Clinical Trials Register

Summary
EudraCT Number:	2012-000439-17
Sponsor's Protocol Code Number:	MK-8457-008
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-06-15
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

Denmark - DHMA

A.2

EudraCT number

2012-000439-17

A.3

Full title of the trial

A Phase II, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Dose-Ranging Clinical Trial with a Proof-of-Concept Lead Cohort to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 + MTX in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy

Et randomiseret, dobbeltblindt, placebokontrolleret, verdensomspændende, dosisbestemmende klinisk multicenterforsøg i fase II med parallelle grupper med en bevis-for-effekt ledende kohorte, der vurderer sikkerhed, tolerance og effekt af MK-8457 + MTX til patienter med aktiv kronisk leddegigt på trods af behandling med methotrexat

A.3.1

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

A Study to Evaluate Safety, Tolerability and Effecacy of MK-8457 plus Methotrexate in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy

Et forsøg som undersøger sikkerhed, tolerance samt effekt af MK-8457 plus methotrexat til patienter med aktiv kronisk leddegigt, som tidligere er behandlet med methotrexat

A.3.2

Name or abbreviated title of the trial where available

Proof-of-Concept of MK-8457 in patients with Rheumatoid Arthritis

A.4.1

Sponsor's protocol code number

MK-8457-008

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,
B.1.3.4	Country	United States
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MSD Danmark ApS
B.5.2	Functional name of contact point	GCTO
B.5.3	Address:
B.5.3.1	Street Address	Lautrupbjerg 4
B.5.3.2	Town/ city	Ballerup
B.5.3.3	Post code	2750
B.5.3.4	Country	Denmark
B.5.4	Telephone number	454482 4000
B.5.5	Fax number	454482 4099

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	No
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	MK-8457
D.3.2	Product code	MK-8457
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	MK-8457
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	25
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	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	No
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	MK-8457
D.3.2	Product code	MK-8457
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	MK-8457
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	100
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	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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

active rheumatoid arthritis

Aktiv leddegigt

E.1.1.1

Medical condition in easily understood language

arthritis due to overactive immune system

leddegigt grundet overaktivt immunsystem

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the optimal dose of MK-8457 + MTX as compared to placebo + MTX, as demonstrated the RA subjects who achieve ACR20 (American College of Rheumatology 20) response after 24 weeks of treatment.

At finde den optimale dosis for MK-8457+methotrexat sammenlignet med placebo+methotrexat hos patienter med leddegigt som opnår ACR20 (American College of Rheumatology 20) respons efter 24 ugers behandling

E.2.2

Secondary objectives of the trial

To determine the effects of 24 weeks of treatment with MK-8457 100 mg BID + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, ACR-N, change from baseline in individual ACR components, DAS28CRP, DAS28ESR (DAS28 response, DAS28 remission, and change from baseline) DAS-AUC, Simplified Disease Activity Index (SDAI), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), change from baseline in Hemoglobin; (2) To determine the effects of 24 weeks of treatment with all other doses of MK-8457 + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, and change from baseline in individual ACR components, DAS28, SDAI, ESR, CRP, SF-36, HAQ, and FACIT-F.

(1) At vurdere effekt af 24 ugers behandling med MK-8457 100 mg daglig+methotrexat sammenlignet med placebo+methotrexat på følgende endepunkter ACR50, ACR70, hybrid ACR respons, ACR-N, ændring fra baseline for individuelle ACR komponenter, DAS28CRP, DAS28ESR (DAS28 respons, DAS28 remission, og ændring fra baseline) DAS-AUC, Simplified Disease Activity Index (SDAI), Erytrocyt-Sedimentations Rate (ESR), C-reaktivt protein (CRP), Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ) og Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), ændring fra baseline i hæmoglobin;
(2) At vurdere effekten af 24 ugers behandling med alle andre doser af MK-8457+methotrexat sammenlignet med placebo+methotrexat på følgende endepunkter: ACR50, ACR70, hybrid ACR respons, ændring fra baseline for individuelle ACR komponenter, DAS28, SDAI, ESR, CRP, SF-36, HAQ og FACIT-F.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

To determine the effects of 24 weeks of treatment with MK-8457 100 mg BID + MTX compared to placebo + MTX on bone erosions, periarticular bone edema, synovitis, and other articular parameters in Magnetic Resonance Imaging (MRI) studies of selected joints.

At vurdere effekten af 24 ugers behandling med MK-8457 100 mg daglig+methotrexat sammenlignet med placebo+methotrexat på knogle-erosioner, periartikulær knogleødem, synovitis og andre artikulære parametre i MRI undersøgelser af udvalgte led.

