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

NCT01751776 | Completed Phase 1 Results

• 2 other identifiers: 1293.22012-004090-16
• Study Type: interventional
• Target: 107
• Locations: 6 countries
• Sites: 25

Brief Summary

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

Conditions

Arthritis, Rheumatoid; Healthy

Outcome Measures

Primary Outcomes (5)

• Part 1: Cmax After the First and Last Dose

  Part 1: This outcome measure presents the maximum measured concentration of BI 655064 in plasma (Cmax) after the first and last (fourth) dose. More detailed time frame: Pharmacokinetic (PK) sample times: 0:30 hour (h) prior first administration of BI 655064 and 1 h, 8 h, 12 h, 24 h, 48 h, 72 h, 84 h, 96 h, 108 h, 120 h, 144 h, 167:30 h, 335:30 h, 503:30 h, 505 h, 516 h, 528 h, 552 h, 576 h, 600 h, 624 h, 648 h, 672 h, 696 h, 744 h, 816 h, 912 h, 1008 h, 1176 h, 1344 h, 1512 h, 1848 h thereafter; further administration times for BI 655064: 168 h, 336 h, and 504 h after first administration.

  From first day of drug administration till end of trial, up to 77 days. Detailed PK can be found in the endpoint description.

• Part 1: AUC 0-infinity After the Last Dose

  Part 1: Area under the concentration-time curve of BI 655064 in plasma over the time interval from 0 extrapolated to infinite (AUC 0-infinity).

  PK sample times: 1 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, 312 h, 408 h, 504 h, 672 h, 840 h, 1008 h, 1344 h after the last administration of BI 655064 on day 22

• Part 1: AUCtau After the Last Dose

  Area under the concentration-time curve of BI 655064 in plasma after the 4th dose over a uniform dosing interval t (AUC t,4) after the first and 4th dose. AUCtau is synonymous with AUC0-168.

  PK sample times: 1 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, 312 h, 408 h, 504 h, 672 h, 840 h, 1008 h, 1344 h after the last administration of trial drug on day 22

• Part 1: Percentage of Subjects With Drug Related Adverse Events

  In Part 1 (Phase Ib): The primary safety endpoint was the percentage of subjects with AEs related to treatment with trial medication.

  from first administration of study medication (day 1) up to day 64 (dosing groups 80, 120, 180mg) or up to day 78 post-treatment (dosing group 240mg)

• Part 2: American College of Rheumatology (ACR)20 Response Rate at Week 12

  ACR 20 criteria at week 12 relative to the patient's status at baseline: that is, at least 20 percent (%) improvement in swollen joint count, at least 20% improvement in tender joint count, and at least 20% improvement in ≥3 of the following 5 variables: 1) patient's assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient's global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator's global assessment of disease on the VAS; 4) patient's assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better. The ACR20 were evaluated descriptively. The data were analysed with a Bayesian approach using an informative prior for the placebo treatment group; predictive probability that the treatment difference was larger than 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% was to be evaluated.

  at week 12 (day 85) from the initiation of study treatment

Secondary Outcomes (6)

• Part 2: ACR50 Response Rates at Week 12

  at week 12 (day 85)

• Part 2: ACR70 Response Rates at Week 12

  at week 12 (day 85)

• Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12

  baseline (day 1) and week 12 (day 85)

• Part 2: EULAR DAS28-ESR at Week 12

  baseline (day 1) and week 12 (day 85)

• Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12

  baseline (day 1) and week 12 (day 85)

Study Arms (8)

Part 1, Placebo BI 655064 80/120mg (HV)

PLACEBO COMPARATOR

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Drug: Placebo matching BI 655064

Part 1, Placebo BI 655064 180/240mg (HV)

PLACEBO COMPARATOR

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 180 or 240 mg injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks (180mg dosing group) or 8 weeks (240mg dosing group) follow-up period.

Drug: Placebo matching BI 655064

Part 1, BI 655064 80mg (HV)

EXPERIMENTAL

Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Drug: BI 655064

Part 1, BI 655064 120mg (HV)

EXPERIMENTAL

Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Drug: BI 655064

Part 1, BI 655064 180mg (HV)

EXPERIMENTAL

Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Drug: BI 655064

Part 1, BI 655064 240mg (HV)

EXPERIMENTAL

Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period.

Drug: BI 655064

Part 2, Placebo BI 655064 120mg (RA)

PLACEBO COMPARATOR

Part 2, patients with Rheumatoid arthritis (RA) who had prior inadequate response to Methotrexat (MTX) therapy: Placebo matching BI 655064 120 milligram (mg) injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Drug: Placebo matching BI 655064

Part 2, BI 655064 120mg (RA)

EXPERIMENTAL

Part 2, patients with RA who had prior inadequate response to MTX therapy: 120 milligram (mg) of BI 655064 injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Drug: BI 655064

Interventions

Placebo matching BI 655064 DRUG

Placebo matching BI 655064 injected subcutaneous.

