Roche trials database

Protocol number:

ML18542

Title of Study:

A randomized, open-label study of first-line treatment with dexamethasone or dexamethasone plus MabThera on sustained treatment response in adult patients with idiopathic thrombocytopenic purpura

Sponsor:

Roche S.p.A.

Company division:

Pharmaceutical

Product name:

rituximab

Generic name:

rituximab

Therapeutic area:

• Idiopathic Thrombocytopenic Purpura

Clinical study summary:

This was a randomized, multicenter, open-label, prospective, phase III clinical trial investigating the effect of adding MabThera (rituximab) to dexamethasone vs a dexamethasone alone regimen in 101 adult patients with idiopathic thrombocytopenic purpura  (ITP). Eligible patients were randomized to receive a single course of  dexamethasone (arm A) or a single course of dexamethasone plus rituximab (arm B).

Study center(s):

22 centers in Italy

Phase of development:

III

Objectives:

The objectives of the study were to investigate the efficacy and safety of rituximab plus dexamethasone versus dexamethasone alone in adult patients with idiopathic thrombocytopenic purpura (ITP), to evaluate the effect of treatment on cellular and humoral immune response and to explore the pharmacokinetic parameters of rituximab and their relationship with response.

Methodology:

Patients with symptomatic, previously untreated ITP were enrolled with a 1:1 randomization to receive a single course of  dexamethasone (arm A) or a single course of dexamethasone plus rituximab (arm B). Patients were evaluated for sustained response. Patients who achieved a sustained response (platelets ≥ 50 x 10⁹/L) completed the study without receiving any further treatment. Patients in the dexamethasone arm who failed to achieve a sustained response and had a platelet count ≤ 20 x 10⁹/L were treated with the experimental arm (dexamethasone plus rituximab). For those patients with severe bleeding or platelets count ≤ 20 x 10⁹/L a single course with immunoglobulin i.v. 400 mg/kg daily for 5 days, with or without steroids or steroids alone (administration and dosage free at discretion of the physician), was allowed before day +30 with the aim to start treatment with dexamethasone plus rituximab at least 2 weeks after the administration of immunoglobulin. After salvage treatment patients who failed to achieve a sustained response were treated, if necessary, according to the indications of the single center. Patients in the dexamethasone plus rituximab arm who failed to achieve a sustained response were also treated, if necessary, according to the indications of the single center. In the test arm, an additional treatment based on one immunoglobulin cycle administered i.v. and/or a low/medium dose steroid treatment (at investigator discretion) was proposed for patients non responsive to dexamethasone and with platelets < 20 x 10⁹/L or with active bleeding. The above mentioned treatment was administered within +28 days and concomitant with rituximab. When the treatment with immunoglobulin occurred at the same time of the rituximab administration (+7, + 14, + 21 and + 28), rituximab infusion was delayed on the day after the last treatment with immunoglobulin and the following administrations were maintained at a weekly schedule. The patients treated with immunoglobulin and or/steroid were not evaluated for early response (secondary objective of the study). They were evaluated for sustained response (primary objective). The patients needing further treatment after the day +28 were considered non responsive.   

Number of patients (planned/analyzed):

198 planned; 101 patients enrolled and treated.

Diagnosis and main criteria for inclusion:

- adult patients >=18 years of age; - untreated ITP.

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

Rituximab 375 mg/m² administered IV on days 7, 14, 21 and 28. Dexamethasone – Arm B: 40 mg orally daily for 4 consecutive days (days 1, 2, 3, 4)

Duration of treatment:

1 month

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy
Primary: Sustained response - platelet count ≥ 50 x 10⁹/L at month + 6 after initial treatment.

Secondary: Initial response - increase in platelet count ≥ 50 x 10⁹/L by day 30 after the initiation of treatment in both arms; Initial complete response - increase in platelet count  ≥ 100 x 10⁹/L by day 30 after the initiation of treatment in both arms.

Pharmacokinetics 
Serum samples obtained from all patients in Arm B at week 4 (1 week after the last rituximab dose), week 8, week 10 and week 12 from start of  rituximab treatment, were analyzed for their content of rituximab antibody by an ELISA assay.

Safety
Incidence of severe, life-threatening serious adverse events (common terminology criteria for adverse event (NCI-CTCAE) version 3.0 grade 3, 4 and 5) commencing during treatment and up to six months after dexamethasone (arm A) or dexamethasone and rituximab (arm B).

