Plain English Summary
Background and study aims
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder which causes chronic inflammation (swelling) of nerves causing weakness and sensory problems in legs and arms. Induction treatment (the first phase of treatment) CIDP currently consists of either intravenous immunoglobulin (IVIg) (treatment made from donated blood that contains health anitbodies) infusions or high dose corticosteroids (anti-inflammatory medication), including daily oral prednisolone, pulsed dexamethasone or pulsed intravenous methylprednisolone (IVMP) (types of steroids). Both IVIg and IVMP are recommended as first line treatment, but choice of induction treatment is usually based on patients' and physicians' preferences as both treatment options have their own specific advantages. Patients treated with IVIg usually respond fast, but this treatment rarely leads to long term remissions (meaning the symptoms are gone). Corticosteroids may lead to long term remissions. Both fast clinical response and long term remissions can be considered equally important. The aim of this study is to determine whether the addition of methylprednisolone to IVIg as induction treatment leads to a better outcome.
Who can participate?
Adults aged 18 and older who have probably or definite CIDP.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive intravenous immunoglobulin (IVIg) + intravenous methylprednisolone. Those in the second group receive intravenous immunoglobulin (IVIg) + placebo (saline infusion). Participants receive seven infusions every three weeks over the course of 18 weeks. During the 18 week intervention period participants are prescribed osteoporosis prophylactics (vitamin D daily and alendronic acid weekly). In the Netherlands the first treatment is given in the hospital and the remaining six infusions are given at home. Outpatient clinic visits are planned every six weeks during the intervention period and a consultation by phone is planned three weeks after start of intervention period. Three follow-up visits are planned in week 24, 52 and 104. Unscheduled visits can be planned at any time during study.
What are the possible benefits and risks of participating?
Participants can benefit from the combination therapy: a fast improvement of symptoms(attributed to the IVIg) and long term remission (attributed to the methylprednisolone), without the need for further treatments. Risks include medication induced side effects. These side effects include (and not limited to) gastro-intestinal complaints, headaches, muscle aches, oedema, mood/behavior disorders (methylprednisolone); musculoskeletal complaints (muscle, joint and/or bone aches) and gastro-intestinal complaints (alendronic acid); skin rash, hypertension, headaches and gasto-intestinal complaints (IVIg, standard care).
Where is the study run from?
This study is being run by the Academic Medical Center (AMC) (The Netherlands). A total of 14 hospitals (8 in The Netherlands and 6 in the United Kingdom) are participating in this trial.
When is the study starting and how long is it expected to run for?
January 2018 to December 2023
Who is funding the study?
The Academic Medical Center (AMC) (The Netherlands)
Who is the main contact?
Dr Filip Eftimov (Scientific)
f.eftimov@amc.nl
2. Mr Sander Bus (Public)
s.r.bus@amc.nl
Trial website
Contact information
Type
Scientific
Primary contact
Dr Filip Eftimov
ORCID ID
http://orcid.org/0000-0002-0146-0776
Contact details
Academic Medical Center
Department of Neurology
PO Box 22660
Amsterdam
1100 DD
Netherlands
+31 20 566 8728
f.eftimov@amc.nl
Type
Public
Additional contact
Mr Sander Bus
ORCID ID
Contact details
Academic Medical Center
Department of neurology
H2-235
PO Box 22660
Amsterdam
1100DD
Netherlands
+31 20 566 6889
s.r.bus@amc.nl
Additional identifiers
EudraCT number
2017-002511-34
ClinicalTrials.gov number
Protocol/serial number
Protocol version 1.0 (26NOV2017); ABR: NL 62561.018.17
Study information
Scientific title
Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in CIDP
Acronym
OPTIC
Study hypothesis
Primary objective of this randomized controlled trial is to assess whether combining IVIg and methylprednisolone leads to more frequent long-term remission in CIDP compared to treatment with IVIg alone.
Ethics approval
The Medical Ethical Committee of the Academic Medical Center, 15/01/2018, ref: 2017_316
Study design
Multicentre randomised double-blind placebo-controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Condition
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Intervention
All participants are treated with intravenous IVIg, which is considered standard care. In addition, participants are randomized to receive either 7 infusions methylprednisolone (IVMP) 1000 mg in sodium chloride 0,9%, or placebo (100 ml sodium chloride 0,9%). Participants are treated every 3 weeks during an 18-week intervention period. In addition, all patients receive osteoporosis prophylactics (calcium/vitamin D 500 mg/800IE daily and alendronic acid 80 mg weekly) during the 18 week intervention period.
