Centers for Disease Control and Travere; consulting fees from Eli Lilly, Boehringer Ingelheim, Gilead, Goldfinch Bio, Bayer, Novo Nordisk and AstraZeneca; honoraria from Eli Lilly, AstraZeneca, Gilead, Goldfinch Bio and Bayer; support for travel and meetings from Eli Lilly and Novo Nordisk; has participated on a data safety monitoring board/advisory board for NIDDK/NIH and George Clinical Institute; was Chair of the Diabetic Kidney Disease Collaborative Task Force, American Society of Nephrology and was on the Board of Directors for Kidney Health Initiative, US Food and Drug Administration and the American Society of Nephrology.