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ADAGIO

A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease

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Year of Publication: 2009

Authors: C. Warren Olanow, Olivier Rascol, Robert Hauser, ..., Eduardo Tolosa

Journal: New England Journal of Medicine

Citation: N Engl J Med 2009;361:1268-1278

Link: https://doi.org/10.1056/NEJMoa0809335

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does early initiation of rasagiline delay disease progression in Parkinson's disease compared to delayed initiation?

Bottom Line

Rasagiline 1 mg/day met all three hierarchical delayed-start primary endpoints in early PD, suggesting possible disease-modifying effect (early- vs delayed-start UPDRS diff −1.68, 95% CI −3.15 to −0.21, P=0.02 at 72 weeks). 2 mg/day met endpoints 1 and 3 but failed endpoint 2 (week-72 change 3.47 vs 3.11, P=0.60). Published NEJM 2009. 1176 patients. The inconsistent dose-response weakened the disease-modification interpretation.

        Major Points
        Three hierarchical primary endpoints: (1) superiority to placebo in slope of UPDRS change weeks 12–36, (2) superiority to delayed-start in baseline-to-week-72 UPDRS change, (3) noninferiority to delayed-start in slope weeks 48–72.
1 mg met all three endpoints; 2 mg met endpoints 1 and 3 but failed endpoint 2 (week-72 change 3.47 vs 3.11, P=0.60).
Rasagiline 1 mg early- vs delayed-start UPDRS change at 72 wk: −1.68±0.75 (95% CI −3.15 to −0.21), P=0.02.
1176 early PD patients (delayed-start 1 mg N=300, early-start 1 mg N=288, delayed-start 2 mg N=295, early-start 2 mg N=293). Delayed-start design: 36 weeks rasagiline vs placebo → 36 weeks all on rasagiline.
Phase-1 secondary (baseline to wk 36): 1 mg diff vs placebo −3.01 (CI −3.86 to −2.15), P<0.001; 2 mg diff −3.15 (CI −4.00 to −2.31), P<0.001. Both doses had symptomatic benefit.
Slope weeks 12–36 (endpoint 1): 1 mg vs placebo diff −0.05 (CI −0.08 to −0.01), P=0.01; 2 mg diff −0.07 (CI −0.11 to −0.04), P<0.001.
FDA ultimately did not grant disease-modification label due to dose inconsistency.
Published NEJM 2009 (Olanow et al.). Teva sponsored.
Rasagiline: irreversible MAO-B inhibitor. 1 mg/day is the approved PD dose.
Highlighted challenges of demonstrating disease modification in PD using delayed-start designs.

      

Design

Study Type: Randomized, double-blind, placebo-controlled delayed-start trial

Randomization: 1

Blinding: Participants and investigators were blinded

Follow-up Duration: 72 weeks

Centers: 129

Countries: 14 countries (not listed)

Sample Size: 1176

Analysis: Mixed-model repeated-measures ANCOVA; hierarchical testing with Hochberg step-up Bonferroni correction across the two doses

Inclusion Criteria

Age 30–80 years
Untreated idiopathic Parkinson's disease
At least two of three cardinal features (resting tremor, bradykinesia, rigidity); if resting tremor was absent, unilateral onset of symptoms required
Disease duration ≤18 months since diagnosis
Hoehn and Yahr stage <3

Exclusion Criteria

Previous antiparkinsonian medication for more than 3 weeks
Rasagiline or selegiline at any dose, or coenzyme Q10 at more than 300 mg/day, within the previous 120 days
Atypical or secondary parkinsonism
Disease duration >18 months since diagnosis
Hoehn and Yahr stage ≥3
Severe psychiatric or cognitive illness

Baseline Characteristics

Age: 62.2 ± 9.7 years

Sex - Male: 61.1%

Time since diagnosis: 4.5 ± 4.6 months

UPDRS Total (0–176): 20.4 ± 8.5

UPDRS Motor (0–108): 14.2 ± 6.4

ADL Subscale (0–52): 5.2 ± 3.0

Hoehn and Yahr (1–5): 1.51 ± 0.5

Arms

Field	Early-start rasagiline 1 mg	Control	Early-start rasagiline 2 mg	Control
N	288	300	293	295
Intervention	Rasagiline 1 mg/day for 72 weeks	Placebo for 36 weeks, then rasagiline 1 mg/day for 36 weeks	Rasagiline 2 mg/day for 72 weeks	Placebo for 36 weeks, then rasagiline 2 mg/day for 36 weeks
Duration	72 weeks	72 weeks	72 weeks	72 weeks

Outcomes

Outcome	Type	Control
Change in total UPDRS from baseline to last observed value in phase 1 (~week 36)	Secondary	Placebo: 4.27 ± 0.26 · Rasagiline 1 mg: 1.26 ± 0.36; diff vs placebo −3.01 ± 0.43 (95% CI −3.86 to −2.15), P<0.001 · Rasagiline 2 mg: 1.11 ± 0.36; diff vs placebo −3.15 ± 0.43 (95% CI −4.00 to −2.31), P<0.001
Headache (placebo phase)	Adverse	Placebo: 37/595 (6.2%) · Rasagiline 1 mg: 14/288 (4.9%) · Rasagiline 2 mg: 15/293 (5.1%)
Back pain (placebo phase)	Adverse	Placebo: 32/595 (5.4%) · Rasagiline 1 mg: 14/288 (4.9%) · Rasagiline 2 mg: 15/293 (5.1%)
Depression (placebo phase)	Adverse	Placebo: 36/595 (6.1%) · Rasagiline 1 mg: 10/288 (3.5%) · Rasagiline 2 mg: 10/293 (3.4%)
Nasopharyngitis (placebo phase)	Adverse	Placebo: 32/595 (5.4%) · Rasagiline 1 mg: 12/288 (4.2%) · Rasagiline 2 mg: 11/293 (3.8%)
Anxiety (placebo phase)	Adverse	Placebo: 34/595 (5.7%) · Rasagiline 1 mg: 10/288 (3.5%) · Rasagiline 2 mg: 9/293 (3.1%)
Fatigue (placebo phase)	Adverse	Placebo: 17/595 (2.9%) · Rasagiline 1 mg: 17/288 (5.9%) · Rasagiline 2 mg: 10/293 (3.4%)
Note	Adverse	No significant differences in adverse events among study groups; the two placebo groups were combined (N=595). One melanoma in early-start 1 mg group; no tyramine or serotonin reactions.

Subgroup Analysis

Post hoc analysis in highest baseline UPDRS quartile (>25.5): 2 mg early-start had −3.63 ± 1.72 lesser worsening at wk 72 vs delayed-start (P=0.04, N=114); 1 mg early-start had −3.40 ± 1.66 lesser worsening (P=0.04, N=105). Both doses met all three primary endpoints in this subgroup. In the lower three quartiles (≤25.5), neither dose met all three endpoints.

Criticisms

1 mg showed positive results while 2 mg did not on endpoint 2, raising questions about dose consistency
Placebo phase might have been too short to reveal disease modification
First primary endpoint (slope analysis) not previously validated in PD studies; linearity of UPDRS worsening not assured
Post hoc high-quartile subgroup analysis supports 2 mg but is exploratory
Very-early disease population with low baseline UPDRS may have limited ability to detect modification

Funding

Teva Pharmaceutical Industries

Based on: ADAGIO (New England Journal of Medicine, 2009)