Part 1, Placebo BI 655064 180/240mg (HV); Part 1, Placebo BI 655064 80/120mg (HV); Part 2, Placebo BI 655064 120mg (RA)

BI 655064 DRUG

BI 655064 injected subcutaneous

Part 1, BI 655064 120mg (HV); Part 1, BI 655064 180mg (HV); Part 1, BI 655064 240mg (HV); Part 1, BI 655064 80mg (HV); Part 2, BI 655064 120mg (RA)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part 1 (phase Ib) (HVs):
• 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
• Age \>= 18 and \<= 60 years
• Body Mass Index \>= 18.5 and \<= 29.9 kg/m2
• Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation
• 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):
• Age \>= 18 and \<= 70 years
• Patients classified as having RA according to the 1987 ACR Classification Criteria
• 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.

You may not qualify if:

• Part 1 (phase Ib in HVs):
• Any finding in the medical examination (including BP, PR or ECG) deviating from normal and judged clinically relevant by the investigator
• Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
• Any evidence of a concomitant disease judged clinically relevant by the investigator
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders
• History of relevant orthostatic hypotension, fainting spells, or blackouts
• History of relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients)
• Part 2 (phase IIa in RA patients):
• 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.
• 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.
• DAS28 \< 3.2 in at least 2 occasions during the last 6 months before screening
• 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
• Treatment with any standard DMARD except MTX (including but not limited to sulfasalazine, leflunomide, hydroxychloroquine, D-penicillamine
• Impaired hepatic function, defined as serum AST/ALT, bilirubin or alkaline phosphatase levels \> 2 x ULN

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (25)

1293.2.00049 Boehringer Ingelheim Investigational Site

Olomouc, Czechia

Location

1293.2.00024 Boehringer Ingelheim Investigational Site

Uherské Hradiště, Czechia

Location

1293.2.00028 Boehringer Ingelheim Investigational Site

Zlín, Czechia

Location

1293.2.00015 Boehringer Ingelheim Investigational Site

Bad Kreuznach, Germany

Location

1293.2.00010 Boehringer Ingelheim Investigational Site

Berlin, Germany

Location

1293.2.00013 Boehringer Ingelheim Investigational Site

Berlin, Germany

Location

1293.2.00043 Boehringer Ingelheim Investigational Site

München, Germany

Location

1293.2.00012 Boehringer Ingelheim Investigational Site

Zerbst, Germany

Location

1293.2.00031 Boehringer Ingelheim Investigational Site

Amsterdam, Netherlands

Location

1293.2.00032 Boehringer Ingelheim Investigational Site

Leeuwarden, Netherlands

Location

1293.2.00038 Boehringer Ingelheim Investigational Site

Leiden, Netherlands

Location

1293.2.00040 Boehringer Ingelheim Investigational Site

Sneek, Netherlands

Location

1293.2.00001 Boehringer Ingelheim Investigational Site

Grafton Auckland NZ, New Zealand

Location

1293.2.00039 Boehringer Ingelheim Investigational Site

Bialystok, Poland

Location

1293.2.00034 Boehringer Ingelheim Investigational Site

Bydgoszcz, Poland

Location

1293.2.00041 Boehringer Ingelheim Investigational Site

Bydgoszcz, Poland

Location

1293.2.00025 Boehringer Ingelheim Investigational Site

Lublin, Poland

Location

1293.2.00050 Boehringer Ingelheim Investigational Site

Poznan, Poland

Location

1293.2.00023 Boehringer Ingelheim Investigational Site

Warsaw, Poland

Location

1293.2.00026 Boehringer Ingelheim Investigational Site

Warsaw, Poland

Location

1293.2.00021 Boehringer Ingelheim Investigational Site

A Coruña, Spain

Location

1293.2.00017 Boehringer Ingelheim Investigational Site

Barcelona, Spain

Location

1293.2.00022 Boehringer Ingelheim Investigational Site

Granada, Spain

Location

1293.2.00016 Boehringer Ingelheim Investigational Site

La Laguna (Sta Cruz Tenerife), Spain

Location

1293.2.00020 Boehringer Ingelheim Investigational Site

Santiago de Compostela, Spain

Location

Related Publications (1)

• Visvanathan S, Daniluk S, Ptaszynski R, Muller-Ladner U, Ramanujam M, Rosenstock B, Eleftheraki AG, Vinisko R, Petrikova A, Kellner H, Dokoupilova E, Kwiatkowska B, Alten R, Schwabe C, Baum P, Joseph D, Fine JS, Padula SJ, Steffgen J. Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study. Ann Rheum Dis. 2019 Jun;78(6):754-760. doi: 10.1136/annrheumdis-2018-214729. Epub 2019 Mar 22.

  PMID: 30902820 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

BI 655064

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2012
• First Posted: December 18, 2012
• Study Start: December 18, 2012
• Primary Completion: March 2, 2015
• Study Completion: April 27, 2015
• Last Updated: March 21, 2024
• Results First Posted: March 21, 2024

Record last verified: 2023-09

Locations

NZ (1); CZ (3); PL (7); ES (5); NL (4); DE (5)