Clinical Trial Result Information

Protocol number:
WA19923
Title of Study:
A Mechanism of Action study to evaluate the effects of IL-6 receptor blockade with tocilizumab (TCZ) on lipids, arterial stiffness, and markers of atherogenic risk in patients with moderate to severe active rheumatoid arthritis (RA).
Sponsor:
Hoffmann-La Roche
Company division:
Pharmaceutical
Product name:
ACTEMRA
Generic name:
TOCILIZUMAB
Therapeutic area:
  • Rheumatoid Arthritis
Clinical study summary:

This randomized, multi-center, two-part (24-week double-blind period followed by 80-week open-label period) study was designed to evaluate the efficacy and the safety of RoActemra/Actemra (tocilizumab, TCZ) in combination with methotrexate (MTX). Patients were randomized to one of two treatment arms; Arm A: RoActemra/Actemra+MTX, Arm B: Placebo+MTX. After 24 weeks of treatment, patients could continue with RoActemra/Actemra+MTX for 80 weeks.

Study center(s):

34 centers in Canada, U.S.A., United Kingdom

Phase of development:
III
Objectives:

The primary objectives were to investigate the effect of 12 weeks of treatment with RoActemra/Actemra on small low density lipoprotein (LDL) -L1 particle number and to investigate the effect of 12 weeks of treatment with RoActemra/Actemra on arterial stiffness as assessed by pulse-wave velocity (PWV)

The secondary objectives were to investigate the effect of 24 weeks of treatment with RoActemra/Actemra on small LDL-L1 particle number and to investigate the effect of 24 weeks of treatment with TCZ on arterial stiffness as assessed by PWV.

The exploratory objectives were to investigate the effect of RoActemra/Actemra on lipid parameters and serum markers of CV risk and the relationship of these effects to the change in clinical response.

Methodology:

This was a phase 3, multi-center, two part, mechanism of action study of 2 years duration to evaluate the effects of IL-6R blockade by tocilizumab on lipids, arterial stiffness, and markers of CV risk in patients with moderate to severe active RA:

  • Part 1 was a 24-week, randomized, double-blind, parallel group study of the PD activity of TCZ+MTX vs. placebo+MTX. Patients who showed less than 20% improvement from baseline in both SJC and TJC at Week 16 had the option to receive escape therapy (8 mg/kg TCZ every 4 weeks + background MTX and intra-articular corticosteroids or an increase in oral corticosteroid dosage up to a maximum dose of 10 mg total dose/day).
  • Part 2 was an 80-week open-label follow-up of selected measures for patients continuing on TCZ treatment.

Upon completion of Part 2, patients had the option to remain on TCZ until it became available in their respective country

Number of patients (planned/analyzed):
132 patients enrolled and treated
Diagnosis and main criteria for inclusion:

Patients with moderate to severe active RA who had shown an inadequate clinical response to MTX. Specific requirements were a swollen joint count (SJC) ≥ 6, a tender joint count (TJC) ≥ 6, and high-sensitivity C-reactive protein (hsCRP) ≥ 1.0 mg/L or erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr. Patients had to have been on MTX therapy for at least 12 weeks immediately prior to baseline, of which the last 8 weeks must have been at a stable dose between 7.5 and 25 mg/week.

Test product, dose and mode of administration or test procedure:

Tocilizumab 8 mg/kg (intravenous infusion) every 4 weeks

Methotrexate 7.5 to 25 mg (oral or parenteral) weekly

Duration of treatment:
104 weeks
Reference therapy, dose and mode of administration or reference procedure:

Placebo (intravenous infusion) every 4 weeks

Methotrexate 7.5 to 25 mg (oral or parenteral) weekly

Criteria for evaluation (efficacy, safety):

Efficacy: Lipoprotein subclasses, pulse-wave velocity (PWV), pulse wave analysis (PWA), disease activity for 28 joint indices score (DAS28), ACR 20/50/70, markers of cardiovascular (CV) risk

Pharmacodynamics: IL6, sIL6R

Pharmacokinetics: Tocilizumab single-dose Cmax, Tlast, Tmax, AUClast, AUCinfinity, t½, CL, Vz. tocilizumab multiple-dose: Ctrough

Safety: Adverse events (AEs), safety laboratory parameters, vital signs, anti-TCZ antibodies.

