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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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Boehringer Ingelheim
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01751776
First received: December 14, 2012
Last updated: November 19, 2014
Last verified: November 2014
  Purpose

To evaluate the safety and tolerability of multiple doses of BI 655064 administered subcutaneously in healthy volunteers (HVs) and in rheumatoid arthritis (RA) patients. To explore the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of multiple doses of BI 655064 in healthy volunteers (HVs) and rheumatoid arthritis (RA) patients. To assess clinical effect of BI 655064 in RA patients with prior inadequate response to methotrexate (MTX) after 12 weeks of treatment


Condition Intervention Phase
Arthritis, Rheumatoid
Healthy
Drug: BI 655064 medium dose
Drug: BI 655064 high dose
Drug: Placebo
Drug: BI 655064 low dose
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Primary PK endpoint (Part 1): Cmax (after first and 4th dose) [ Time Frame: up to Day 64 post-treatment ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Number of subjects with drug related Adverse Events (Part 1). [ Time Frame: Up to Day 64 post-treatment ] [ Designated as safety issue: No ]
  • ACR20 (American College of Rheumatology) response rate at week 12 (day 85) from the initiation of study treatment (Part 2) [ Time Frame: week 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • ACR50 and 70 response rates at week 12 (day 85) (Part 2) [ Time Frame: week 12 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Change in DAS28-4v at week 12 (day 85) compared to baseline (Part 2) [ Time Frame: baseline and week 12 ] [ Designated as safety issue: No ]

Estimated Enrollment: 106
Study Start Date: December 2012
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BI 655064 Part 1
3 different doses plus placebo in healthy volunteers
Drug: BI 655064 medium dose
Medium dose
Drug: BI 655064 high dose
High dose
Drug: Placebo
Placebo
Drug: BI 655064 low dose
Low dose
Experimental: BI 655064 Part 2
2 different doses plus placebo in rheumatoid arthritis patients
Drug: BI 655064 high dose
High dose
Drug: Placebo
Placebo
Drug: BI 655064 medium dose
Medium dose

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 (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
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01751776

Contacts
Contact: Boehringer Ingelheim Call Center 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com

Locations
Czech Republic
1293.2.00049 Boehringer Ingelheim Investigational Site Recruiting
Olomouc, Czech Republic
1293.2.00024 Boehringer Ingelheim Investigational Site Recruiting
Uherske Hradiste, Czech Republic
1293.2.00028 Boehringer Ingelheim Investigational Site Recruiting
Zlin, Czech Republic
Germany
1293.2.00015 Boehringer Ingelheim Investigational Site Recruiting
Bad Kreuznach, Germany
1293.2.00014 Boehringer Ingelheim Investigational Site Recruiting
Bad Nauheim, Germany
1293.2.00010 Boehringer Ingelheim Investigational Site Recruiting
Berlin, Germany
1293.2.00013 Boehringer Ingelheim Investigational Site Recruiting
Berlin, Germany
1293.2.00037 Boehringer Ingelheim Investigational Site Recruiting
Hamburg, Germany
1293.2.00035 Boehringer Ingelheim Investigational Site Recruiting
Köln, Germany
1293.2.00043 Boehringer Ingelheim Investigational Site Recruiting
München, Germany
1293.2.00012 Boehringer Ingelheim Investigational Site Recruiting
Zerbst, Germany
Netherlands
1293.2.00031 Boehringer Ingelheim Investigational Site Recruiting
Amsterdam, Netherlands
1293.2.00032 Boehringer Ingelheim Investigational Site Recruiting
Leeuwarden, Netherlands
1293.2.00038 Boehringer Ingelheim Investigational Site Recruiting
Leiden, Netherlands
1293.2.00040 Boehringer Ingelheim Investigational Site Recruiting
Sneek, Netherlands
New Zealand
1293.2.00001 Boehringer Ingelheim Investigational Site Recruiting
Grafton Auckland NZ, New Zealand
Poland
1293.2.00039 Boehringer Ingelheim Investigational Site Recruiting
Bialystok, Poland
1293.2.00034 Boehringer Ingelheim Investigational Site Recruiting
Bydgoszcz, Poland
1293.2.00041 Boehringer Ingelheim Investigational Site Recruiting
Bydgoszcz, Poland
1293.2.00025 Boehringer Ingelheim Investigational Site Recruiting
Lublin, Poland
1293.2.00050 Boehringer Ingelheim Investigational Site Recruiting
Poznan, Poland
1293.2.00023 Boehringer Ingelheim Investigational Site Recruiting
Warsaw, Poland
1293.2.00026 Boehringer Ingelheim Investigational Site Recruiting
Warszawa, Poland
Spain
1293.2.00021 Boehringer Ingelheim Investigational Site Recruiting
A Coruña, Spain
1293.2.00017 Boehringer Ingelheim Investigational Site Recruiting
Barcelona, Spain
1293.2.00019 Boehringer Ingelheim Investigational Site Recruiting
El Palmar - Murcia, Spain
1293.2.00022 Boehringer Ingelheim Investigational Site Recruiting
Granada, Spain
1293.2.00016 Boehringer Ingelheim Investigational Site Recruiting
La Laguna (Sta Cruz Tenerife), Spain
1293.2.00042 Boehringer Ingelheim Investigational Site Recruiting
Sabadell, Spain
1293.2.00020 Boehringer Ingelheim Investigational Site Recruiting
Santiago de Compostela, Spain
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01751776     History of Changes
Other Study ID Numbers: 1293.2, 2012-004090-16
Study First Received: December 14, 2012
Last Updated: November 19, 2014
Health Authority: Australia: Human Research Ethics Committee
Czech Republic: State Institute for Drug Control
Germany: Paul-Ehrlich-Institut
Netherlands: Central Committee Research Involving Human Subjects
New Zealand: Medsafe
Poland: Registration Medicinal Product Medical Device Biocidal Product
Spain: Spanish Agency of Medicines

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014