Clinical Trials Register

Summary
EudraCT Number:	2017-002511-34
Sponsor's Protocol Code Number:	V1.0.14062017
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-04-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2017-002511-34

A.3

Full title of the trial

Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in CIDP
(OPTIC trial)

Intraveneus immunoglobuline en intraveneus methylprednisolon als optimale inductie behandeling in CIDP
(OPTIC trial)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in CIDP
(OPTIC trial)

Intraveneus immunoglobuline en intraveneus methylprednisolon als optimale inductie behandeling in CIDP
(OPTIC trial)

A.3.2

Name or abbreviated title of the trial where available

OPTIC trial

A.4.1

Sponsor's protocol code number

V1.0.14062017

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Academisch Medisch Centrum
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Princes Beatrix Spierfonds
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ZonMW
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Sanquin
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Academisch Medisch Centrum
B.5.2	Functional name of contact point	Filip Eftimov
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105 AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310205668728
B.5.6	E-mail	f.eftimov@amc.uva.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Methylprednisolone (Solu-Medrol)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer b.v.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Methylprednisolon (Solu-Medrol)
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sodium Chloride 0.9%
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sodium Chloride 0.9%
D.3.2	Product code	RVG 56083
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Chronische inflammatoïre demyeliniserende polyneuropathie (CIDP)

E.1.1.1

Medical condition in easily understood language

Chronic inflammatory demyelinating neuropathy (CIDP) is a disorder of the peripheral nerves which leads to loss of muscle strength and / or sensory loss in the arms and legs

Chronische inflammatoïre demyeliniserende polyneuropathie (CIDP) is een zenuwontsteking van de perifere zenuwen resulterend in krachtverlies en/of gevoelsstoornissen aan armen en benen.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective of this randomized controlled trial is to assess whether combining IVIg and IVMP leads to more frequent long-term remission in CIDP compared to treatment with IVIg alone.

Het doel van dit onderzoek is om te bestuderen of het toevoegen van methylprednisolon aan de standaard behandeling met intraveneuze immunoglobulines (IVIg) tot een betere uitkomst leidt dan het gebruik van IVIg alleen.

E.2.2

Secondary objectives of the trial

Secondary objectives are to explore whether this leads to a higher and faster rate of improvement and whether this combination reduces CIDP associated health care costs en increases quality of life.

Secundaire doelstelling is om te bepalen of er sneller en betere klinische verbetering optreedt en of deze behandelcombinatie CIPD gerelateerde zorgkosten verlaagd en kwaliteit van leven verbeterd.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion of patients is based on the presence of active disease and fulfillment of the probable or definite
EFNS/PNS criteria for CIDP. All new and untreated adult patients are eligible for the study. In addition we will include CIDP patients, treated previously, who have a disease relapse after a remission of at least 1 year, and patients who have responded to their first course of IVIg in the last three months but deteriorated afterwards.

Patiënten worden geincludeerd als wordt voldaan aan de EFNS/PNS criteria van zeker ('definite') of waarschijnlijk (' probable') CIPD. Alle nieuwe en onbehandelde patiënten komen in aanmerking voor de studie. Ook reeds behandelde CIPD patiënten komen in aanmerking, indien zij een tenminste een jaar in remissie zijn geweest. Ook patiënten die in de laatste 3 maanden klinisch zijn verbeterd na hun eerste IVIg kuur, maar daarna verslechterden, komen in aanmerking.

E.4

Principal exclusion criteria

1) Presence of IgM paraproteinemia , 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), with the exception of low dose prednisone (20 mg or less for the 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

1) aanwezigheid van IgM paraproteinemie, anti-MAG antilichamen en CIDP specifieke antilichamen (geassocieerd met een slechte response op behandeling met IVIg)
2) Gebruik van geneesmiddelen die geassocieerd zijn met (het ontstaan van) demyeliniserende polyneuropathieen
3) Gebruik van immunosuppresieve geneesmiddelen in de afgelopen 6 maanden, met uitzondering van een (enkele) oplaaddosis IVIg in de laatste 3 maanden en een lage dosis prednison (< 20 mg) gedurende 2 weken.
4) Bekende allergische reactie of ernstige bijwerkingen na eerdere behandeling met IVIg of corticosteroiden
5) Een of meerdere risicofactoren geassocieerd met een verhoogde kans op 'adverse events' vanwege IVIg en/of IVMP gebruik, of factoren die op zichzelf kunnen leiden tot deblindering: diabetes mellitus, IgA deficientie, ulcus pepticum, psychose, ernstige hypertensie (180/110 mmHg of hoger, op herhaalde metingen), hypocalciemie (lager dan 2.20, gecorrigeerd voor serum albumine), matig tot ernstig hartfalen, ernstig cardiovasculair lijden ( 1 of meer hartinfarcten of herseninfarcten), nierfalen (eGFR < 30 ml).
6) Voorgeschiedenis bekend met osteoporose of osteoporotische fracturen
7) Bekende maligniteit met een levensverwachting van < 1 jaar
8) Gewicht > 120 kg
9) Zwangerschap of het geven van borstvoeding; actieve zwangerschapswens tijdens duur studie; vrouwen die geen betrouwbare anticonceptie gebruiken of willen gebruiken gedurende de studie periode.
10) Staar/ cataract
11) Psychose
12) Slechte staat van het gebit
13) Wilsonbekwame volwassenen
14) Ontbreken van (ondertekende) informed consent