In the Netherlands the first treatment is given in the hospital and the remaining six infusions are given at home. Outpatient clinic visits are planned every 6 weeks during the intervention period and a consultation by phone is planned 3 weeks after start of intervention period. Three follow-up visits are planned in week 24, 52 and 104. Unscheduled visits can be planned at any time during study. A total of 14 hospitals (8 in The Netherlands and 6 in the United Kingdom) are participating in this trial. The Academic Medical Center (AMC) in Amsterdam (The Netherlands) is the study sponsor.
Intervention type
Drug
Phase
Phase III
Drug names
IVIg (standard care)
Methylprednisolone (intervention)
Sodium chloride 0.9% (placebo)
Calcium/vitamin D (osteoporosis prophylactic)
Alendronic acid (osteoporosis prophylactic)
Primary outcome measure
The number of patients in remission is a value determined 1 year after start of the intervention period by accounting for the patients who fit the criteria for remission. Remission is defined as: sustained improvement without the need for further treatment. Improvement is defined as improvement by at least the minimal clinical important difference (MCID) on the inflammatory Rasch Disability Scale (I-RODS) and/or improvement (ie, decrease) of one point or more on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale at 18 weeks compared to baseline. Sustained is defined as no deterioration between week 18 and week 52, i.e. difference on the I-RODS of less than the individual MCID difference and/or no increase on the adjusted INCAT disability scale.
Secondary outcome measures
Secondary parameters are assessed at 18 and 52 weeks, or earlier if a preliminary endpoint is reached:
1. The number of patients with improvement on disability equal or more than the MCID: disability is measured using the iRODS and the INCAT disability scale, the number of patients are calculated by counting the patients who fit the definition of improvement
2. Time to improvement (≥ MCID) on disability: time to improvement is calculated and given in days and/or weeks
3. Mean change in disability: disability is measured using the iRODS and INCAT disability scale
4. Mean change in grip strength: grip strength (in kPa) is measured using a handheld (Martin) Vigorimeter
5. Mean change in muscle strength: The Medical Research Council (MRC) sum score of 12 predefined muscle groups (including shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension and foot dorsiflexion) is used to measure muscle strength
6. Mean change in sensory impairment: measured using the Inflammatory Neuropathy Cause and Treatment sensory sumscore (INCAT-SS)
7. Mean change in fatigue: measured using the Fatigue Severity Scale (FSS)
8. Mean change in pain: measured using the pain intensity numeric rating scale (PI-NRS)
9. Mean change in health related quality of life (HRQL): measured using the EuroQol
10. Number of (serious) adverse events (including corticosteroid associated adverse events): number of (serious) adverse events (including corticosteroid associated adverse events) are measured using a structured questionnaire with short term corticosteroid and IVIg related AE’s at the 18 week visit. AEs are scored as mild, moderate or severe by the investigator. Long-term corticosteroid related AEs will be filled in by the investigator at 52 weeks (secondary outcome) and 104 weeks (safety follow-up). Adverse events questionnaires will be filled in only after completion of all other outcome assessments.
11. Care use and overall healthcare-related costs: measured using the working documents and the Medical Consumption Questionnaire (iMCQ) complemented with extra questions relevant for the study population and the Productivity Cost Questionnaire (iPCQ)
Overall trial start date
01/01/2018
Overall trial end date
31/12/2023
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Probable or definite CIDP according to the EFNS/PNS criteria 2010 (all CIDP phenotypes)
2. Age ≥ 18 years
3.1. Treatment naïve patients; or
3.2. Previously treated patients who have a relapse after a remission of at least 1 year; or
3.3. Patients treated with subjective or objective improvement after a single loading dose of IVIg in the last 3 months, and subsequent deterioration as judged by his or her treating physician.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
96
Participant exclusion criteria
Current exclusion criteria as of 30/05/2018, to reflect changes approved by ethics committee 25/05/2018:
1. Presence of IgM paraproteinemia and/or anti-MAG antibodies or CIDP specific antibodies associated with poor treatment response to IVIg
2. Use of drugs associated with a demyelinating neuropathy
3. Use of any immunosuppressive or immunomodulatory drugs in previous 6 months (except for a single loading dose of IVIg within 3 months or low dose prednisolone (20 mg or less) during a short period (maximum duration of two weeks).
