Clinical trial NCT01962571: Treatment of Optic Neuritis With Erythropoietin: a Randomised, Double-blind, Placebo-controlled Trial
Official title: Treatment of Optic Neuritis With Erythropoietin: a Randomised, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Optic Neuritis
Keywords: Optic neuritis
Multiple Sclerosis
Clinically isolated syndrome
Erythropoietin
Lead sponsor: University Eye Hospital, Freiburg
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
First posted: 2013-10-14
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Global retinal nerve fibre layer thickness (RNFLT-G)
timeFrame: 6 months
measure: Low contrast visual acuity (LCVA)
timeFrame: 6 months
Secondary outcomes:
measure: Absolute values of the global retinal nerve fibre layer thickness
timeFrame: 6 months
measure: Retinal nerve fibre layer thickness in the papillomacular bundle
timeFrame: 6 months
measure: Retinal nerve fibre layer thickness in the temporal quadrant
timeFrame: 6 months
measure: Total macular volume
timeFrame: 6 months
measure: Visual acuity
timeFrame: 6 months
measure: Contrast sensitivity
timeFrame: 6 months
measure: Mean visual field defect
timeFrame: 6 months
measure: Latency [ms] and amplitude [µV] of visual evoked potentials (VEP)
timeFrame: 6 months
measure: Expanded Disability Status Scale (EDSS) score
timeFrame: 6 months
measure: Quality of life
timeFrame: 6 months
measure: Safety
timeFrame: Screening until end of study
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: Medical Center - University of Freiburg, Eye Hospital
state: Baden-Wuerttemberg
city: Heidelberg
country: Germany
facility: Heidelberg University Hospital, Department of Neurooncology
state: Baden-Wuerttemberg
city: Tuebingen
country: Germany
facility: Tuebingen University Hospital
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: University Hospital Erlangen
state: Bayern
city: Munich
country: Germany
facility: University Hospital of Munich
state: Bayern
city: Munich
country: Germany
facility: University Hospital Klinikum rechts der Isar, Munich
state: Bayern
city: Göttingen
country: Germany
facility: University Medical Center Göttingen
state: Niedersachsen
city: Hannover
country: Germany
facility: Hannover Medical School
state: Niedersachsen
city: Duesseldorf
country: Germany
facility: Duesseldorf University Hospital
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: University Medical Center of the Johannes Gutenberg University Mainz
state: Rheinland-Pfalz
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
Study officials:
affiliation: Eye Hospital, Medical Center - University of Freiburg
name: Wolf A. Lagrèze, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.