Clinical Trial Result Information

Protocol number
WX17798

Title of Study
A prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 36-week trial to assess the efficacy and safety of adjunct mycophenolate mofetil (MMF) to maintain or improve symptom control with reduced corticosteroids in subjects with myasthenia gravis.

Sponsor
F Hoffmann-La Roche Ltd/Inc/AG/ Aspreva Pharmaceuticals Corporation

Company division
Pharmaceutical

Product name
CellCept

Generic name
mycophenolate mofetil

Therapeutic area
Myasthenia Gravis generalised

Clinical study summary
This was a prospective, randomized, double-blind, placebo-controlled, parallel group, 36-week, two-arm comparison study of CellCept and placebo given as adjunct therapy to underlying treatment with oral prednisone in patients with myasthenia gravis (MG).

Study center(s)
A total of 43 centers in Canada, Czech Republic, France, Germany, Israel, Italy, Mexico, Netherlands, Ukraine, UK and USA.

Phase of development
III

Objectives
Primary: To assess the efficacy of CellCept (mycophenolate mofetil) therapy compared to placebo in myasthenia gravis (MG) patients receiving prednisone.
Secondary: To assess the safety and tolerability of CellCept therapy compared to placebo in myasthenia gravis patients receiving prednisone.

Methodology
Eligible patients with myasthenia gravis were randomized to receive either CellCept 1g bid or matching placebo orally for 36 weeks. Patients were required to receive prednisone (or equivalent dose of other corticosteroid) at a dose of ≥20mg/day (or equivalent alternate day dose) for at least 4 weeks prior to randomization and at baseline, with dose reduction to a minimum of 7.5mg/day. After baseline assessments and randomization, patients returned at intervals up to week 36 for assessments of efficacy, safety and prednisone and cholinesterase inhibitor dose reductions according to the guidelines.

Number of patients (planned/analyzed)
Planned: 136. Enrolled: 176.

Diagnosis and main criteria for inclusion
Male or female patients, 18-80 years old, with diagnosis of myasthenia gravis, and a history of myasthenic weakness involving more than ocular or peri-ocular muscles, positive edrophonium chloride test or abnormal neuromuscular transmission demonstrated by electrodiagnostic testing, and elevated acetylcholine receptor (AChR) antibodies. Patients were also required to have a disease severity history classified by Myasthenia Gravis Foundation of America (MGFA) as II, III, IVa or IVb.

Test product, dose and mode of administration or test procedure
CellCept (mycophenolate mofetil) 1g bid po bid.
Prednisone ≥20mg/day for at least 4 weeks prior to randomization; dose tapered every 4 weeks to a minimum of 7.5mg/day according to the protocol-specified taper.

Duration of treatment
36 weeks

Reference therapy, dose and mode of administration or reference procedure
Placebo po bid.
Prednisone ≥20mg/day for at least 4 weeks prior to randomization; dose tapered every 4 weeks to a minimum of 7.5mg/day according to the protocol-specified taper.

Criteria for evaluation (efficacy, safety)
Efficacy: Primary: The proportion of patients who reached responder status, as defined by the following criteria:
1) Minimal manifestations or pharmacologic remission from Week 32 until study termination at Week 36, and 2) Prednisone dose of ≤7.5mg/day from Week 32 until study termination at Week 36, and 3) Cholinesterase inhibitor dose of ≤120mg/day from Week 33 until study termination at Week 36.
Patients had one week to reduce the cholinesterase inhibitor dose after reaching 7.5mg/day prednisone.
Secondary: Time to start of response, defined as the time that the patient first demonstrated all of the following conditions provided that these conditions were maintained through to study termination at Week 36:
1) Minimal Manifestations or Pharmacologic Remission and 2) Prednisone dose of 7.5 mg/day, and 3) Cholinesterase inhibitor dose of ≤120 mg/day.
Prednisone dose area under the curve (AUC); prednisone dose at study termination; cholinesterase inhibitor dose at study termination; number of intravenous immunoglobulin (IVIG) and plasma exchange (PE) treatments received during the study; Quantitative Myasthenia Gravis Score (QMGS) (change from baseline); Quality of Life measures (36-item short form (SF-36) health survey and Myasthenia Gravis Activities of Daily Living (MG ADL scale) (change from baseline); patient and investigator global assessments (change from baseline); AChR antibody titers.

Safety: Clinical laboratory tests, adverse events, serious adverse events, physical examinations, vital signs, ECGs.

