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

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.

Study Overview

• Status: Completed
• Conditions: Optic Neuritis
• Intervention / Treatment: Drug: Placebo; Drug: Erythropoietin alfa

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg-Eppendorf
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • Medical Center - University of Freiburg, Eye Hospital
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Heidelberg University Hospital, Department of Neurooncology
    • Tuebingen, Baden-Wuerttemberg, Germany, 72076
      • Tuebingen University Hospital
  • Bayern
    • Erlangen, Bayern, Germany, 91054
      • University Hospital Erlangen
    • Munich, Bayern, Germany, 81377
      • University Hospital of Munich
    • Munich, Bayern, Germany, 81675
      • University Hospital Klinikum rechts der Isar, Munich
  • Niedersachsen
    • Göttingen, Niedersachsen, Germany, 37075
      • University Medical Center Göttingen
    • Hannover, Niedersachsen, Germany, 30625
      • Hannover Medical School
  • Nordrhein-Westfalen
    • Duesseldorf, Nordrhein-Westfalen, Germany, 40225
      • Duesseldorf University Hospital
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • University Medical Center of the Johannes Gutenberg University Mainz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erythropoietin alfa; 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 Comparator: Placebo; 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; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Contrast sensitivity		6 months
Mean visual field defect		6 months
Latency [ms] and amplitude [µV] of visual evoked potentials (VEP)		6 months
Expanded Disability Status Scale (EDSS) score		6 months
Quality of life	Determined by NEI-VFQ-25	6 months
Safety	Assessment of AEs / SAEs	Screening until end of study

Collaborators and Investigators

• Sponsor: University Eye Hospital, Freiburg
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Principal Investigator: Wolf A. Lagrèze, Prof., Eye Hospital, Medical Center - University of Freiburg

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Study information and useful links in German language

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2014
• Primary Completion (Actual): June 20, 2018
• Study Completion (Actual): November 26, 2019

Study Registration Dates

• First Submitted: September 30, 2013
• First Submitted That Met QC Criteria: October 9, 2013
• First Posted (Estimate): October 14, 2013

Study Record Updates

• Last Update Posted (Actual): December 2, 2019
• Last Update Submitted That Met QC Criteria: November 29, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Optic neuritis; Clinically isolated syndrome; Erythropoietin
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Neuritis; Optic Neuritis; Hematinics; Epoetin Alfa
• Other Study ID Numbers: P000053; 2013-002515-10 (EudraCT Number); DRKS00005298 (Registry Identifier: German Clinical Trials Register (DRKS)); 01KG1306 (Other Grant/Funding Number: Federal Ministry of Education and Research)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No