Statistical methods:

Efficacy analyses: The co-primary efficacy endpoints were analyzed using an analysis of covariance (ANCOVA) model. The statistical model included terms for baseline value, baseline hsCRP (<1.66 vs. ≥1.66 mg/dL), age at baseline (<52 vs. ≥ 52 years), baseline mean arterial pressure (<93.3 vs. ≥ 93.3 mmHg) and treatment group. Since both primary endpoints had to be met in order to conclude positively, no adjustment for multiplicity was needed and statistical tests were performed at the 5% significance level. Since ANCOVA is robust to some departure from normality, and the sample size was not small, the results are presented as the mean, 95% confidence interval (CI) and p-value for the difference between TCZ+MTX and placebo+MTX at Week 12.

Descriptive statistics are also provided for the observed actual values and changes from baseline at each visit.

Pharmacokinetic (PK), pharmacodynamic (PD), and safety analyses: PK evaluation was performed using model independent methods. PK, PD, and safety data are summarized descriptively.

Summary (efficacy, safety, other results):

Efficacy

24-Week Double Blind Period Analyses

Compared with placebo+MTX, treatment with RoActemra/Actemra + MTX for up to 24 weeks did not have a statistically significant or clinically relevant effect on small LDL particle number at either Week 12 (primary endpoint) or Week 24 (secondary endpoint). Likewise, although a small statistically significant effect of RoActemra/Actemra treatment was observed in favor of the placebo group on arterial stiffness as assessed by PWV at Week 12 (primary endpoint), the effect was not considered to be clinically relevant as no difference from placebo was seen at Week 24 (secondary endpoint). Since a statistically significant difference between the placebo+MTX and RoActemra/Actemra+MTX groups at the 5% significance level was not shown for both primary endpoints, the primary objective of study WA19923 was not met.

In exploratory efficacy analyses of DAS28 and ACR response, treatment with RoActemra/Actemra+MTX for up to 24 weeks resulted in clear improvements in DAS28 and in the proportion of patients achieving remission (DAS28 <2.6). Clear improvements were also observed in ACR20, ACR50, and ACR70 as well as for all ACR core set parameters (SJC, TJC, visual analogue scale parameters, Health Assessment Questionnaire Disability Index, and acute phase reactants).

In exploratory analyses of markers of cardiovascular (CV) risk, treatment with RoActemra/Actemra+MTX for up to 24 weeks resulted in quantitative changes from baseline in several nuclear magnetic resonance (NMR) and PD biomarker parameters. Increases (median percent change from baseline ≥  5%) in total triglycerides as well as in total very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol measured by NMR were observed in the RoActemra/Actemra+MTX group only. Including all NMR subclasses, the greatest changes from baseline were found in large VLDL particles, which account for only a small fraction of total VLDL, and in VLDL triglyceride.

Despite the observed increases in cholesterol concentrations and despite the lack of an effect on small LDL particle number after 12 or 24 weeks of treatment with RoActemra/Actemra, several potentially anti-atherogenic qualitative changes in lipoprotein parameters were observed in the RoActemra/Actemra+MTX group only:

• NMR analyses identified that the increases in LDL occurred almost exclusively in the larger more buoyant particles with little or no change in the smallest LDL particles. A substantial decline in Lp(a) was also observed.

• The increases in HDL occurred mainly in the smaller particles without any change in larger particles. An increase in paraoxonase (a component of normal HDL with anti-oxidant activity) and a reduction in several acute phase reactants including HDL-associated SAA (bind to HDL and play an important role in the activation of inflammatory cells within atherosclerotic plaques) were also observed.

Long-term Open Label Analyses (W52Com [patients who completed the study up to Week 52] and All RoActemra/Actemra Populations)

The changes in efficacy parameters observed over time in RoActemra/Actemra patients of the W52com and All RoActemra/Actemra populations after initiation of RoActemra/Actemra treatment were generally consistent with the changes observed at Week 12 in the RoActemra/Actemra+MTX group of the intent to treat (ITT) population.

Pharmacodynamics

Median sIL-6R (free + RoActemra/Actemra-bound sIL-6R) and IL-6 concentrations increased rapidly after dosing in the RoActemra/Actemra+MTX group but remained close to baseline levels in the placebo+MTX group throughout the 24-week double-blind treatment period. At Week 12, median concentrations of sIL-6R and IL-6 in the RoActemra/Actemra+MTX group were approximately 13- and 3-fold higher than at baseline, respectively.

In the long-term open-label analyses, median sIL-6R concentrations showed a slight trend for a further increase after Week 12 whereas IL-6 concentrations remained close to Week 12 levels for the duration of treatment.