Statistical methods
Formal hypothesis testing was conducted on the primary efficacy parameter. Fisher's exact test was used to compare response rates between the treatment groups in the intent-to-treat (ITT) population. The primary analysis was tested with a two-tailed test (alpha=0.05). A logistic regression analysis was performed to adjust for factors potentially prognostic of outcome.
For secondary efficacy endpoints, support was provided by the 95% confidence interval, when applicable. For all secondary efficacy outcomes assessed by visit, descriptive analyses were carried out by visit and early termination in the ITT population using observed cases (no imputation performed for missing assessments). In addition, the endpoint was also summarized, where applicable, and was defined using the assessment at early termination or Week 36. If a patient was not evaluated at early termination, then imputation for endpoint was performed using last observation carried forward (LOCF).
Concentrations of MPA and MPAG were analyzed and presented descriptively.

Summary (efficacy, safety, other results)
Efficacy: For the primary efficacy parameter of response, there was no difference between the treatment groups. In the IT population, 38.6% of the placebo patients and 44.3% of the CellCept patients met the criteria for response (p=0.541). When the primary efficacy parameter was adjusted for factors potentially prognostic of outcome, there was no difference in response between the groups.
For each of the secondary efficacy endpoints of time to start of response, cholinesterase inhibitor dose, QMGS, quality of life, and investigator and patient global assessments, the results between the two treatment groups were similar and consistent with the results of the primary endpoint. For the secondary endpoint of prednisone dose, although there appeared to be no meaningful difference between the CellCept and placebo groups, substantially fewer patients in the CellCept group (n=1) were unable to reduce their prednisone dose and were prematurely terminated from the study compared to the placebo group (n=8). For the secondary efficacy endpoints regarding the number of IVIG and PE treatments and AChR antibody titers, the results suggested differences between the two treatment groups. Fewer patients in the CellCept group (n=3) received an IVIG and/or PE treatment compared to the placebo group (n=8), suggesting that CellCept use may reduce the need for administration of these rescue medications. In addition, CellCept patients showed a larger decline in AChR antibody titers (with median values of 8.00 nmol/L at Week 0 and 3.46 nmol/L at Week 36) compared to patients in the placebo group (with median values of 8.00 nmol/L at Week 0 and 7.61 nmol/L at Week 36); this difference suggests CellCept may play a role in decreasing circulating AChR antibody levels over the course of 36 weeks.

Pharmacokinetics: In the CellCept treatment group, mean MPA and MPAG levels were reflective of levels expected in patients who were taking CellCept 1g bid. The levels seen in the placebo group.

Safety: Extent of exposure to study medications was similar between the treatment groups. A similar proportion of patients received study medication through week 36 (80.7% placebo group, 83.0% CellCept group) and the mean duration of treatment was 236.0 days in the placebo group and 229.7 days in the CellCept group.
The overall incidence of AEs was similar between the treatment groups (84.1% placebo vs 80.7% CellCept). The most common AEs were infections and infestations (39.8% in the placebo group and 44.3% in the CellCept group), musculoskeletal disorders (28.4% in each group), gastrointestinal disorders (30.7% in the placebo group and 22.7% in the CellCept group), and nervous system disorders (21.6% in each group). For individual events, headache (12.5%) and nausea (9.1%) were the most frequent in the CellCept group. Diarrhea (10.2%), and muscle spasms (10.2%) were the most common events reported in the placebo group. The proportion of patients who experienced an AE considered related to study drug was higher in the placebo group (45.5% compared to 37.5% in the CellCept group).
Three patients died; two of the deaths occurred while on study and one ooccurred 11 days after the patient completed the study. One patient in the CellCept group died due to pneumonia, considered by the investigator to be possibly related to treatment. The other two deaths (alcohol poisoning in a patient in the placebo group and hemorrhagic fever in a patient in the CellCept group) were considered unrelated to treatment.
A total of 46 SAEs occurred in 33 patients in the study, with the higher incidence in the CellCept group (15.9% of placebo patients and 21.6% of CellCept patients experienced at least one SAE). A similar proportion of patients withdrew from treatment due to AEs in each group (4 placebo patients and 3 CellCept patients).

Conclusions
Results of this study showed that 44.3% of patients who received CellCept together with a background therapy of oral corticosteroids and cholinesterase inhibitors demonstrated good disease control with steroid sparing; this was similar to the 38.6% of patients who received only background therapy and demonstrated good disease control with steroid sparing. The results indicated no difference between treatment groups with respect to the primary efficacy response in MG patients.
The addition of CellCept to background therapy was generally well tolerated; the frequency, nature, and intensity of AEs were generally similar between the two treatment groups.

Date of report
5/28/2007

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