Treatment of Optic Neuritis With Erythropoietin: a Randomised, Double-blind, Placebo-controlled Trial

NCT01962571 | Completed Phase 3 DMC

• 4 other identifiers: P0000532013-002515-10DRKS0000529801KG1306
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 11

Brief Summary

This clinical trial aims at preventing visual dysfunction and optic nerve degeneration associated with autoimmune optic neuritis by systemic i.v. administration of 33.000 IU erythropoietin over 3 days. The primary objective is to determine the efficacy of erythropoietin compared to placebo given as add-on to methylprednisolone as assessed by measurements of retinal nerve fibre layer thickness and low contrast visual acuity 6 months after acute optic neuritis.

Conditions

Optic Neuritis

Keywords

Optic neuritis; Multiple Sclerosis; Clinically isolated syndrome; Erythropoietin

Outcome Measures

Primary Outcomes (2)

• Global retinal nerve fibre layer thickness (RNFLT-G)

  Determination of the efficacy of erythropoietin compared to placebo given as add-on to methylprednisolone (standard of care) as assessed by measurement of global retinal nerve fibre layer thickness (RNFLT-G) in the affected eye 6 months after randomisation.

  6 months

• Low contrast visual acuity (LCVA)

  Determination of the efficacy of erythropoietin compared to placebo given as add-on to methylprednisolone (standard of care) as assessed by measurement of low contrast visual acuity (LCVA) in the affected eye 6 months after randomisation.

  6 months

Secondary Outcomes (11)

• Absolute values of the global retinal nerve fibre layer thickness

  6 months

• Retinal nerve fibre layer thickness in the papillomacular bundle

  6 months

• Retinal nerve fibre layer thickness in the temporal quadrant

  6 months

• Total macular volume

  6 months

• Visual acuity

  6 months

Study Arms (2)

Erythropoietin alfa

EXPERIMENTAL

Recombinant human EPO (Epoetin alfa HEXAL®) will be given as an i.v. bolus injection on days 1, 2 and 3. The dosage per day will be 33.000 IU in accordance with previous trials.

Drug: Erythropoietin alfa

Placebo

PLACEBO COMPARATOR

As matched placebo for this study, sterile normal saline (0.9% sodium chloride for i.v. administration) will be used. It will be given as a bolus injection in the same manner as EPO.

Drug: Placebo

Interventions

Erythropoietin alfa DRUG

Erythropoietin alfa

Placebo DRUG

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

Patients eligible for inclusion in this trial must meet all of the following criteria: 1. Written informed consent obtained according to international guidelines and local laws 2. Male and female patients aged ≥ 18 to ≤ 50 years 3. Patients with ON 4. First symptoms of ON ≤ 10 days prior to the first administration of investigational product 5. High contrast visual acuity (HCVA) of ≤ 0.5 (decimal system) 6. Adequate OCT measurements available Patients eligible for this trial must not meet any of the following criteria: 1. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial 2. Simultaneous participation in another interventional trial which could interfere with this trial and/or participation in a clinical trial within the last 3 months before enrolment in this trial 3. Refractive anomalies: Hyperopia \> 5 dpt, myopia \< -7 dpt, astigmatism \> 3 dpt 4. Media opacity 5. Severe papillitis 6. Previous ON 7. Any other optic nerve and retinal disease 8. Pre-existing MS or any other neurological disease 9. Congenital diseases: * thrombophilia * phenylketonuria 10. Acquired diseases: * autoimmune diseases, * cardiovascular diseases, * diabetes mellitus, * uncontrolled hypertension (with blood pressure \> 140 / 90 mm Hg (cf. chapter 7.7.5)), * any malignancy, * epilepsy, * known tuberculosis with ongoing or unknown activity, * acute gastrointestinal ulceration within the last 3 months prior to randomisation, * acute viral, bacterial or fungal infection, * known infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis C Virus, * history of colitis ulcerosa, diverticulitis, or acute enteroanastomosis, * known osteoporosis, * history of thromboembolic events, * elevated haemoglobin level (\>17 g/dl in men or \>15 g/dl in women) * polycythaemia * any other significant illness potentially interfering with any trial assessment or trial treatment 11. Performing semi-professional or professional sporting activities or physical training 12. Pre-treatment with corticosteroids in the last 30 days prior to the onset of optic neuritis 13. Pre-treatment with EPO 14. Known or persistent abuse of medication, drugs or alcohol 15. Active immunization within 2 weeks prior to randomisation 16. Significant surgery within 4 weeks prior to randomisation 17. Blood donation or bloodletting within 4 weeks prior to screening 18. Pre-treatment with immunosuppressive or immunomodulatory agents 19. Persons who are in a relationship of dependence/employment with the sponsor or the investigator This section concerns only female patients who are able to have a child: 20. Current or planned pregnancy; nursing period within 3 months from investigational product administration 21. Unwillingness to use one of the following safe combination methods of contraception within 3 months from investigational product administration to achieve a PEARL index of \<1: female condom, diaphragm or coil, each used in combination with a spermicide; hormonal intra-uterine device or hormonal contraception in combination with a mechanical method of contraception

