Clinical Trials Register

Summary
EudraCT Number:	2014-001355-23
Sponsor's Protocol Code Number:	40960
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-05-14
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

2014-001355-23

A.3

Full title of the trial

Ephedrine as add-on therapy for patients with myasthenia gravis

Efedrine als toegevoegde behandeling voor patiënten met myasthenia
gravis

A.3.1

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

Ephedrine as add-on therapy for patients with myasthenia gravis

Efedrine als toegevoegde behandeling voor patiënten met myasthenia
gravis

A.3.2

Name or abbreviated title of the trial where available

Ephedrine for MG

Efedrine voor MG

A.4.1

Sponsor's protocol code number

40960

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	Leiden University Medical Center
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	ZonMw
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	Leiden University Medical Center
B.5.2	Functional name of contact point	Ephedrine study contact
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031715262118
B.5.5	Fax number	0031715266671
B.5.6	E-mail	myasthenie@lumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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	Hidrocloruro de efedrina (In English: Ephedrine HCl)
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorias ERN, S.A. Spain
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EPHEDRINE HYDROCHLORIDE
D.3.9.1	CAS number	50-98-6
D.3.9.3	Other descriptive name	EPHEDRINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB13686MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

myasthenia gravis

E.1.1.1

Medical condition in easily understood language

myasthenia

myasthenie

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10028417
E.1.2	Term	Myasthenia gravis
E.1.2	System Organ Class	10029205 - Nervous system disorders

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

To determine the effect of ephedrine on muscle strength/endurance as measured by the QMG for all patients with AChR MG enrolled in this study when ephedrine is added to regular treatment with pyridostigmine and / or a stable low-dose prednisone and / or a stable dose of immunosuppressive treatment.

Bepalen van het effect van efedrine op spierkracht/uithoudingsvermogen, gemeten m.b.v. de QMG test, in alle patiënten met AChR MG geïncludeerd in deze studie, bij toevoegen van efedrine aan de bestaande behandeling met pyridostigmine en/of een stabiele lage dosis prednison en/of stabiele dosis andere immunosuppressiva.

E.2.2

Secondary objectives of the trial

a) To determine the effect of add-on therapy with ephedrine to regular treatment with pyridostigmine and / or low-dose prednisone for individual patients enrolled in this study.
b) To determine the feasibility of a larger series of n-of-one trials to investigate the effect of add-on therapy in patients with myasthenia gravis. The feasibility of a larger series of n-of-one trials under the current protocol will be based on the number of completed cycles in this series of n-of-one trials.
c) To determine the number of people who are initially eligible for the study, the number of people who enrol in and complete the multiple crossover phase and the number of people who subsequently proceed to the open label extension phase.
d) To explore patients’, physicians’ and pharmacists’ perspectives on the use of series of n-of-one trials;
e) To record any adverse events of ephedrine when added to the existing treatment of the MG patient.

a) Bepalen van het effect van toegevoegde behandeling met efedrine aan reguliere behandeling met pyridostigmine en/of lage dosis prednison voor individuele geïncludeerde patiënten in deze studie
b) Bepalen van de uitvoerbaarheid van een grotere serie n=1-trials om het effect van toegevoegde behandelingen bij myasthenia gravis te onderzoeken. De uitvoerbaarheid zal worden gebaseerd op basis van het aantal afgeronde cycli in deze serie van n=1-trials.
c) Bepalen van het aantal patiënten dat geschikt is voor de huidige studie, het aantal geïncludeerde patiënten in de cross-over en open label extensie fase.
d) Verkennen van het perspectief van patiënten, artsen en apothekers op het gebruik van (seriële) n=1-trials
e) Vastleggen van complicaties ("adverse events") bij toegevoegde behandeling met efedrine.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult patient with a diagnosis of generalised MG based on
a) Clinical signs or symptoms suggestive of generalised myasthenia gravis (for example, slowly progressive fluctuating muscle weakness in specific muscle groups); and
b) A positive serologic test for acetylcholine receptor (AChR) antibodies

2. Treatment with pyridostigmine, and / or low dose (max. 15 mg/day) prednisone and / or other immunosuppressive drugs does not (or no longer) adequately improve myasthenic symptoms.
The dosage of pyridostigmine, prednisone and other immunosuppressive drugs need to have been stable for at least 6 weeks prior to the trial.

1. Volwassen patiënt met de diagnose gegeneraliseerde myasthenia gravis, gebaseerd op:
a) klinische verschijnselen suggestief voor gegeneraliseerde myasthenie (bijvoorbeeld langzaam progressieve, fluctuerende spierzwakte in specifieke spiergroepen); en
b) Aanwezigheid van antistoffen tegen de acetylcholinereceptor (AChR)

2. Behandeling met pyridostigmine en/of lage dosis (max. 15mg/dag) prednison en/of andere immunsuppresiva biedt onvoldoende verlichting van symptomen passend bij myasthenia gravis.
De dosering van pyridostigmine, prednison en andere immunosuppresiva moeten minimaal 6 weken stabiel zijn vooraf aan inclusie.

E.4

Principal exclusion criteria

1. Purely ocular myasthenia (i.e. myasthenic symptoms that are limited to the extraocular muscles, such as ptosis and diplopia)
2. Treatment with ephedrine is contraindicated or was not tolerated in the past.
Contraindications include myocardial ischemia (angina pectoris and / or myocardial infarction), any cardiac arrhythmia, angle-closure glaucoma, current treatment by a psychologist or psychiatrist, current hypertension (defined as 2 measurements ≥ 140 / 90 mm Hg), poorly regulated diabetes mellitus, inherited QT syndrome or a prolonged QT interval (as indicated by ECG), prostatic hypertrophy and thyrotoxicosis. Patients with relevant drug interactions (MAO inhibitors, alpha and beta blockers) are also excluded.
3. Reliance upon medium-high dose prednisone (> 15 mg/day) and recent (< 3 months) or regular intravenous immunoglobulin (ivIG) or plasma exchange therapy. This excludes steroid-sparing therapy such as azathioprine and excludes supportive therapy such as any form of physical therapy.
These treatments are not exclusion criteria for the open label extension phase.
4. Myasthenic crisis in the past 3 months
5. Thymectomy in the past 6 months, or thymectomy (expected) to take place during the trial
6. The patient is unable to fill out the study questionnaires or be interviewed in Dutch, or is unable to undergo the tests needed for the study, or is unable to give informed consent for participation in the study.
7. The investigator can exclude patients for this trial which are deemed not suitable for any reason.

1. Pure oculaire myasthenia gravis (d.w.z. symptomen beperkt tot de extra-oculaire spieren, zoals ptosis en diplopie)
2. Behandeling met efedrine is gecontra-indiceerd of werd eerder niet verdragen.
Contra-indicaties zijn: myocardischemie (angina pectoris en/of myocardinfarct), cardiale aritmie, nauwe-kamerhoekhoek glaucoom, huidige behandeling bij psycholoog of psychiater, huidige hypertensie (gedefinieerd als 2 metingen ≥ 140 / 90 mm Hg), slecht ingestelde diabetes mellitus, aangeboren QT syndroom / verlengd QT interval (op ECG, verricht vooraf aan inclusie), prostaathypertrofie, thyrotoxicose. Patiënten met relevante interacties met andere medicatie (MAO remmers, alfa en beta blokkers) worden ook ge-excludeerd.
3. Afhankelijkheid van matig-hoge dosering prednison (> 15 mg/dag) en recente (< 3 maanden) of periodieke behandeling met intraveneuze immunoglobuline (ivIG) of plasmaferese. Hier valt dus niet onder: andere steroid-sparende immunosuppressiva zoals azathioprine, begeleidende behandeling zoals fysiotherapie.
NB: dit zijn geen exclusie criteria voor de open label extensiefase
4. Myasthene crise in de laatste 3 maanden
5. Thymectomie in de laatste 6 maanden of tijdens het onderzoek
6. De patiënt is niet in staat om de vragenlijsten in te vullen, een interview of benodigde onderzoeken te ondergaan in het Nederlands; of is niet in staat (geïnformeerde) toestemming te geven voor deelname aan het onderzoek
7. De onderzoeker kan patiënten excluderen voor dit onderzoek indien ze - om welke reden dan ook - ongeschikt worden geacht

E.5 End points

E.5.1

Primary end point(s)

The efficacy of add-on ephedrine for all patients enrolled. This will be done based on an individual’s results on the multiple Quantitative Myasthenia Gravis (QMG, Tindall 1993) measurements taken during the double-blind, multiple crossover phase of the trial.

De werkzaamheid van toegevoegde behandeling met efedrine voor alle geïncludeerde patiënten, gebaseerd op individuele resultaten op de QMG (“Quantified Myasthenia Gravis", Tindall 1993) test, gedurende de dubbelblinde, multipele cross-over fase van de studie.

