Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effects of Multiple Rising Subcutaneous Doses of BI 655064 in Healthy Volunteers and in Rheumatoid Arthritis Patients With Prior Inadequate Response to Methotrexate Therapy

• Register: ClinicalTrials.gov
• Last refreshed on: 25 May 2015
• Main ID: NCT01751776
• Date of registration: 14/12/2012
• Prospective Registration: No
• Primary sponsor: Boehringer Ingelheim
• Public title: Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effects of Multiple Rising Subcutaneous Doses of BI 655064 in Healthy Volunteers and in Rheumatoid Arthritis Patients With Prior Inadequate Response to Methotrexate Therapy
• Scientific title: 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
• Date of first enrolment: December 2012
• Target sample size: 107
• Recruitment status: Completed
• URL: http://clinicaltrials.gov/show/NCT01751776
• Study type: Interventional
• Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
• Phase: Phase 1

Countries of recruitment

Czech Republic, Germany, Netherlands, New Zealand, Poland, Romania, Spain

Contacts

• Name: Boehringer Ingelheim
• Affiliation: Boehringer Ingelheim

Key inclusion & exclusion criteria

Inclusion criteria:

Part 1 (phase Ib) (HVs):

1. Healthy males and females according to the investigators 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 (phase IIa) (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

Exclusion criteria:

Part 1 (phase Ib in 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)

9. Within 10 days prior to administration of trial medication, use of drugs that might
reasonably influence the results of the trial 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 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

Further exclusion criteria applicable for part 1 only are given in the CTP.

Part 2 (phase IIa in RA patients):

Part 1 (phase Ib) 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

4. RA patients with severe disability (func


Age minimum: 18 Years
Age maximum: 70 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Healthy

Arthritis, Rheumatoid

Intervention(s)

Drug: BI 655064 low dose

Drug: Placebo

Drug: BI 655064 medium dose

Drug: BI 655064 high dose

Primary Outcome(s)

Primary PK endpoint (Part 1): AUC 0-infinity (Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinite) [Time Frame: Up to Day 64 post-treatment]

Primary PK endpoint (Part 1): AUC t,4 (Area under the concentration-time curve of the analyte in plasma after the 4th dose over a uniform dosing interval t) after the first and 4th dose) [Time Frame: Up to Day 64 post-treatment]

ACR20 (American College of Rheumatology) response rate at week 12 (day 85) from the initiation of study treatment (Part 2) [Time Frame: week 12]

Number of subjects with drug related Adverse Events (Part 1). [Time Frame: Up to Day 64 post-treatment]

Primary PK endpoint (Part 1): Cmax (after first and 4th dose) [Time Frame: up to Day 64 post-treatment]

Secondary Outcome(s)

Change in DAS28-4v at week 12 (day 85) compared to baseline (Part 2) [Time Frame: baseline and week 12]

Percentage of patients with a decrease in DAS28 4v-CRP of >1.2 at week 12 (day 85) compared to baseline (Part 2) [Time Frame: baseline and week 12]

EULAR (European League Against Rheumatism) response criteria (DAS28 4v-CRP and DAS 28 4v-ESR) at week 12 (day 85) (Part 2) [Time Frame: week 12]

ACR50 and 70 response rates at week 12 (day 85) (Part 2) [Time Frame: week 12]

Secondary ID(s)

2012-004090-16

1293.2

Source(s) of Monetary Support

Please refer to primary and secondary sponsors