The Effect of Roxadustat on Renal Oxygenation in Diabetes Nephropathy

NCT05810311 | Not Yet Recruiting Phase 2

• 1 other identifier: FOXTROT
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The study will investigate if treatment with Roxadustat improves kidney oxygenation in diabetic patients with nephropathy receiving treatment for renal anemia, compared to patients receiving treatment with darbepoetin alpha. Participants will be randomized to either treatment, and receive equal care for renal anemia. Kidney oxygenation will be examined before treatment start and after 24 weeks using BOLD-MRI (blood oxygen level-defendant MRI), a non-invasive method available for measurement of tissue oxygenation levels that is comparable with direct invasive measurement of partial oxygen pressure. Blood and urin samples will be collected in connection to these visits. The primary endpoint is the change in medullary and cortical R2\* (inversely proportional to the tissue oxygenation content) after 24 weeks. Secondary endpoints will be albuminuria and urinary levels of ROS (evaluated by electron paramagnetic resonance (EPR) spectroscopy with CPH spin probes).

Conditions

Diabetes Complications; Diabetes; Nephropathy (Manifestation)

Keywords

HIF; Hypoxia; Diabetes mellitus; Nephropathy; BOLD-MRI; Kidney oxygenation

Outcome Measures

Primary Outcomes (1)

• Change in kidney oxygenation levels

  Kidney oxygenation will be evaluated using BOLD-MRI prior to start of therapy, and once again after 24 weeks of treatment with either RD or DA. Primary endpoint is the change in medullary and cortical R2\* (inversely proportional to the tissue oxygenation content) after 24 weeks.

  24 Weeks

Secondary Outcomes (2)

• Change in albuminuria

  24 Weeks

• Change in urinary reactive oxygen species (ROS)

  24 Weeks

Study Arms (2)

Roxadustat

ACTIVE COMPARATOR

The group will receive Roxadustat (Evrenzo) three times weekly at an initial dose of 70mg (for body weight \<100.0 kg) or 100 mg (for body weight weight ≥100.0 kg). The dosage for both arms will be adjusted to keep Hb at the recommended levels between 11-12g/dl.

Drug: Roxadustat

Darbepoietin alpha

ACTIVE COMPARATOR

The control group will receive darbepoietin alpha (Aranesp) s.c. 0.45mg/kg once a week. The dosage for both arms will be adjusted to keep Hb at the recommended levels between 11-12g/dl.

Drug: Darbepoietin Alfa

Interventions

Roxadustat DRUG

The group will receive Roxadustat (Evrenzo) three times weekly at an initial dose of 70mg (for body weight \<100.0 kg) or 100 mg (for body weight weight ≥100.0 kg). The dosage for both arms will be adjusted to keep Hb at the recommended levels between 11-12g/dl. The aim is to investigate the effects of systemic administration of Evrenzo (Roxadustat \[RD\]) or Aranesp (darbepoetin alpha \[DA\]) on the levels of renal oxygenation in patients with diabetic nephropathy and associated anemia.

Also known as: Evrenzo

Roxadustat

Darbepoietin Alfa DRUG

The control group will receive darbepoietin alpha (Aranesp) s.c. 0.45mg/kg once a week. The dosage for both arms will be adjusted to keep Hb at the recommended levels between 11-12g/dl. The aim is to investigate the effects of systemic administration of Evrenzo (Roxadustat \[RD\]) or Aranesp (darbepoetin alpha \[DA\]) on the levels of renal oxygenation in patients with diabetic nephropathy and associated anemia.

Also known as: Aranesp

Darbepoietin alpha

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diabetes mellitus with anemia caused by DKD, and indication for treatment with erythropoetin/erythropoietin-stimulating drugs.
• Age 18-75
• HbA1c \>55
• Diabetes duration 10+ years.
• Chronic kidney disease (CKD) stage 3-4
• Symptomatic anemia with Hb \<10g/dl
• Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal (and not surgically sterile), be prepared to use ≥1 effective method of contraception during the study and for 30 days after the last visit. Effective methods of contraception are those listed below:
• Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with spermicide; or
• Intrauterine device; or
• Vasectomy (partner); or
• Hormonal (e.g., contraceptive pill, patch, intramuscular implant, or injection); or
• Abstinence, if in line with the preferred and usual lifestyle of the subject.
• Signed informed consent.