E.5 End points

E.5.1

Primary end point(s)

Primary outcome is the number of patients in remission at 1 year after start of an 18 weeks treatment period. 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 I-RODS and/or improvement of one or more points on the INCAT disability scale at 18 weeks compared to baseline. Sustained is defined as no deterioration between 18 weeks and 52 weeks, i.e. difference on the I-RODS of less than the individual MCID difference and one or more points on the INCAT disability scale. Patients will be considered as a treatment failure if they 1) receive additional CIDP treatment during the 18-week intervention period, 2) do not improve at 18 weeks, 3) restart CIDP treatment for any reason between 18 and 52 weeks, or 4) do not show a sustained improvement at 52 weeks as defined above.

Aantal patiënten in remissie, 1 jaar na start van de behandeling. Remissie is gedefineerd als een stabiel ziektebeloop zonder noodzaak tot verdere behandeling. Klinisch verbetering is gedefinieerd als verbetering van invaliditeit (MCID) op de iRODS vragenlijst en/of verbetering van 1 of meer punten op de INCAT disability scale. Patiënten worden gerekend tot 'treatment failure' als 1) er opnieuw behandeld moet worden in de eerste 18 weken, 2) er geen verbetering heeft opgetreden in de eerste 18 weken, 3) er opnieuw behandeling moet worden gestart tussen 18 en 52 weken, 4) als er geen sprake is van een remissie na 52 weken.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint will be evaluated at 52 weeks.

Primaire uitkomst wordt op 52 bepaald.

E.5.2

Secondary end point(s)

1) The number of patients with improvement on disability equal or more than the MCID;
2) Time to improvement (≥ MCID) on disability;
3) Mean change in disability;
4) Mean change in grip strength;
5) Mean change in muscle strength;
6) Mean change in sensory impairment (INCAT SS);
7) Mean change in fatigue;
8) Mean change in pain;
9) Mean change in health related quality of life (HRQL);
10) Number of (serious) adverse events (including corticosteroid associated adverse events);
11) Care use and overall healthcare-related costs;

1) Het aantal patiënten met verbetering van hun invaliditeit (meer dan de MCID);
2) Tijd tot verbetering (≥ MCID) invaliditeit;
3) Gemiddelde verandering in invaliditeit;
4) Gemiddelde verandering knijpkracht;
5) Gemiddelde verandering spierkracht;
6) Gemiddelde verandering sensibele beperkingen (INCAT SS);
7) Gemiddelde verandering met betrekking tot vermoeidheid;
8) Gemiddelde verandering met betrekking tot pijnklachten;
9) Gemiddelde verandering kwaliteit van leven (HRQL);
10) Aantal bijwerkingen: (serious) adverse events, (S)AEs;
11) Zorggebruik en algemene zorg gerelateerde kosten;

E.5.2.1

Timepoint(s) of evaluation of this end point

At 18 and 52 weeks. Measuring of these parameters is done consistently (table 1 and 2 in the study protocol, version 4.4.) in the intervention and follow up period. Main secondary outcomes are evaluated at 18 and 52 weeks. Secondary outcomes are also determined according to follow-up protocol (the schedule of which is refered to previously) in case an early endpoint is reached.

op 18 en 52 weken. Deze parameters worden frequent gemeten (tabel 1 en 2 van het protocol, versie 4.4.). Secundaire uitkomstmaten worden primair geëvalueerd op 18 en 52 weken. Het follow-up protocol en het meten van secundaire uitkomstmaten verloopt volgens het eerder genoemde schema, ook als een vroege eindpunt wordt gehaald.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last day of follow up for last included patient

Na het einde van de follow up voor de laatst geincludeerde patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception