Clinical Trials Register

Summary
EudraCT Number:	2011-002068-26
Sponsor's Protocol Code Number:	BEL115123
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-10-05
Trial results	View 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

Germany - PEI

A.2

EudraCT number

2011-002068-26

A.3

Full title of the trial

A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamics of Belimumab in Subjects with Generalized Myasthenia Gravis (MG).

A.3.1

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

A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamics of Belimumab in Subjects with Generalized Myasthenia Gravis (MG)

A.4.1

Sponsor's protocol code number

BEL115123

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	GlaxoSmithKline Research & Development Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline Research & Development Limited
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	GSK Clinical Support Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44(0)208990 4466
B.5.5	Fax number	+44(0)208990 1234
B.5.6	E-mail	GSKClinicalSupportHD@gsk.com

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	BENLYSTA® (belimumab)
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Benlysta (belimumab)
D.3.2	Product code	GSK1550188
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	belimumab
D.3.9.1	CAS number	356547-88-1
D.3.9.2	Current sponsor code	GSK1550188
D.3.9.4	EV Substance Code	SUB25607
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

Myasthenia Gravis

E.1.1.1

Medical condition in easily understood language

Myasthenia Gravis

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 assess the efficacy of belimumab in subjects with MG by testing the hypothesis that belimumab will be more effective than placebo in reducing signs of MG as measured by the Quantitative Myasthenia Gravis (QMG) score.

E.2.2

Secondary objectives of the trial

• To further assess efficacy of belimumab in subjects with MG
• To assess safety, tolerability, and pharmacodynamics of belimumab in subjects with MG

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Subjects aged 18 years and older, with life expectancy of greater than 1 year.
2. MG of class II to IVa inclusive.
3. Acetylcholine receptor (AChR) or muscle-specific kinase (MuSK)antibody positive.
4. Stable dose (defined as no dose changes) not exceeding the maximum doses given in Section 5.6.1 of protocol, the following therapy(ies) prior to screening:
A. Cholinesterase inhibitor(pyridostigmine or equivalent) for at least 2 weeks prior to screening and no immunosuppressants;
or
B. Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to screening and/or only one of the following:
i. prednisone (up to 40 mg/day or equivalent) for at least 1 month prior to screening,
ii. azathioprine for at least 6 months prior to screening,
iii. mycophenolate for at least 6 months prior to screening,
iv. cyclosporine for at least 3 months prior to screening;
v. methotrexat for at least 3 months prior to screening
or
C. Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to screening and/or prednisone (up to 20 mg/day or
equivalent) for at least 1 month prior to screening and only one of the following:
i. azathioprine for at least 6 months prior to screening,
ii. mycophenolate for at least 6 months prior to screening,
iii. cyclosporine for at least 3 months prior to screening
iv. methotrexat for at least 3 months prior to screening
5. Quantitative Myasthenia Gravis (QMG) score of 8 or greater, with at least 4 points derived from signs other than ocular
6. A female subject is eligible to participate if she is:
A. Of non-childbearing potential
B. Of childbearing potential and NOT pregnant or nursing, has a negative serum
pregnancy test at screening, and agrees to one of the following:
a. Complete abstinence from penile-vaginal intercourse, when this is the
female’s preferred and usual lifestyle, for the period from consent into the study until 16 weeks after the last dose of investigational product; or,
b. Consistent and correct use of one of the following acceptable methods of
birth control for the period from consent into the study until 16 weeks
after the last dose of investigational product:
i. Oral contraceptives (either combined or progesterone only)
ii. Injectable progesterone
iii. Implants of etonogestrel or levonorgestrel
iv. Estrogenic vaginal ring
v. Percutaneous contraceptive patches
vi. Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of <1% per year
vii. Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject’s entry into the study;
this male must be the sole partner for the subject
viii. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent(foam/gel/film/cream/suppository).
A female is considered “Non-childbearing potential” if she is status-post hysterectomy,
status-post surgical removal of both ovaries, has current, documented tubal ligation, or is
postmenopausal and >2 years without menses. Female subjects who are post-menopausal
<2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and
estradiol levels.
A female is considered “childbearing potential” if she has functional ovaries, ducts, and
uterus with no impairment that would cause sterility. This includes women with oligomenorrhea (even severe), and women who are perimenopausal or who have just
begun to menstruate.
7. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
8. Single QTc < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.
9. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
French subjects: In France, a subject will be eligible for inclusion in this study only if
either affiliated to or a beneficiary of a social security category.

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria must not be enrolled in the study:
1. The subject has participated in a clinical trial and has received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to screening or planning to take any investigational drug for the planned duration of study participation (6
months after the last dose of study drug).
2. Presence or previous history of thymoma.
3. Thymectomy within 12 months
4. Clinically significant (in the opinion of investigator) abnormal laboratory values.
5. Pregnant females as determined by positive (serum) hCG test at screening or prior to dosing, or lactating females or planning to become pregnant within 16 weeks after last dose of investigational product.
6. History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
7. May require (in the opinion of investigator) treatment with IVIg and/or plasmapheresis during the 12 weeks after the screening visit.
8. Have received IVIg and/or plasmapheresis within 4 weeks prior to screening.
9. Have received any other biopharmaceutical agent (except IVIg as described in exclusion criteria #8) in the 364 days prior to screening.
10. Have received treatment with rituximab within 12 months prior to screening or have received treatment with belimumab or any other B cell targeted therapy at any time.
11. Have received a live vaccine within 30 days of study Day 0 (baseline).
12. Have received cyclophosphamide or any other immunosuppressive agent apart from
the ones allowed by the inclusion criteria #4, within the past 6 months.
13. Have another medical condition that requires treatment with steroids or immunosuppressive agents.
14. Hospitalization due to infection or use of parenteral antibacterial, antifungal or antiviral agents within 60 days prior to screening; or history of recurrent or chronic infection, or currently active systemic infection.
15. Have a history of malignant neoplasm within the last 5 years, except for adequately
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the
uterine cervix.
16. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
17. Have a historically positive test or test positive at screening for HIV-1, hepatitis B surface antigen, hepatitis B core antibody or hepatitis C antibody (Patients who are positive for hepatitis C antibody but negative for a confirmatory RNA test will be eligible to participate.)
18. Have an IgG Grade 3 or greater deficiency (≤ 400mg/dL).
19. Have an IgA deficiency (IgA < 10mg/dL).
20. Have a history of an anaphylactic reaction to parenteral administration of contrast
agents, human or murine proteins or monoclonal antibodies.
21. The subject has a progressive medical, neurological or psychological condition or
situation that, in the investigator’s judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures, to complete all scheduled assessments, or precludes accurate assessments.
22. Is currently abusing drugs or alcohol or has history of abuse in the last 12 months.
23. Subjects who have evidence of serious suicide risk including any history of suicidal
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the CSSRS (Appendix 4 of Protocol) in the last 2 months or who in the investigator's judgment, pose a significant suicide risk.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the mean change from baseline for QMG score at Week 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

E.5.2

Secondary end point(s)

QMG Score:
• Proportion of subjects with improvement by ≥ 3points from baseline to Week 24 in QMG score
• Proportion of subjects with a sustained response (improve by ≥ 3 points from baseline to Week 12 and maintain the response through Week 24) in the QMG score
• Proportion of subjects with a worsening by ≥ 3 points in QMG score from baseline to Week 24
• Median time to QMG response which is sustained (from earliest time point at which
improvement by ≥ 3 points from baseline is observed and maintained through Week 24)
• Mean change from baseline for QMG score at Week 28, Week 32, and Week 36.

MG Composite (MGC) Score:
• Mean change from baseline in MGC at Week 24
• Proportion of subjects with improvement by ≥ 3points from baseline to Week 24 in the MG Composite (MGC) score
• Proportion of subjects with a sustained response (improve by ≥ 3 points from
baseline to Week 12 and maintain the response through Week 24) in MGC score
• Proportion of subjects with a worsening by ≥ 3 points in MGC score from baseline to Week 24
• Median time to MGC score response which is sustained (from earliest time point at which improvement by ≥ 3 points from baseline is observed and maintained through Week 24)
• Mean change from baseline for MGC score at Week 28, Week 32, and Week 36.

Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status:
• Proportion of subjects with a MGFA post-intervention status of Minimal Manifestation (MM) or better at Week 24 and Week 36
• Proportion of subjects with MGFA post-intervention status of Pharmacologic Remission (PR) or better at Week 24 and Week 36
• Proportion of subjects with a MGFA post-intervention status of MM sustained response (MM at Week 12 and maintained the response through Week 24)
• Proportion of subjects with MGFA post-intervention status of PR sustained response
(PR at Week 12 and maintained the response through Week 24)
• Proportion of subjects with MGFA post-intervention status (Unchanged, Improved,
Worsened) at Week 24
MG Activities of Daily Living Scale (MG-ADL):
• Mean change from baseline in the MG-ADL at Week 12 and Week 24
• Mean change from baseline in the MG-ADL at Week 28, Week 32, and Week 36

Other
Pharmacokinetics:
• Individual serum concentrations of belimumab at Day 0, Week 2, Week 8, Week 20, Week 24 and Week 28.

Pharmacodynamics/biomarkers:
• Change from baseline to Week 8, Week 24, Week 28 and to Week 36 in acetylcholine receptor (AChR/MuSK) antibody titre
• Change from baseline to Week 8, Week 24, Week 28 and Week 36 in B cell and T cell subsets
Safety
• Frequency and severity of adverse events (AEs)
• Frequency of serious adverse events (SAEs)
• Percentage of subjects withdrawing due to AEs
• Percentage of subjects with drug-related AEs
• Change from baseline in vital signs.
• Frequency of vital signs of clinical concern
• Change from baseline in hematology and chemistry parameters.
• Frequency of hematology and chemistry parameters of potential clinical concern
• Percentage of subjects withdrawing from study due to MG worsening/exacerbation
• Percentage of subjects withdrawing from the study due to MG improvement and the
need to decrease dose of MG concomitant medications more than allowed per protocol.
• Percentage of subjects that decrease dose of MG concomitant medications due to MG improvement (regardless of withdrawal status).
• Incidence of positive immunogenicity demonstrating the presence of anti-belimumab
antibodies.

E.5.2.1

Timepoint(s) of evaluation of this end point

QMG:Mean change from baseline for QMG score at:
wk4, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk36.
MG Composite (MGC) Score:Mean change from baseline for MGC score at wk2, wk4, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk36.
MGFA Post-Intervention Status: wk12, wk24, wk 36
MG Activities of Daily Living Scale (MG-ADL):
wk4, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk36.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

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)

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

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)

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Germany

Italy

United States

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

last subject’s last safety visit (16 week post last dose)

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