E.3

Principal inclusion criteria

• Subject must be ≥18 years of age on the day of signing the informed consent.
RA diagnosis and disease activity:
• Subject has a diagnosis of RA for at least 6 months prior to screening.
• Subject has active RA as defined by the presence of 6 swollen joints (of 66 joint count) AND 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2).
• Subject has a C-reactive protein (CRP) blood level > 0.9 mg/dL from the central reference laboratory at screening.
• Subject is anti-cyclic citrullinated antibody positive and/or rheumatoid factor positive at screening.
• Subject is ACR functional Class I, II, or III.
• Subjects has received MTX for a minimum of 3 months with a regionally appropriate stable weekly dose (15-25 mg/wk for regions outside of Asia, 6–16 mg/week for Asia) for at least 4 wks prior to entering study.

Forsøgsdeltagere skal opfylde følgende kriterier for at kunne deltage:
Skal være fyldt 18 år. Have fået diagnosen leddegigt, mindst 6 måneder inden screeningen. Have aktiv leddegigt som defineres ved tilstedeværelse af 6 hævede led (af 66 vurderede led) OG 6 ømme led (af 68 vurderede led) ved screeningen (besøg 1) og baseline (besøg 2). Have fået behandling med methotrexat i mindst 3 måneder. Har ingen ubehandlet latent eller aktiv tuberkulose i anamnesen inden baseline. Forstår formålet og risiciene ved forsøget, er villig og i stand til at overholde protokollen. Må ikke have en anden klinisk signifikant sygdom eller situation end leddegigt, som vil påvirke forsøgsvurderingerne eller optimal deltagelse i forsøget. En forsøgsperson der er i stand til at få børn, skal indvillige i at anvende 2 acceptable præventionsmetoder. Forsøgspersonens laboratorieprøver ved screening, skal ligge inden for bestemte parametre.

E.4

Principal exclusion criteria

• Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease.
• Previous exposure to fostamatinib or other splenic tyrosine kinase (SYK) inhibitors.
• Previous exposure to TNF-alpha targeted therapy or any biological agents for RA.
• Subject has received any treatment listed below more recently than the indicated washout period prior to Screening.
Prohibited Medications, Supplements, and Other Substances Washout Period Prior to Screening
Disease modifying anti-rheumatic drugs such as but not limited to (not including cytotoxic agents):
Leflunomide, cyclosporine, mycophenolate mofetil, azathioprine, corticosteroids (parenteral, intra-articular), sulfasalazine, hydroxychloroquine 30 days (8 weeks for leflunomide unless subject undergoes standard cholestyramine or activated charcoal washout)
Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months
Live vaccinations 1 month
Investigational medications 30 days or 5 half lives of the investigational agent whichever is longer
Bacille Calmette-Guerin (BCG) vaccination 1 month

Følgende kriterier vil udelukke forsøgsdeltagere for at deltage:
Forsøgspersonen har anden inflammatorisk sygdom end leddegigt. Har tegn eller symptomer på svær, progressiv eller ukontrolleret renal, hepatisk, hæmatologisk, endokrin, pulmonal, kardial, neurologisk eller cerebral sygdom. Har gennemgået en organtransplantation. Har haft en tidligere malignitet eller samtidig malignitet (bortset fra basalcellekarcinom og pladecellekarcinom in situ i huden). Har et positivt testresultat for hepatitis B-overfladeantigen eller hepatitis C. Vides at være HIV-positiv. Har klinisk signifikante unormale laboratorieværdier for sikkerhedsmæssige laboratorietest inden forsøget/screening.

E.5 End points

E.5.1

Primary end point(s)

American College of Rheumatology 20 (ACR20) response

American College of Rheumatology 20 (ACR20) respons

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

24 uger

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.7.1

Other trial design description

Adaptive Design

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

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

Brazil

Canada

Chile

Denmark

Germany

Hungary

India

Japan

Korea, Democratic People's Republic of

Lithuania

Mexico

Moldova, Republic of

Peru

Poland

Russian Federation

South Africa

Taiwan

United Kingdom

United States

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 patient last visit

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:

419

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.4.2

For a multinational trial

F.4.2.1

In the EEA

116

F.4.2.2

In the whole clinical trial

342

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)

RA subjects ending participation in the study will be treated per their physician.

Leddegigtpatienter, der træder ud af studiet vil blive behandlet efter deres læges ordination.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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