Clinical Trials Register

Summary
EudraCT Number:	2012-002181-12
Sponsor's Protocol Code Number:	MK-8457-010
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:	2012-09-24
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

2012-002181-12

A.3

Full title of the trial

A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects with Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-α Therapy

Et fase IIa, randomiseret, dobbeltblindet, placebokontrolleret, parallel-gruppe, verdensomspændende "bevis-for-effekt" (Proof-of-Concept) klinisk multicenterforsøg med, der vurderer sikkerhed, tolerance og effekt af MK-8457 til patienter med aktiv leddegigt

A.3.1

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

A Phase IIa POC study to evaluate Safety, Tolerability and Efficacy in Subjects with RA

Et forsøg med SYK-hæmmer til forsøgspersoner med leddegigt, der ikke mere har tilstrækkelig effekt af TNF-α hæmmere.

A.3.2

Name or abbreviated title of the trial where available

RADIUS-010

A.4.1

Sponsor's protocol code number

MK-8457-010

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., Inc. (hereafter referred to as
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	Merck
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	Merck
B.5.2	Functional name of contact point	Global Clinical Trials Operations (
B.5.3	Address:
B.5.3.1	Street Address	One Merck Drive, P.O. Box 100
B.5.3.2	Town/ city	Whitehouse Station, NJ
B.5.3.3	Post code	08889-0100
B.5.3.4	Country	United States
B.5.4	Telephone number	908740-7324
B.5.6	E-mail	Haoling.weng@merck.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	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	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.3.9.2	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.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

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

Kronisk leddegigt

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis due to overactive immune system

Kronisk 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	15.0
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 effects of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment as measured by ACR20 response.
- To determine the safety and tolerability of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment.

- at sammenholde effekterne af MK-8457 100 mg to gange daglig med placebo over en 12 ugers behandling, målt ved ACR20 respons.
- at sammenholde sikkerhed og tolerabilitet af MK-8457 100 mg to gange daglig med placebo over en 12 ugers behandling.

E.2.2

Secondary objectives of the trial

Key Secondary: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by ACR20 at Week 24; DAS28CRP change from baseline at Week 12; and ACR50 at Week 12.

- Base Study: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by change from baseline in DAS28CRP at Week 24; ACR50 at Week 24; and HAQ change from baseline at Weeks 12 and 24.

Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period through Week 100.

At sammenholde effekterne af MK-8457 100 mg to gange daglig med placebo målt ved ACR20 ved uge 24; DAS28CRP ændringer fra baseline ved uge 12; og ACR50 ved uge 12.

- Hovedstudiet: at sammenholde effekterne af MK-8457 100 mg to gange daglig med placebo målt ved ændringer fra baseline i DAS28CRP ved uge 24; ACR50 ved uge 24; og HAQ ændringer fra baseline ved ugerne 12 og 24.

- Sikkerhedsforlængelsen: At vurdere sikkerhed og tolerabilitet for MK-8457 i løbet af sikkerhedsforlængelsen op til uge 100

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• 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.
• Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject’s dose of weekly MTX must remain stable through week 24 of the study.
• Subject must have either failed treatment with 1 or 2 anti-TNFtherapies or was intolerant to anti-TNFtherapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF therapies must have been for at least 3 months.

Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator’s assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response

• Personen er diagnosticeret med kronisk leddegigt mindst 6 måneder før screening.
• Personen har 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).
• Personen har et C-reaktivt protein (CRP) niveau > 0.9 mg/dl målt af et centralt laboratorium ved screening.
• Personen er anti-cyclic citrullinated antibody positiv og/eller rheumatoid factor positiv ved screening.
• Personen er ACR functional Class I, II, or III.
• Personen har fået behandling med methotrexat i mindst 3 måneder inden screening med en passende stabil ugentlig dosis i mindst 4 uger inden screening (15-25 mg/ugentlig for regioner udenfor Asien og 6-25 mg/ugentlig for Asien). Deltagerens dosis for den ugentlige methotrexat skal være stabil helt til uge 24 i forsøget.
• Personen har ikke haft effekt med 1 ellerr 2 anti-TNF-alfa behandlinger eller kunne ikke tåle anti-TNF-alfa behandling før screening. For personeer, der ikke havde effekt skal behandlingen med anti-TNF-alfa behandlingen have pågået i mindst 3 måneder.

NB: Den manglende effekt eller intolerancen over for anti-TNF-alfa behandlingen vurderes af Investigator og vil blive dokumenteret. Typisk vil manglende effekt være baseret på kliniske grunde (eksempelvis ingen bedring eller forværring af leddegigten). At der ikke adgang til medicinen rent praktisk eller økonomisk anses ikke for at være manglende effekt)

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 any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA.

