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Optic NeuritisPhase 3TONENCT01962571

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

A Phase 3 study testing Erythropoietin alfa in people with Optic Neuritis, run by University Eye Hospital, Freiburg at 11 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 50 years
Conditions the study is for
Optic Neuritis
What is being tested?
Erythropoietin alfa
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
108 participants
Where
11 sitesGermany
Study dates
25 Nov 2014to 26 Nov 2019
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • All sexes
  • No healthy volunteers
  • Adult

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
  1. 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
  1. Performing semi-professional or professional sporting activities or physical training
  2. Pre-treatment with corticosteroids in the last 30 days prior to the onset of optic neuritis
  3. Pre-treatment with EPO
  4. Known or persistent abuse of medication, drugs or alcohol
  5. Active immunization within 2 weeks prior to randomisation
  6. Significant surgery within 4 weeks prior to randomisation
  7. Blood donation or bloodletting within 4 weeks prior to screening
  8. Pre-treatment with immunosuppressive or immunomodulatory agents
  9. 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:
  10. Current or planned pregnancy; nursing period within 3 months from investigational product administration
  11. 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

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

Germany11 sites

  • Duesseldorf University Hospital

    Düsseldorf, North Rhine-Westphalia, 40225

  • University Hospital Erlangen

    Erlangen, Bavaria, 91054

  • Medical Center - University of Freiburg, Eye Hospital

    Freiburg im Breisgau, Baden-Wurttemberg, 79106

  • University Medical Center Göttingen

    Göttingen, Lower Saxony, 37075

  • University Medical Center Hamburg-Eppendorf

    Hamburg, 20246

  • Hannover Medical School

    Hanover, Lower Saxony, 30625

  • Heidelberg University Hospital, Department of Neurooncology

    Heidelberg, Baden-Wurttemberg, 69120

  • University Medical Center of the Johannes Gutenberg University Mainz

    Mainz, Rhineland-Palatinate, 55131

  • University Hospital of Munich

    Munich, Bavaria, 81377

  • University Hospital Klinikum rechts der Isar, Munich

    Munich, Bavaria, 81675

  • Tuebingen University Hospital

    Tübingen, Baden-Wurttemberg, 72076

Other trials in Germany

About this study

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
Being tested
Erythropoietin alfa, Placebo
Keywords
Optic neuritis, Multiple Sclerosis, Clinically isolated syndrome, Erythropoietin
Medical subject headings
Optic Neuritis, Multiple Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Erythropoietin alfaDrug

  • PlaceboDrug

    Also called Saline

Study groups in NCT01962571
Study groupRoleWhat they receive
Erythropoietin alfaExperimentalRecombinant 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.
Receives: Drug: Erythropoietin alfa
PlaceboPlacebo comparatorAs 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.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 6 months

  2. 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.

    Measured: 6 months

Secondary outcomes (11)

  1. Absolute values of the global retinal nerve fibre layer thickness

    Measured: 6 months

  2. Retinal nerve fibre layer thickness in the papillomacular bundle

    Measured: 6 months

  3. Retinal nerve fibre layer thickness in the temporal quadrant

    Measured: 6 months

  4. Total macular volume

    Measured: 6 months

  5. Visual acuity

    Measured: 6 months

  6. Contrast sensitivity

    Measured: 6 months

  7. Mean visual field defect

    Measured: 6 months

  8. Latency [ms] and amplitude [µV] of visual evoked potentials (VEP)

    Measured: 6 months

  9. Expanded Disability Status Scale (EDSS) score

    Measured: 6 months

  10. Quality of life

    Determined by NEI-VFQ-25

    Measured: 6 months

  11. Safety

    Assessment of AEs / SAEs

    Measured: Screening until end of study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Oct 2013 (estimated)
  2. Study start25 Nov 2014
  3. Primary completion20 Jun 2018
  4. Study completion26 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
108 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01962571
Sponsor's protocol ID
P000053
Other IDs
2013-002515-10, DRKS00005298, 01KG1306
Acronym
TONE
Status last verified
Nov 2019
First submitted
30 Sep 2013
Last updated
2 Dec 2019
Results posted
No
Data monitoring committee
Yes

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.

    PubMed 22926853

  • 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.

    PubMed 26932144

  • 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.

    PubMed 39827907

  • 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.

    PubMed 38588480

  • 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.

    PubMed 37094997

  • 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.

    PubMed 34800417

  • 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.

    PubMed 26396053

  • 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.

    PubMed 25063544

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Erythropoietin alfa in people with Optic Neuritis, run by University Eye Hospital, Freiburg at 11 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Global retinal nerve fibre layer thickness (RNFLT-G) (time frame: 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01962571, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2019.

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