Clinical Trials Register

Summary
EudraCT Number:	2012-004090-16
Sponsor's Protocol Code Number:	1293.2
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:	2012-11-06
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

2012-004090-16

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled trial for establishing safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of multiple subcutaneous doses of BI 655064 in healthy volunteers and in rheumatoid arthritis patients with prior inadequate response to methotrexate therapy

A.3.1

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

Safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects of multiple rising subcutaneous doses of BI655064 in healthy volunteers and in rheumatoid arthritis patients with prior inadequate response to methotrexate therapy.

A.4.1

Sponsor's protocol code number

1293.2

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	Boehringer Ingelheim Pharma GmbH & Co. KG
B.1.3.4	Country	Germany
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	Boehringer Ingelheim Pharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+18002430127
B.5.5	Fax number	+18008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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.3.2	Product code	BI 655064
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BI 655064
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	120
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)	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	Yes
D.3.11.13.1	Other medicinal product type	humanized antibody

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 injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid arthritis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

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 evaluate the safety and the systemic and local tolerability of repeated doses of BI 655064 (120 mg/mL in buffer solution for injection), administered s.c. at doses of 80, 120, 180 and 240 mg every week in healthy volunteers (HVs) (treatment duration 4 weeks per dose group) and 120 mg every week in rheumatoid arthritis (RA) patients with prior inadequate response to methotrexate (MTX) therapy (treatment duration 12 weeks per dose group).

E.2.2

Secondary objectives of the trial

1. To evaluate PK and PD parameters of BI 655064 administered in repeated doses in HVs and in RA patients
2. To evaluate the clinical effect of BI 655064 of 120mg s.c. q1w after 12 weeks of treatment in RA patients with prior inadequate response to MTX – establishing the proof of concept in RA.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1 (HVs):
1. Healthy males and females according to the investigator’s assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests
2. Age ≥ 18 and ≤ 60 years
3. Body Mass Index ≥ 18.5 and ≤ 29.9 kg/m2
4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation
5. Female subjects who meet any of the following criteria from at least 30 days before the first study drug administration and until 30 days after trial completion: - using adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral contraceptives, intrauterine device (IUD) - sexually abstinent - have a vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) - surgically sterilised (including hysterectomy) - postmenopausal defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)

Part 2 (RA Patients):
1. Age ≥ 18 and ≤ 70 years
2. Patients classified as having RA according to the 1987 ACR Classification Criteria
3. Inadequate clinical response to methotrexate monotherapy defined as moderate/high active disease after oral or s.c. MTX treatment given continuously for at least 3 months and for the last 6 weeks before screening at a stable weekly dose ≥15mg. For patients who do not tolerate the minimum weekly dose of at least 15 mg due to side effects, a stable weekly dose as low as 7.5 mg is also permitted.
4. DAS28 4v-CRP ≥ 3.5 with ≥ 6 tender and ≥ 6 swollen joints out of 68/66 joint count at screening and confirmed by ≥ 6 tender and ≥ 6 swollen joints out of 68/66 joint count only at randomisation visit (Visit 2)
5. Serum CRP level ≥ 0.8 mg/dL or ESR ≥ 28 mm/1h at screening
6. Anti-CCP2 or Rheumatoid Factor positivity as per the limits of used assay at screening
7. Female patients who meet any of the following criteria from at least 30 days before the first study drug administration and until at least 6 months after last dose of MTX taken in the current trial:

using adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral contraceptives, intrauterine device (IUD)
- sexually abstinent
- have a vasectomised sexual partner (vasectomy at least 1 year prior
to enrolment)
- surgically sterilised (including hysterectomy)
- postmenopausal defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)

OR

Male patients who:

- are documented to be sterile or consistently and correctly use a condom while their female partners (if of childbearing potential) agree to use any of the following adequate contraception methods: implants, injectables, combined oral contraceptives, intrauterine device (IUD) from the date of screening until at least 6 months after the last dose of MTX taken in the current trial
- don’t donate any sperm sample for procreation purposes, from the date of screening until at least 6 months after last dose of MTX taken in the current trial.
8. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation

E.4

Principal exclusion criteria

Part 1 (HVs):
1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal and judged clinically relevant by the investigator
2. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
3. Any evidence of a concomitant disease judged clinically relevant by the investigator
4. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
5. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders
6. History of relevant orthostatic hypotension, fainting spells, or blackouts
7. History of relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients)
8. Intake of drugs with a long half-life (>24 hours) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication
9. Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial
10. Participation in another trial with investigational drug administration within 60 days prior to administration of trial medication
11. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes/day)
12. Alcohol abuse (consumption of more than 140 g/week in females and 210 g/week in males)
13. Drug abuse or positive drug screen
14. Blood donation (more than 100 mL within 30 days prior to administration of trial medication or intended during the trial)
15. Intention to commence new exercise regimen within one week prior to administration of trial medication or during the trial
16. Inability to comply with dietary regimen of trial site
17. Chronic or relevant acute infections, including but not limited to HIV, Hepatitis B and C and tuberculosis (including a history of clinical TB and/or a positive QuantiFERON TB-Gold test)
18. Subject is assessed by the investigator as unsuitable for inclusion e.g. considered not able to understand and comply with study requirements or has a condition that would not allow safe participation in the study
19. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion
20. Lactation

Part 2 (RA patients):
Part 1 exclusion criteria 7, 9, 12, 13 and 17-20 plus:
1. Current or previous use of more than two anti-TNF biologic drugs or use of other biologic agent targeting any other approved mechanism (any biologic drug with mechanism of action other than direct anti-TNF blockade, (e.g. CTLA4, anti-IL6, or anti CD-20) or new oral compounds targeting any other approved mechanism (e.g. JAK inhibitors) for treating RA.
2. Current or previous participation in a clinical trial testing an investigational drug for RA within 3 months prior to screening or within 5 half-lives of the investigational drug, whichever is longer , except of previous participation in trials testing NSAIDs, corticosteroids, analgesics or patients documented as receiving placebo in previous RA trials.
3. DAS28 < 3.2 in at least 2 occasions during the last 6 months before screening
Note: DAS28 results during the last 6 months before screening visit will be provided as source documents if available. However, patients with less than 2 DAS28 results available during this time will not be excluded.
4. RA patients with severe disability (functional class IV) or with confirmed severe systemic manifestations e.g. known amyloidosis, Felty´s syndrome, lymphoproliferative disorders, rheumatoid vasculitis
5. Treatment with any standard DMARD except MTX (including but not limited to sulfasalazine, leflunomide, hydroxychloroquine, D-penicillamine, azathioprine, cyclosporin, gold salts) continuing after randomisation
Note: If patient is on treatment with any other standard DMARD (except MTX) at the time of the screening visit, this should be tapered and stopped before randomisation. MTX should be continued during the screening period at a stable dose between 15-25mg per week.
6. Impaired hepatic function, defined as serum AST/ALT, bilirubin or alkaline phosphatase levels > 2 x ULN
7. Impaired renal function defined as calculated creatinine clearance < 50ml/min
8. Pre-existing blood dyscrasias e.g. bone marrow hypoplasia, significant anaemia, leucopenia or thrombocytopenia
9. Hypersensitivity to MTX or any of its excipients
10. Previous intolerance to MTX as the main cause for stopping treatment (instead of lack of efficacy)
11. Any active or suspected malignancy or history of documented malignancy within the last 5 years before screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.

E.5 End points

E.5.1

Primary end point(s)

There are no primary safety, PK, PD endpoints in a statistical sense in this study.

Primary Endpoint(s) of efficacy - Part 2:
• ACR20 response rate

E.5.1.1

Timepoint(s) of evaluation of this end point

At Week12 (Day 85) from the initiation of study treatment

E.5.2

Secondary end point(s)

• ACR50 and 70 response rates
• EULAR Response Criteria (DAS28 4v-CRP and DAS28 4v-ESR)
• Percentage of patients with a decrease in DAS28 4v-CRP of >1.2
• Change in DAS28-4v at Week 12 (Day 85) compared to baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

- At Week 12 (Day 85)
- At Week 12 (Day 85)
- At Week 12 (Day 85) compared to baseline

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Multiple rising dose in HVs

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

Multiple rising dose for Part 1

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

Czech Republic

Germany

Netherlands

New Zealand

Poland

Spain

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

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

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

Yes

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

106

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)

None.

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

2013-04-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-04-27

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