E.5.1.1

Timepoint(s) of evaluation of this end point

Six weeks after inclusion (per patient, analysis after inclusion of all patients)

Zes weken na inclusie (per patiënt, analyse na inclusie van alle patiënten)

E.5.2

Secondary end point(s)

a) The effect of add-on ephedrine as measured by QMG for individual patients enrolled in this study.
b) The feasibility of a larger series of n-of-one trials. We will conclude that a larger series of n-of-one trials is feasible under the current protocol if, on average, every patient in this pilot study completes two cycles of the multiple crossover phase.
c) Changes in secondary outcome parameters: MG Composite, MG ADL questionnaire. Subjective outcome measures include treatment preference and VAS score of muscle strength in a muscle group chosen by the patient.
d) After the cross-over part of the trial, patients who decide to continue ephedrine add-on treatment will be asked to participate in the open label extension study. We will study the long-term effect of ephedrine and compare outcome parameters with baseline and short-term effect.
e) The experiences of patients with n-of-one trials by means of semistructured interviews (by telephone) and to evaluate participating professionals’ (physicians’, pharmacists’ and statisticians’) experiences.
f) Adverse events of ephedrine treatment as measured by ECG, laboratory tests (haematology, liver and renal function tests) and a questionnaire specifically developed for this purpose.

a) Het effect van efedrine voor individuele patiënten in deze studie, gebaseerd op de QMG test.
b) Uitvoerbaarheid van een grotere serie n=1-trials. Dit zal als uitvoerbaar worden beschouwd indien per patiënt gemiddeld twee of meer cycli van de multipele cross-over fase worden afgerond.
c) Veranderingen in de secundaire uitkomstmaten: MG Composite en MG-ADL (vragenlijst). Subjectieve uitkomstmaten betreffen voorkeur voor een behandeltak en een VAS score voor spierkracht in een door de patiënt gekozen spiergroep.
d) Patiënten die de cross-over fase van de studie hebben afgerond en besluiten door te gaan met efedrine, worden gevraagd deel te nemen aan de open label extensie fase. Het lange-termijn effect van efedrine zal worden bepaald en vergeleken met zowel baseline als het korte-termijn effect.
e) Ervaringen van patiënten met n=1-trials middels een telefonisch semigestructureerd interview. Evaluatie van ervaringen van deelnemende professionals (artsen, apothekers en statistici).
f) Complicaties van behandeling met efedrine zoals gemeten middels ECG, bloedonderzoek (hematologie, nier- en leverfunctie) en een vragenlijst ontwikkeld voor dit doel.

E.5.2.1

Timepoint(s) of evaluation of this end point

a) After completion of the multiple cross-over phase (6 weeks after inclusion)
b) After completion of the trial
c) After completion of the multiple cross-over phase (6 weeks after inclusion)
d) After completion of the open label extension phase (duration 6 months, this will be 8 months after initial inclusion in the trial)
e) After completion of the trial
f) During the entire trial (initially double-blind)

a) Na afronden van de multipele cross-over fase (6 weken na inclusie)
b) Na afronden van de studie
c) Na afronden van de multipele cross-over fase (6 weken na inclusie)
d) Na afronden van de open label extensie fase (duur: 6 maanden, afronding 8 maanden na initiële inclusie)
e) Na afronden van de studie
f) Gedurende de gehele studie (initieel dubbel-blind)

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

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Feasibility of future series of n-of-one trials and experiences of patients and professionals with the study design

Uitvoerbaarheid van toekomstige seriële n=1-trials en ervaringen van patiënten en professionals met de studie opzet.

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Optioneel open label extensie fase voor patiënten die besluiten door te gaan met efedrine

Optional open label extension phase for patients who decide to continue ephedrine

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

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

LVLS

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

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)

Yes

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

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients can elect to continue ephedrine for 6 months after the cross-over phase as a part of the open label extension phase. After completion of the trial, their treating neurologist can request reimbursement of continued ephedrine treatment with the patient's health insurance provider. The results of these trial will be discussed with the Dutch Medicines Evaluation Board (Dutch: CBG) and the National Health Care Institute (Dutch: ZIN), which are involved in reimbursement decisions.

Patiënten kunnen besluiten 6 maanden met efedrine door te gaan na de cross-over fase als onderdeel van de open label extensiefase. Na afronding van de studie kunnen behandelend neurologen vergoeding aanvragen voor efedrine bij de zorgverzekeraar van de patiënt. De resultaten van de studie zullen worden besproken met het College ter Beoordeling van Geneesmiddelen (CBG) en het Zorginstituut Nederland (ZIN). Deze instanties zijn betrokken bij besluitvorming over vergoeding van medicatie.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Spierziekten Nederland
G.4.3.4	Network Country	Netherlands

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-05-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-08-29

P. End of Trial
P.	End of Trial Status	Ongoing

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