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

NCT ID: NCT01751776

Last Updated: 2024-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-12-18
• Study Completion Date: 2015-04-27

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo matching BI 655064

Intervention Type: DRUG

Placebo matching BI 655064 injected subcutaneous.

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo matching BI 655064

Intervention Type: DRUG

Placebo matching BI 655064 injected subcutaneous.

Part 1, BI 655064 80mg (HV)

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.

Group Type: EXPERIMENTAL

BI 655064

Intervention Type: DRUG

BI 655064 injected subcutaneous

Part 1, BI 655064 120mg (HV)

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.

Group Type: EXPERIMENTAL

BI 655064

Intervention Type: DRUG

BI 655064 injected subcutaneous

Part 1, BI 655064 180mg (HV)

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.

Group Type: EXPERIMENTAL

BI 655064

Intervention Type: DRUG

BI 655064 injected subcutaneous

Part 1, BI 655064 240mg (HV)

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.

Group Type: EXPERIMENTAL

BI 655064

Intervention Type: DRUG

BI 655064 injected subcutaneous

Part 2, Placebo BI 655064 120mg (RA)

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.

Group Type: PLACEBO_COMPARATOR

Placebo matching BI 655064

Intervention Type: DRUG

Placebo matching BI 655064 injected subcutaneous.

Part 2, BI 655064 120mg (RA)

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.

Group Type: EXPERIMENTAL

BI 655064

Intervention Type: DRUG

BI 655064 injected subcutaneous

Interventions

Placebo matching BI 655064

Placebo matching BI 655064 injected subcutaneous.

Intervention Type: DRUG

BI 655064

BI 655064 injected subcutaneous

Intervention Type: DRUG

Eligibility 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

Part 2 (phase IIa in RA patients):

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Boehringer Ingelheim

Role: STUDY_CHAIR

Boehringer Ingelheim

Locations

1293.2.00049 Boehringer Ingelheim Investigational Site

Olomouc, , Czechia

1293.2.00024 Boehringer Ingelheim Investigational Site

Uherské Hradiště, , Czechia

1293.2.00028 Boehringer Ingelheim Investigational Site

Zlín, , Czechia

1293.2.00015 Boehringer Ingelheim Investigational Site

Bad Kreuznach, , Germany

1293.2.00010 Boehringer Ingelheim Investigational Site

Berlin, , Germany

1293.2.00013 Boehringer Ingelheim Investigational Site

Berlin, , Germany

1293.2.00043 Boehringer Ingelheim Investigational Site

München, , Germany

1293.2.00012 Boehringer Ingelheim Investigational Site

Zerbst, , Germany

1293.2.00031 Boehringer Ingelheim Investigational Site

Amsterdam, , Netherlands

1293.2.00032 Boehringer Ingelheim Investigational Site

Leeuwarden, , Netherlands

1293.2.00038 Boehringer Ingelheim Investigational Site

Leiden, , Netherlands

1293.2.00040 Boehringer Ingelheim Investigational Site

Sneek, , Netherlands

1293.2.00001 Boehringer Ingelheim Investigational Site

Grafton Auckland NZ, , New Zealand

1293.2.00039 Boehringer Ingelheim Investigational Site

Bialystok, , Poland

1293.2.00034 Boehringer Ingelheim Investigational Site

Bydgoszcz, , Poland

1293.2.00041 Boehringer Ingelheim Investigational Site

Bydgoszcz, , Poland

1293.2.00025 Boehringer Ingelheim Investigational Site

Lublin, , Poland

1293.2.00050 Boehringer Ingelheim Investigational Site

Poznan, , Poland

1293.2.00023 Boehringer Ingelheim Investigational Site

Warsaw, , Poland

1293.2.00026 Boehringer Ingelheim Investigational Site

Warsaw, , Poland

1293.2.00021 Boehringer Ingelheim Investigational Site

A Coruña, , Spain

1293.2.00017 Boehringer Ingelheim Investigational Site

Barcelona, , Spain

1293.2.00022 Boehringer Ingelheim Investigational Site

Granada, , Spain

1293.2.00016 Boehringer Ingelheim Investigational Site

La Laguna (Sta Cruz Tenerife), , Spain

1293.2.00020 Boehringer Ingelheim Investigational Site

Santiago de Compostela, , Spain

Countries

Czechia; Germany; Netherlands; New Zealand; Poland; Spain

References

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.

Reference Type: DERIVED

PMID: 30902820 (View on PubMed)

Other Identifiers

2012-004090-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1293.2

Identifier Type: -

Identifier Source: org_study_id