4. Known serious adverse events with previous IVIg or corticosteroid treatment
5. One of more of the risk factors associated with increased risk of adverse events of IVIg or IVMP or conditions that could lead to unblinding of treatment (i.e. diabetes; IgA deficiency; gastric ulcers; psychosis; severe hypertension (180/110 mmHg or more on repeated measurements); hypocalcaemia (lower than 2.20 mmol/L, corrected for albumin); moderate or severe heart failure; severe cardiovascular disease (i.e. more than one myocardial infarction and or ischemic stroke); renal failure (glomerulal filtratrion rate < 30 ml/min)
6. History of osteoporosis or osteoporotic fractures
7. Known malignancy with survival expectancy of less than 1 year
8. Bodyweight more than 120 kg
9. Pregnancy or nursing mother; intention to become pregnant during the course of the study; female patients of childbearing potential either not using or not willing to use a medically reliable method of contraception for the entire duration of the study
10. Cataract
11. Psychosis
12. Poor dental status
13. Known pulmonary embolism or other deep venous thrombosis in patient’s medical history, without current anticoagulant therapy
14. Legally incompetent adults
15. Lack of written informed consent
Previous exclusion criteria:
1. Presence of IgM paraproteinemia and/or anti-MAG antibodies or CIDP specific antibodies associated with poor treatment response to IVIg
2. Use of drugs associated with a demyelinating neuropathy
3. Use of any immunosuppressive or immunomodulatory drugs in previous 6 months (except for a single loading dose of IVIg within 3 months or low dose prednisolone (20 mg or less) during a short period (maximum duration of two weeks).
4. Known serious adverse events with previous IVIg or corticosteroid treatment
5. One of more of the risk factors associated with increased risk of adverse events of IVIg or IVMP or conditions that could lead to unblinding of treatment (i.e. diabetes; IgA deficiency; gastric ulcers; psychosis; severe hypertension (180/110 mmHg or more on repeated measurements); hypocalcaemia (lower than 2.20 mmol/L, corrected for albumin); moderate or severe heart failure; severe cardiovascular disease (i.e. more than one myocardial infarction and or ischemic stroke); renal failure (glomerulal filtratrion rate < 30 ml/min)
6. History of osteoporosis or osteoporotic fractures
7. Known malignancy with survival expectancy of less than 1 year
8. Bodyweight more than 120 kg
9. Pregnancy or nursing mother; intention to become pregnant during the course of the study; female patients of childbearing potential either not using or not willing to use a medically reliable method of contraception for the entire duration of the study
10. Cataract
11. Psychosis
12. Poor dental status
13. Legally incompetent adults
14. Lack of written informed consent
Recruitment start date
01/02/2018
Recruitment end date
01/11/2021
Locations
Countries of recruitment
Netherlands, United Kingdom
Trial participating centre
Academic Medical Center (AMC)
Meibergdreef 9
Amsterdam
1105 AZ
Netherlands
Trial participating centre
Erasmus Medical Center
Rotterdam
3015 CE
Netherlands
Trial participating centre
University Medical Center Utrecht
Utrecht
3584 CX
Netherlands
Trial participating centre
Maastricht University Medical Center
Maastricht
6229 HX
Netherlands
Trial participating centre
Radboud University Medical Center
Nijmegen
6525 GA
Netherlands
Trial participating centre
HaGa Hospital
The Hague
2545 AA
Netherlands
Trial participating centre
Martini Hospital Groningen
Groningen
9728 NT
Netherlands
Trial participating centre
Catharina Hospital Eindhoven
Eindhoven
5623 EJ
Netherlands
Trial participating centre
University College London Hospital
London
London NW1 2BU
United Kingdom
Trial participating centre
King's College Hospital
London
SE5 9RS
United Kingdom
Trial participating centre
University Hospitals of Birmingham
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Queen Elizabeth University Hospital
Glasgow
G51 4TF
United Kingdom
Trial participating centre
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP
United Kingdom
Trial participating centre
The Walton Centre
Liverpool
L9 7LJ
United Kingdom
Funders
Funder type
Charity
Funder name
ZonMw
Alternative name(s)
Netherlands Organisation for Health Research and Development
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit organizations
Location
Netherlands
Funder name
Prinses Beatrix Spierfonds
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Sanquin Plasma Products B.V.
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal, with the intent to publish the results in one year following overall trial end date.
Added 28/02/2020:
Protocol, including statistical analysis plan, will be published in a peer-reviewed journal in 2020 (prior to inclusion of last patient).
IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date. When this information becomes available we will disclose it.
Added 28/02/2020:
The manuscript reporting on the results of this clinical trial will include an Individual Participant Data (IPD) sharing statement, which is in line with the 2017 ICMJE statement.
Intention to publish date
31/12/2024
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list