Prescription Drug Information: Azilect (Page 5 of 6)

14.1 Monotherapy Use of AZILECT

Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson’s disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson’s disease before receiving AZILECT.

In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), AZILECT 1 mg/day (134 patients) or AZILECT 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline, or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson’s disease duration was approximately 1 year (range 0 to 11 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number.

AZILECT (1 or 2 mg once daily) was superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of AZILECT 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo.

Table 4: Change in Total UPDRS Score in Study 1

Baseline score

Change from baseline to termination score

p-value vs. placebo

Placebo

24.5

3.9

AZILECT 1 mg

24.7

0.1

0.0001

AZILECT 2 mg

25.9

0.7

0.0001

14.2 Adjunct Use of AZILECT

Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating AZILECT 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson’s disease symptoms.

In Study 2, 321 patients randomly received placebo (162 patients) or AZILECT 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson’s disease duration was approximately 2 years (range 0.1 to 14.5 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)].

In Study 2, AZILECT 1 mg was superior to placebo on the primary measure of effectiveness (see Table 5).

Table 5: Change in Total UPDRS Score in Study 2

Baseline score

Change from baseline to termination score*

p-value vs. placebo

Placebo

29.8

–1.2

AZILECT1 mg

32.1

–3.6

0.012

*A negative change from baseline indicates improvement in the UPDRS

Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall AZILECT effect on the UPDRS score (see Table 6).

Table 6: Secondary Measures of Effectiveness in Study 2

Baseline (score)

Change from baseline to termination score

UPDRS Part II ADL (Activities of Daily Living) subscale score

Placebo

7.9

0.4

AZILECT 1 mg

8.6

-0.3

UPDRS Part III Motor subscale score

Placebo

20.4

-1.2

AZILECT 1 mg

22.2

-3.7

Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson’s disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared AZILECT 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina, and Israel, and compared AZILECT 1 mg daily to placebo.

Patients had Parkinson’s disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson’s disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient’s daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist.

In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period.

In Study 3, patients were randomly assigned to receive placebo (159 patients), AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 4, patients were randomly assigned to receive placebo (229 patients), AZILECT 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 3 and Study 4, AZILECT 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of AZILECT also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of AZILECT. In Study 4, the active comparator also reduced “OFF” time when compared to placebo.

Table 7: Change in mean total daily “OFF” time in Study 3

Baseline (hours)

Change from baseline to treatment period (hours)

p-value vs. placebo

Placebo

6.0

-0.9

AZILECT 0.5 mg

6.0

-1.4

0.0199

AZILECT 1.0 mg

6.3

-1.9

< 0.0001

Table 8: Change in mean total daily “OFF” time in Study 4

Baseline (hours)

Change from baseline to treatment period (hours)

p-value vs. placebo

Placebo

5.5

– 0.40

AZILECT 1.0 mg

5.6

-1.2

0.0001

In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day AZILECT groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the AZILECT 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the AZILECT groups, respectively.

There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo.

Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4.

Table 9: Secondary Measures of Effectiveness in Study 3

Baseline (score)

Change from baseline to last value

UPDRS ADL (Activities of Daily Living) subscale score while “OFF”

Placebo

15.5

0.68

AZILECT 0.5 mg

15.8

-0.60

AZILECT 1 mg

15.5

-0.68

UPDRS Motor subscale score while “ON”

Placebo

20.8

1.21

AZILECT 0.5 mg

21.5

-1.43

AZILECT 1 mg

20.9

-1.30

Table 10: Secondary Measures of Effectiveness in Study 4

Baseline (score)

Change from baseline to last value

UPDRS ADL (Activities of Daily Living) subscale score while “OFF”

Placebo

18.7

-0.89

AZILECT 1 mg

19.0

-2.61

UPDRS Motor subscale score while “ON”

Placebo

23.5

-0.82

AZILECT 1 mg

23.8

-3.87

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