Pharmacokinetics

Following the first intravenous dose of 8 mg/kg RoActemra/Actemra, mean ± SD Cmax and AUCinfinity of RoActemra/Actemra were 200 ± 47 μg/mL and 36123 ± 10331 μg⋅hr/mL, respectively, with inter patient variabilities of 24% and 29%, respectively. Terminal t1/2 was 162 ± 57 hours, CL was 18.6 ± 6.0 mL/hr, and Vz was 4.12 ± 1.36 L.

Following repeated dosing with 8 mg/kg RoActemra/Actemra every 4 weeks, mean ± SD predose RoActemra/Actemra concentrations (Ctrough) increased during the remainder of the double-blind period from 8.50 ± 6.75 μg/mL at Week 4 to 19.9 ± 14.7 μg/mL at Week 24. The RoActemra/Actemra accumulation ratio based on mean Ctrough values after the first (Week 24) and sixth (Week 24) doses was approximately 2.3.

In the W52Com population (ie, in patients who completed the study up to Week 52), median Ctrough values in patients who received active RoActemra/Actemra treatment from the start of the study ranged from 17.5 to 20.3 μg/mL between Week 24 and the end of the 2 year study period, confirming that PK concentrations were stable over 2 years of treatment.

Safety

24-Week Double Blind Period Analyses

The safety and tolerability profile of RoActemra/Actemra+MTX compared with placebo+MTX in the 24-week double-blind period of the study was consistent with the known safety profile of RoActemra/Actemra.

The proportion of patients who experienced at least one AE up to Week 24 was higher in the RoActemra/Actemra+MTX group (84%) than in the placebo+MTX group (73%). The difference was primarily due to a higher incidence of infections, gastrointestinal AEs, and AEs that occurred during or within 24 hours of the RoActemra/Actemra infusion. These events are consistent with AEs previously reported with RoActemra/Actemra. The majority of AEs reported during Part 1 of the study were mild or moderate in intensity, reversible, and not treatment-limiting as evidenced by the low incidence of AEs leading to withdrawal (3%). SAEs were reported in <5% of patients in both groups (3% placebo+MTX, 4% RoActemra/Actemra+MTX) and there were no deaths.

Mean white blood cell (WBC), neutrophil and platelet counts decreased and mean ALT and AST concentrations increased from baseline in the RoActemra/Actemra+MTX group compared with the placebo+MTX group. No clinically relevant changes in vital signs, anthropometric assessments, or 12-lead ECGs were observed in either treatment group.

Long-term Open Label Analyses (All RoActemra/Actemra Population)

The safety and tolerability profile of RoActemra/Actemra 8 mg/kg + MTX in the All RoActemra/Actemra population was consistent with that observed in the 24-week safety population and with the known safety profile of RoActemra/Actemra. Almost all patients in the All RoActemra/Actemra Population experienced at least one AE after receiving RoActemra/Actemra (124/130, 94%). The overall rate of AEs was 444.08 (95% CI: 419.26, 469.99) events per 100 patient years. As observed in the RoActemra/Actemra+MTX group of the 24-week safety population, common AEs included infections and infestations (SOC incidence 75%), GI disorders (SOC incidence 49%), and AEs occurring within 24 hours of an infusion (28%). SAEs were experienced by a total of 30/130 (23%) patients. There was one death due to hemorrhagic shock (secondary to right chest tube removal for bilateral small pneumothoraxes and hemothorax), and 13/130 (10%) patients experienced an AE that led to withdrawal from treatment.

Mean WBC, neutrophil and platelet counts decreased and mean ALT, AST, and bilirubin concentrations increased following treatment with RoActemra/Actemra+MTX. There was a slight increase in mean body weight but no clinically relevant changes in vital signs over time.

Two patients tested positive for neutralizing anti-RoActemra/Actemra antibodies; neither patient was withdrawn for insufficient therapeutic response or experienced an anaphylactic reaction.

Conclusions:

The primary objective of study WA19923 was not met since treatment with RoActemra/Actemra for 12 weeks did not have a clinically relevant effect on small LDL particle number and aortic stiffness (as assessed by PWV) in patients with moderate to severe RA. However, qualitative changes in lipid parameters as well as reductions in inflammatory and prothrombic parameters suggest that lipoprotein properties altered by chronic inflammation may be reversed with RoActemra/Actemra treatment.

The safety and tolerability profile of RoActemra/Actemra 8 mg/kg + MTX in study WA19923 was consistent with the known safety profile of RoActemra/Actemra. No new safety signals were identified.

Date of report:
01.01.2012

Click here for the protocol registry listing of this trial.