Clinical trial NCT01751776: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Arthritis, Rheumatoid
Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2012-12-18
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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

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.

Primary outcomes:
measure: Part 1: Cmax After the First and Last Dose
timeFrame: From first day of drug administration till end of trial, up to 77 days. Detailed PK can be found in the endpoint description.
measure: Part 1: AUC 0-infinity After the Last Dose
timeFrame: 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
measure: Part 1: AUCtau After the Last Dose
timeFrame: 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
measure: Part 1: Percentage of Subjects With Drug Related Adverse Events
timeFrame: 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)
measure: Part 2: American College of Rheumatology (ACR)20 Response Rate at Week 12
timeFrame: at week 12 (day 85) from the initiation of study treatment
Secondary outcomes:
measure: Part 2: ACR50 Response Rates at Week 12
timeFrame: at week 12 (day 85)
measure: Part 2: ACR70 Response Rates at Week 12
timeFrame: at week 12 (day 85)
measure: Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12
timeFrame: baseline (day 1) and week 12 (day 85)
measure: Part 2: EULAR DAS28-ESR at Week 12
timeFrame: baseline (day 1) and week 12 (day 85)
measure: Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12
timeFrame: baseline (day 1) and week 12 (day 85)
measure: Part 2: Change in DAS28-CRP Score at Week 12
timeFrame: baseline (day 1) and week 12 (day 85)
Other outcomes:
Locations:
city: Olomouc
country: Czechia
facility: 1293.2.00049 Boehringer Ingelheim Investigational Site
city: Uherske Hradiste
country: Czechia
facility: 1293.2.00024 Boehringer Ingelheim Investigational Site
city: Zlin
country: Czechia
facility: 1293.2.00028 Boehringer Ingelheim Investigational Site
city: Bad Kreuznach
country: Germany
facility: 1293.2.00015 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1293.2.00010 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1293.2.00013 Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: 1293.2.00043 Boehringer Ingelheim Investigational Site
city: Zerbst
country: Germany
facility: 1293.2.00012 Boehringer Ingelheim Investigational Site
city: Amsterdam
country: Netherlands
facility: 1293.2.00031 Boehringer Ingelheim Investigational Site
city: Leeuwarden
country: Netherlands
facility: 1293.2.00032 Boehringer Ingelheim Investigational Site
city: Leiden
country: Netherlands
facility: 1293.2.00038 Boehringer Ingelheim Investigational Site
city: Sneek
country: Netherlands
facility: 1293.2.00040 Boehringer Ingelheim Investigational Site
city: Grafton Auckland NZ
country: New Zealand
facility: 1293.2.00001 Boehringer Ingelheim Investigational Site
city: Bialystok
country: Poland
facility: 1293.2.00039 Boehringer Ingelheim Investigational Site
city: Bydgoszcz
country: Poland
facility: 1293.2.00034 Boehringer Ingelheim Investigational Site
city: Bydgoszcz
country: Poland
facility: 1293.2.00041 Boehringer Ingelheim Investigational Site
city: Lublin
country: Poland
facility: 1293.2.00025 Boehringer Ingelheim Investigational Site
city: Poznan
country: Poland
facility: 1293.2.00050 Boehringer Ingelheim Investigational Site
city: Warsaw
country: Poland
facility: 1293.2.00023 Boehringer Ingelheim Investigational Site
city: Warszawa
country: Poland
facility: 1293.2.00026 Boehringer Ingelheim Investigational Site
city: A Coruña
country: Spain
facility: 1293.2.00021 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1293.2.00017 Boehringer Ingelheim Investigational Site
city: Granada
country: Spain
facility: 1293.2.00022 Boehringer Ingelheim Investigational Site
city: La Laguna (Sta Cruz Tenerife)
country: Spain
facility: 1293.2.00016 Boehringer Ingelheim Investigational Site
city: Santiago de Compostela
country: Spain
facility: 1293.2.00020 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.