• Subject has received any treatment (listed in the table below) more recently than the indicated washout period prior to randomization.
Washout Period for Medications Prior to Randomization

Medications, Supplements, and Other Substances Washout Period Prior to Randomization
Anti-TNF-α Therapies:
Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
8 weeks
8 weeks
4 weeks
8 weeks
8 weeks
Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine 4 weeks
Leflunomide² 8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required.
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

1 Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of ≤10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications.
2 Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment.

• Forsøgspersonen har anden inflammatorisk sygdom end leddegigt, inkl. men ikke begrænset til psoriasisgigt, aktiv rygsøjlegigt, systemisk lupus erythematosus eller Lymes sygdom.
• Tidligere behandling med fostamatinib eller andre splenisk tyrosine kinase (SYK) hæmmere.
• Tidligere behandlet med et hvilket som helst biologisk produkt med ud over anti-TNF produkter, inkl. men ikke begrænset til abatacept, tocilizumab, rituximab eller andre biologiske produkter til behandling af leddegigt.
• Personen er blevet behandlet med en hvilken som helst af nedenstående stoffer indenfor udvaskningsperioden før randomisering.
Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine
Leflunomide²
Cytotoxic stoffer inkl. chlorambucil, cyclophosphamid, nitrogen mustard, eller andre alkylerende stoffer
Vaccination med levende microorganismer
Forsøgslægemidler
Bacille Calmette-Guerin (BCG) vaccination

1 Det er tilladt for forsøgsdeltagerne at tage stabile doser af perorale corticosteroider: forsøgsdeltagerne kan være på stabil dosis ≤10 mg prednison daglig (eller tilsvarende) i mindst 2 uger inden første dosis af studie-medicinen.
2 Det er tilladt for forsøgsdeltagere at bruge leflunomid i stedet for methotrexat på eller efter uge 24 af studie-medicineringen.

E.5 End points

E.5.1

Primary end point(s)

• The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
The primary safety endpoints are:
• Percentage of subjects with adverse experiences;
• Change from baseline in laboratory parameters;
• Change from baseline in vital signs parameters;
• Change in blood pressure from predose to 1 hour, 2 hours and 3 hours after the morning study drug dose at Week 2 and Week 12; and
• Average change in blood pressure from predose in the 3 hours time period after am study drug dose at Week 2 and Week 12

• Det primære effekt-endepunkt er anddelen af deltagere der når ACR20 respons ved uge 12.
De primære sikkerhedsendepunkt er:
• Procentdelen af deltagere med uønskede hændelser;
• Ændring fra baseline i laboratorium-parametre;
• Ændring fra baseline i vital signs parametre;
• Ændring i blodtryk fra før dosering til 1 time, 2 timer og 3 timer efter dosering af studiemedicinen om morgenen ved uge 2 og uge 12
• Gennemsnitlig ændring i blodtryk fra før dosering i den 3 timers periode efter morgen-doseringen af studiemedicinen ved uge 2 og uge 12

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

Uge 12

E.5.2

Secondary end point(s)

The key secondary efficacy endpoints are:

• Proportion of subjects achieving ACR20 response at Week 24;
• Change from baseline in DAS28CRP at Week 12; and
• Proportion of subjects achieving ACR50 response at Week 12.

Other secondary efficacy endpoints that will be evaluated include:
• Change from baseline in DAS28CRP at Week 24;
• Proportion of subjects achieving ACR50 response at Week 24; and
• Change from baseline in HAQ at Weeks 12 and 24.
Safety endpoints will also be evaluated through Week 100 of the safety extension.

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 12 and 24

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

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

Yes

E.8.2.3.1

Comparator description

Alle patienter vil tage baggrundsmedicin: methotrexat

All patients will take background methotrexate (MTX).

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

Australia

Brazil

Colombia

Denmark

France

Greece

Hungary

Italy

New Zealand

Peru

Poland

South Africa

Spain

Sweden

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

LVLS (Post-Study Visit is the scheduled last visit for patients.)

Sidste besøg for sidste deltager (post-studie-besøget er det sidste besøg for deltagerne)

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:

178

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

F.4.2.2

In the whole clinical trial

178

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)

No additional follow up monitoring or treatment is planned after the patient completes the Post-Study Visit, performed 14 days after the last dose of study medication.

Der vil ikke være nogen opfølgning eller planlagt behandling efter at patienten har gennemført det opfølgende/afsluttende besøg 14 dage efter sidste dosis af studiemedicinen.

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

2012-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-24

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-10-08

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