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

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01751776
• Other study ID #: 1293.2
• Secondary ID: 2012-004090-16
• Status: Completed
• Phase: Phase 1
• Start date: December 18, 2012
• Est. completion date: April 27, 2015

Study information

• Verified date: September 2023
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: April 27, 2015
• Est. primary completion date: March 2, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Healthy

Intervention

Drug:
• Placebo matching BI 655064
Placebo matching BI 655064 injected subcutaneous.
• BI 655064
BI 655064 injected subcutaneous

Locations

Country	Name	City	State
Czechia	1293.2.00049 Boehringer Ingelheim Investigational Site	Olomouc
Czechia	1293.2.00024 Boehringer Ingelheim Investigational Site	Uherske Hradiste
Czechia	1293.2.00028 Boehringer Ingelheim Investigational Site	Zlin
Germany	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
Netherlands	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
New Zealand	1293.2.00001 Boehringer Ingelheim Investigational Site	Grafton Auckland NZ
Poland	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	Warszawa
Spain	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

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Czechia,  Germany,  Netherlands,  New Zealand,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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
Primary	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
Primary	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)
Primary	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	Part 2: ACR50 Response Rates at Week 12	ACR 50 criteria at week 12 relative to the patient's status at baseline: that is, at least 50 % improvement in swollen joint count, at least 50% improvement in tender joint count, and at least 50% 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 percentage of subjects with ACR50 response is presented.	at week 12 (day 85)
Secondary	Part 2: ACR70 Response Rates at Week 12	ACR70 criteria at week 12 relative to the patient's status at baseline: that is, at least 70 % improvement in swollen joint count, at least 70% improvement in tender joint count, and at least 70% 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 percentage of subjects with ACR50 response is presented.	at week 12 (day 85)
Secondary	Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12	Assessed by European League Against Rheumatism (EULAR) categorization as good, moderate, or nonresponders based on improvement from baseline using the DAS28-CRP at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. DAS28-CRP is calculated as 0.56*v(TJC) + 0.28*v(SJC) + 0.36*Ln(CRP+1) + 0.014*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.; EULAR response states were classified as follows: good responders were patients with an improvement of >1.2 and a present score of ?3.2; moderate responders were patients with an improvement of >0.6 to ?1.2 and a present score of ?5.1, or an improvement of >1.2 and a present score of >3.2; non-responders were any patients with an improvement of ?0.6, or patients with an improvement of >0.6 to ?1.2 and a present score of >5.1.; Improvement (impr.) is abbreviated in the category names.	baseline (day 1) and week 12 (day 85)
Secondary	Part 2: EULAR DAS28-ESR at Week 12	Response as assessed by European League Against Rheumatism (EULAR) using Disease activity score in 28 joints and the erythrocyte sedimentation rate (DAS28-ESR) at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. DAS28-ESR is calculated as 0.56*v(TJC) + 0.28*v(SJC) + 0.70 *Ln(ESR) + 0.014*VAS. The total score ranges from 0 to 9.4, where a higher score indicates a better outcome.; EULAR response states were classified as follows: good responders were patients with an improvement of >1.2 and a present score of ?3.2; moderate responders were patients with an improvement of >0.6 to ?1.2 and a present score of ?5.1, or an improvement of >1.2 and a present score of >3.2; non-responders were any patients with an improvement of ?0.6, or patients with an improvement of >0.6 to ?1.2 and a present score of >5.1.; Improvement (impr.) is abbreviated in the category names.	baseline (day 1) and week 12 (day 85)
Secondary	Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12	Percentage of patients who had a decrease of >1.2 on the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) at week 12 (day 85) compared to baseline. The adjusted absolute risk difference was adjusted for treatment, region and anti-TNF history. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56*v(TJC) + 0.28*v(SJC) + 0.36*Ln(CRP+1) + 0.014*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.	baseline (day 1) and week 12 (day 85)
Secondary	Part 2: Change in DAS28-CRP Score at Week 12	Change at week 12 in the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) compared with the score at baseline. The mean was adjusted for region, anti-TNF history and baseline DAS28-CRP. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56*v(TJC) + 0.28*v(SJC) + 0.36*Ln(CRP+1) + 0.014*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.	baseline (day 1) and week 12 (day 85)