Statistical methods:

The primary endpoint was the sustained response rate at 6 months after therapy, where response was a platelet count ≥50x10⁹/L. Resistance to therapy and/or loss of response were considered as failures. The primary analysis of this variable was performed in the intent-to-treat (ITT) and per-protocol (PP) populations. Difference in sustained response rate was assessed by Χ² or Fisher tests depending on the assumption check. Results were expressed as proportions, corresponding 95% confidence intervals of the difference between response rates and  respective p-values. Pre-determined secondary efficacy and safety variables were analyzed in the same way as the primary efficacy variables in the ITT, PP and Safety populations. The data relating to response to rescue therapy were listed and summarized using descriptive statistics.
The effect of treatment on cellular and humoral immune response, evaluated as change from baseline, was summarized using descriptive statistics.
The analysis of potential predictive factors was performed using logistic regression. Results were expressed as odds ratios and corresponding 95% confidence intervals.

Summary (efficacy, safety, other results):

Efficacy
Sustained response (SR). One hundred one patients (52 in arm A and 49 in arm B) and 64 patients (38 in arm A and 26 in arm B) made up the ITT and PP population, respectively. The SR analysis indicated a significant advantage for arm B patients. The SR response rate (platelets ≥ 50 x 10⁹/L) was 36 % and 63 % in patients allocated to arm A and B, respectively (P= 0.004). This advantage was also demonstrated for SR100 (platelets ≥ 100 x 10⁹/L) and SR150 (platelets ≥ 150 x 10⁹/L). This difference was further highlighted in the PP analysis where arm B patients reached a 85% SR rate.

Initial response. Sixty-nine patients (44 in arm A and 25 in arm B) and 45 patients (32 in arm A and 13 in arm B) made up the ITT and PP population, respectively. The initial response analysis showed a significant advantage for arm B patients in terms of OR and CR100 in the ITT analysis (arm A vs arm B: OR: 27% vs 68%; P< 0.001; CR100: 23% vs 48%; P= 0.015) and in terms of OR in the PP analysis (arm A vs arm B: OR: 31% vs 69%; P= 0.009).

Salvage therapy with dexamethasone plus rituximab. Twenty-seven patients initially allocated to arm A who failed to achieve initial response or SR received salvage treatment with dexamethasone plus rituximab. Twenty-seven patients were assessed for the ITT and 22 for the PP analysis. SR response rates were 56 % and 59% in the ITT and PP analysis, respectively.

Pharmacokinetics
A total of 149 measurements were performed from samples from 42 patients. Serum concentrations were determined and the decay of rituximab levels compared with historical data. The median serum level of rituximab just before the last infusion (week +4) was 189 μg/ml (range: 84 μg/ml to 379 μg/ml). The median serum concentrations at weeks +5, +8, +10, +12 and +24 after the start of therapy were: 172 μg/ml (range: 0-476 μg/ml), 105 μg/ml (range: 0-310 μg/ml), 59 μg/ml (range: 0-252 μg/ml), 44 μg/ml (range: 0-140 μg/ml) and 3 μg/ml (range: 0-8 μg/ml), respectively. In responding patients, the median 12-week serum rituximab concentration was 43 mcg/ml (range 0-140) mcg/ml which was not significantly different from the median value of 20 mcg/ml (range 0-105) mcg/ml observed in non-responding patients (P= 0.1841). The median T_1/2 observed in patients in the present study was 491 hours and ranged from 253 hours to 740 hours. 

Safety
Treatments were well tolerated and no grade 5 toxicity, toxic or hemorrhagic deaths  were observed. Compared to arm A, a mild increase in the incidence of severe AE (2% vs 6% of patients), of grade 3-4 AE (1 vs 8 events) and of drug-related AE (0 vs 4 events) was seen in arm B patients. During the first rituximab administration was observed one case each of fever, supraventricular tachycardia and seizures: rituximab administration was discontinued because of these events.  

Conclusions:

The results indicate that the association of rituximab and dexamethasone improves patients outcome without significantly affecting the safety profile. This effect is characterized by prolongation of SR, reduction in relapse rate and avoidance of the use of other therapies. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.

Date of report:

01.09.2008

Click here for the protocol registry listing of this trial.