Back to resultsA Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis
Primary Purpose
Rheumatoid Arthritis
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Tocilizumab
Ortho-Novum® 1/35
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
Inclusion Criteria:
- Adult patients with child bearing potential, 18-44 years of age.
- Rheumatoid arthritis (RA) for over 6 months duration.
- On oral contraceptive without interruption for at least 3 months with normal cycle control.
- Treatment with disease-modifying anth-rheumatic drugs (DMARD) for at least 12 weeks prior to study start.
- Body weight < 150 kg.
Exclusion Criteria:
- Functional class IV rheumatoid arthritis (American College of Rheumatology [ACR] classification).
- History of amenorrhea (unrelated to pregnancy).
- History or current inflammatory joint disease other than RA.
- Rheumatic autoimmune disease other than RA.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Other
Arm Label
Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1)
Ortho-Novum® 1/35 (Group 2)
Arm Description
Patients with rheumatoid arthritis received Ortho-Novum® 1/35 daily on Days 1-21 of 3 consecutive 28-day cycles. On the first day of Cycle 2, patients received tocilizumab 8 mg/kg administered intravenously.
Healthy volunteers received Ortho-Novum® 1/35 tablets daily on Days 1-21 of one 28-day cycle.
Outcomes
Primary Outcome Measures
Serum Progesterone Level
Blood samples were collected prior to the administration of Ortho-Novum® 1/35 on Day 21 of each cycle. Serum levels of progesterone were quantitatively determined using the ADVIA Centaur and ADVIA Centaur XP systems (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA). The assay was a competitive immunoassay using direct chemiluminescent technology.
Secondary Outcome Measures
Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The maximum observed plasma concentration (Cmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The time to reach the maximum plasma concentration (Tmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule with the software WinNonlin Enterprise version 5.2 (or above).
Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The terminal half-life (t½) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The apparent oral clearance (CL/F) was derived from the plasma concentrations using a non-compartmental method and computed as dose/AUC0-24 with the software WinNonlin Enterprise version 5.2 (or above).
Maximum Observed Serum Concentration (Cmax) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated enzyme-linked immunosorbent assay (ELISA). The maximum observed plasma concentration (Cmax) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time to Reach Maximum Serum Concentration (Tmax) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The time to reach maximum serum concentration was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Area Under the Serum Concentration-time Curve From 0 to Infinity (AUCinf) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The area under the serum concentration-time curve from 0 to infinity (AUCinf) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). AUCinf was computed using the linear trapezoidal rule to tlast plus Clast/Kel, where tlast is the time of the last measurable concentration, Clast is the last measurable concentration, and Kel is the apparent elimination rate, computed as the magnitude of the slope from the log-linear regression of the apparent terminal elimination phase of the serum concentration-versus-time curve.
Terminal Half-life (t½) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The terminal half-life (t½) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Clearance (CL) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. Clearance (CL), computed as dose/AUCinf, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Apparent Volume of Distribution (Vz) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The apparent volume of distribution (Vz), computed as CL/Kel where CL is clearance and Kel is the apparent elimination rate, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Serum Soluble Interleukin-6 Receptor (sIL-6R) Level
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. Serum levels of soluble interleukin-6 receptor were analyzed using a validated ELISA.
Serum C-reactive Protein (CRP) Level
Blood samples were collected pre-dose of tocilizumab infusion on Day 1 of Cycle 2 and on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and on Days 1, 7, and 21 of Cycle 3. Serum levels of C-reactive protein were measured by the Tina-quant CRP (latex) high-sensitivity Roche Immunoturbidimetric method.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01044498
Brief Title
A Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis
Official Title
An Open-label, Multi-center, One Sequence Cross-over Drug Interaction Study to Investigate the Effect of Tocilizumab (TCZ, RO4877533) on the Pharmacokinetics and Pharmacodynamics of an Oral Contraceptive (OC) in Female Patients With Active Rheumatoid Arthritis (RA)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2013
Overall Recruitment Status
Completed
Study Start Date
December 2009 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
This open-label, randomized, cross-over study evaluated the effect of tocilizumab (TCZ) on the pharmacokinetics and pharmacodynamics of a common oral contraceptive (OC) in female patients with active rheumatoid arthritis (RA) and in healthy female volunteers of child bearing age. The RA patients received OC in combination with TCZ, whereas the healthy volunteers received OC only. The RA patients received OC in 3 cycles of 21 days each; TCZ 8 mg/kg was administered once as an intravenous infusion on the first day of Cycle 2. The healthy volunteers received OC for only one 21-day cycle.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1)
Arm Type
Experimental
Arm Description
Patients with rheumatoid arthritis received Ortho-Novum® 1/35 daily on Days 1-21 of 3 consecutive 28-day cycles. On the first day of Cycle 2, patients received tocilizumab 8 mg/kg administered intravenously.