You may not qualify if:

• Anemia not related to CKD.
• Dialysis dependent CKD
• Currently treated for renal anemia using erythropoietin-stimulating drugs
• Infections during the last 30 days.
• Severe hypertension (≥180mmHg systolic or \>110mmHg diastolic blood pressure)
• Liver failure (Child-Pugh class B-C)
• History of epilepsy or seizures
• Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol.
• Ongoing drug or alcohol abuse.
• Known allergy to RD or DA
• Malignancy
• Severe claustrophobia
• Participation in another ongoing pharmacological study
• If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or currently breastfeeding.
• Unwillingness to participate following oral and written information

Sponsors & Collaborators

• Region Stockholm: lead

Study Sites (1)

Centre for diabetes

Stockholm, Sweden

Location

Related Publications (13)

• Catrina SB, Zheng X. Hypoxia and hypoxia-inducible factors in diabetes and its complications. Diabetologia. 2021 Apr;64(4):709-716. doi: 10.1007/s00125-021-05380-z. Epub 2021 Jan 26.

  PMID: 33496820 BACKGROUND

• Sebastiani G, Grieco FA, Spagnuolo I, Galleri L, Cataldo D, Dotta F. Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes Metab Res Rev. 2011 Nov;27(8):862-6. doi: 10.1002/dmrr.1262.

  PMID: 22069274 BACKGROUND

• Ruiter MS, van Golde JM, Schaper NC, Stehouwer CD, Huijberts MS. Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms. Clin Sci (Lond). 2010 Jun 8;119(6):225-38. doi: 10.1042/CS20100082.

  PMID: 20545627 BACKGROUND

• Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010 Feb;6(2):94-101. doi: 10.1038/nrendo.2009.266.

  PMID: 20098449 BACKGROUND

• Friederich M, Fasching A, Hansell P, Nordquist L, Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):935-40. doi: 10.1016/j.bbabio.2008.03.030. Epub 2008 Apr 7.

  PMID: 18439413 BACKGROUND

• Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Cancer Sci. 2018 Mar;109(3):560-571. doi: 10.1111/cas.13483. Epub 2018 Jan 27.

  PMID: 29285833 BACKGROUND

• Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS, Kung AL. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4260-5. doi: 10.1073/pnas.0810067106. Epub 2009 Mar 2.

  PMID: 19255431 BACKGROUND

• Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000 Nov 1;60(21):6189-95.

  PMID: 11085544 BACKGROUND

• Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004 Aug;10(8):858-64. doi: 10.1038/nm1075. Epub 2004 Jul 4.

  PMID: 15235597 BACKGROUND

• Catrina SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med (Berl). 2014 Oct;92(10):1025-34. doi: 10.1007/s00109-014-1166-x. Epub 2014 Jun 12.

  PMID: 25027070 BACKGROUND

• Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia. 2003 Aug;46(8):1153-60. doi: 10.1007/s00125-003-1155-z. Epub 2003 Jul 17.

  PMID: 12879251 BACKGROUND

• Semenza GL. Pharmacologic Targeting of Hypoxia-Inducible Factors. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:379-403. doi: 10.1146/annurev-pharmtox-010818-021637.

  PMID: 30625281 BACKGROUND

• Pruijm M, Mendichovszky IA, Liss P, Van der Niepen P, Textor SC, Lerman LO, Krediet CTP, Caroli A, Burnier M, Prasad PV. Renal blood oxygenation level-dependent magnetic resonance imaging to measure renal tissue oxygenation: a statement paper and systematic review. Nephrol Dial Transplant. 2018 Sep 1;33(suppl_2):ii22-ii28. doi: 10.1093/ndt/gfy243.

  PMID: 30137579 BACKGROUND

Related Links

• Nationella Diabetesregistret 2023

MeSH Terms

Conditions

Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Hypoxia

Interventions

roxadustat; Darbepoetin alfa

Condition Hierarchy (Ancestors)

Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Sergiu Catrina, Ass. Proff.

  Karolinska institute, Centre for diabetes

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sergiu Catrina, Ass. prof.

CONTACT

+46-8-51775449; sergiu.catrina@ki.se

Andris Elksnis, PhD

CONTACT

andris.elksnis@ki.se

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: The research design is a randomized prospective, open-label study with parallel groups of 15 patients/group with non-dialysis dependent DKD CKD stage 3-4 with Hb \<10g/dl.

Study Record Dates

• First Submitted: March 24, 2023
• First Posted: April 12, 2023
• Study Start: June 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: November 19, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)