A Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Ortho-Novum® 1/35


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 44 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1)<br>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. | Drug: Tocilizumab<br>* Tocilizumab 8 mg/kg was administered in a single 1-hour infusion on Day 1 of Cycle 2.<br>* Other names: Actemra;Drug: Ortho-Novum® 1/35<br>* Each Ortho-Novum® 1/35 tablet contained 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.<br>|
| Other: Ortho-Novum® 1/35 (Group 2)<br>Healthy volunteers received Ortho-Novum® 1/35 tablets daily on Days 1-21 of one 28-day cycle. | Drug: Ortho-Novum® 1/35<br>* Each Ortho-Novum® 1/35 tablet contained 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 21 of Cycles 1-3 for Group 1 and Day 21 of Cycle 1 for Group 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | 
| 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). | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | 
| 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). | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | 
| 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). | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | 
| 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). | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | 
| 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). | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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). | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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. | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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). | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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). | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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). | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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. | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | 
| 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. | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 |