Arm Title
Ortho-Novum® 1/35 (Group 2)
Arm Type
Other
Arm Description
Healthy volunteers received Ortho-Novum® 1/35 tablets daily on Days 1-21 of one 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RoActemra, Actemra
Intervention Description
Tocilizumab 8 mg/kg was administered in a single 1-hour infusion on Day 1 of Cycle 2.
Intervention Type
Drug
Intervention Name(s)
Ortho-Novum® 1/35
Intervention Description
Each Ortho-Novum® 1/35 tablet contained 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.
Primary Outcome Measure Information:
Title
Serum Progesterone Level
Description
Blood samples were collected prior to the administration of Ortho-Novum® 1/35 on Day 21 of each cycle. Serum levels of progesterone were quantitatively determined using the ADVIA Centaur and ADVIA Centaur XP systems (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA). The assay was a competitive immunoassay using direct chemiluminescent technology.
Time Frame
Day 21 of Cycles 1-3 for Group 1 and Day 21 of Cycle 1 for Group 2
Secondary Outcome Measure Information:
Title
Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone
Description
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The maximum observed plasma concentration (Cmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Title
Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone
Description
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The time to reach the maximum plasma concentration (Tmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Title
Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone
Description
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Title
Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone
Description
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The terminal half-life (t½) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Title
Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone
Description
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The apparent oral clearance (CL/F) was derived from the plasma concentrations using a non-compartmental method and computed as dose/AUC0-24 with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Title
Maximum Observed Serum Concentration (Cmax) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated enzyme-linked immunosorbent assay (ELISA). The maximum observed plasma concentration (Cmax) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Time to Reach Maximum Serum Concentration (Tmax) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The time to reach maximum serum concentration was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Area Under the Serum Concentration-time Curve From 0 to Infinity (AUCinf) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The area under the serum concentration-time curve from 0 to infinity (AUCinf) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). AUCinf was computed using the linear trapezoidal rule to tlast plus Clast/Kel, where tlast is the time of the last measurable concentration, Clast is the last measurable concentration, and Kel is the apparent elimination rate, computed as the magnitude of the slope from the log-linear regression of the apparent terminal elimination phase of the serum concentration-versus-time curve.
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Terminal Half-life (t½) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The terminal half-life (t½) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Clearance (CL) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. Clearance (CL), computed as dose/AUCinf, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Apparent Volume of Distribution (Vz) of Tocilizumab
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The apparent volume of distribution (Vz), computed as CL/Kel where CL is clearance and Kel is the apparent elimination rate, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Serum Soluble Interleukin-6 Receptor (sIL-6R) Level
Description
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. Serum levels of soluble interleukin-6 receptor were analyzed using a validated ELISA.
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Title
Serum C-reactive Protein (CRP) Level
Description
Blood samples were collected pre-dose of tocilizumab infusion on Day 1 of Cycle 2 and on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and on Days 1, 7, and 21 of Cycle 3. Serum levels of C-reactive protein were measured by the Tina-quant CRP (latex) high-sensitivity Roche Immunoturbidimetric method.
Time Frame
From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
44 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Adult patients with child bearing potential, 18-44 years of age.
Rheumatoid arthritis (RA) for over 6 months duration.
On oral contraceptive without interruption for at least 3 months with normal cycle control.
Treatment with disease-modifying anth-rheumatic drugs (DMARD) for at least 12 weeks prior to study start.
Body weight < 150 kg.
Exclusion Criteria:
Functional class IV rheumatoid arthritis (American College of Rheumatology [ACR] classification).
History of amenorrhea (unrelated to pregnancy).
History or current inflammatory joint disease other than RA.
Rheumatic autoimmune disease other than RA.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72212
Country
United States
City
Beverly Hills
State/Province
California
ZIP/Postal Code
90211
Country
United States
City
Ormond Beach
State/Province
Florida
ZIP/Postal Code
32174
Country
United States
City
Port Orange
State/Province
Florida
ZIP/Postal Code
32127
Country
United States
City
Duncansville
State/Province
Pennsylvania
ZIP/Postal Code
16635
Country
United States
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78222
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24161161
Citation
Zhang X, Rowell L, Fettner S, Lau C, Teuber D. Assessment of disease-drug-drug interaction between single-dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis. Int J Clin Pharmacol Ther. 2014 Jan;52(1):27-38. doi: 10.5414/CP201951.
Results Reference
derived
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A Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis
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