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University Eye Hospital, Freiburg: lead
• German Federal Ministry of Education and Research: collaborator

Study Sites (11)

Medical Center - University of Freiburg, Eye Hospital

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Heidelberg University Hospital, Department of Neurooncology

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Tuebingen University Hospital

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

University Hospital Erlangen

Erlangen, Bavaria, 91054, Germany

Location

University Hospital of Munich

Munich, Bavaria, 81377, Germany

Location

University Hospital Klinikum rechts der Isar, Munich

Munich, Bavaria, 81675, Germany

Location

University Medical Center Göttingen

Göttingen, Lower Saxony, 37075, Germany

Location

Hannover Medical School

Hanover, Lower Saxony, 30625, Germany

Location

Duesseldorf University Hospital

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

University Medical Center of the Johannes Gutenberg University Mainz

Mainz, Rhineland-Palatinate, 55131, Germany

Location

University Medical Center Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Related Publications (8)

• Suhs KW, Hein K, Sattler MB, Gorlitz A, Ciupka C, Scholz K, Kasmann-Kellner B, Papanagiotou P, Schaffler N, Restemeyer C, Bittersohl D, Hassenstein A, Seitz B, Reith W, Fassbender K, Hilgers R, Heesen C, Bahr M, Diem R. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol. 2012 Aug;72(2):199-210. doi: 10.1002/ana.23573.

  PMID: 22926853 BACKGROUND

• Diem R, Molnar F, Beisse F, Gross N, Druschler K, Heinrich SP, Joachimsen L, Rauer S, Pielen A, Suhs KW, Linker RA, Huchzermeyer C, Albrecht P, Hassenstein A, Aktas O, Guthoff T, Tonagel F, Kernstock C, Hartmann K, Kumpfel T, Hein K, van Oterendorp C, Grotejohann B, Ihorst G, Maurer J, Muller M, Volkmann M, Wildemann B, Platten M, Wick W, Heesen C, Schiefer U, Wolf S, Lagreze WA. Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol. BMJ Open. 2016 Mar 1;6(3):e010956. doi: 10.1136/bmjopen-2015-010956.

  PMID: 26932144 BACKGROUND

• Kuchlin S, Ihorst G, Heinrich SP, Farassat N, Marquez Neila P, Hug MJ, Albrecht P, Lagreze WA. Clinical Predictors in Acute Optic Neuritis: Analysis Based on Clinical Trial Data. Ophthalmology. 2025 Jun;132(6):631-643. doi: 10.1016/j.ophtha.2025.01.010. Epub 2025 Jan 17.

  PMID: 39827907 DERIVED

• Kuchlin S, Ihorst G, Heinrich SP, Marquez Neila P, Albrecht P, Hug MJ, Diem R, Lagreze WA. Disease Course of Clinically Isolated Optic Neuritis. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200223. doi: 10.1212/NXI.0000000000200223. Epub 2024 Apr 8.

  PMID: 38588480 DERIVED

• Kuchlin S, Ihorst G, Grotejohann B, Beisse F, Heinrich SP, Albrecht P, Ungewiss J, Worner M, Hug MJ, Wolf S, Diem R, Lagreze WA; TONE Study Group. Treatment With Erythropoietin for Patients With Optic Neuritis: Long-term Follow-up. Neurol Neuroimmunol Neuroinflamm. 2023 Apr 24;10(4):e200067. doi: 10.1212/NXI.0000000000200067. Print 2023 Jul.

  PMID: 37094997 DERIVED

• Lagreze WA, Kuchlin S, Ihorst G, Grotejohann B, Beisse F, Volkmann M, Heinrich SP, Albrecht P, Ungewiss J, Worner M, Hug MJ, Wolf S, Diem R; TONE study group. Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study. Lancet Neurol. 2021 Dec;20(12):991-1000. doi: 10.1016/S1474-4422(21)00322-7.

  PMID: 34800417 DERIVED

• Wilhelm H, Schabet M. The Diagnosis and Treatment of Optic Neuritis. Dtsch Arztebl Int. 2015 Sep 11;112(37):616-25; quiz 626. doi: 10.3238/arztebl.2015.0616.

  PMID: 26396053 DERIVED

• Lagreze W, Diem R. [New aspects in the therapy of multiple sclerosis and optic neuritis]. Ophthalmologe. 2014 Aug;111(8):709-14. doi: 10.1007/s00347-013-2987-7. German.

  PMID: 25063544 DERIVED

MeSH Terms

Conditions

Optic Neuritis; Multiple Sclerosis

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Eye Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Wolf A. Lagrèze, Prof.

  Eye Hospital, Medical Center - University of Freiburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: September 30, 2013
• First Posted: October 14, 2013
• Study Start: November 25, 2014
• Primary Completion: June 20, 2018
• Study Completion: November 26, 2019
• Last Updated: December 2, 2019

Record last verified: 2019-11

Locations

DE (11)