Trial

Eligibility

Comparison

Treatment Schedule

Additional Treatment

Short-Term Tolerability Trials

Hungary/Scotland ⁽¹⁵⁾

Patients with PD who have never been on LD.

Selegiline vs. Placebo

Selegiline at 10mg/d or matching placebo.

PSG Lazabemide 1 ⁽¹⁶⁾

Patients with idiopathic PD for <7 years in Hoehn & Yahr stage I or II. Subjects excluded if taking any PD medication – specifically if treated within 3 months with LD or dopamine agonists or within 2 months with selegiline.

Lazabemide vs. Placebo

Lazabemide (100, 200 or 400mg/d) or matching placebo. Within each active-treatment group, subjects randomised to receive either 4 or 6 weeks of active medication, followed respectively by either 4 or 2 weeks of placebo.

Use of antidepressants, sedative hypnotics and amphetamines not permitted during study.

PSG Lazabemide 2 ⁽¹⁷⁾

Patients with idiopathic PD for <12 years, treated with LD for <7 years and who were in Hoehn & Yahr stage I-III. Patients had to be on a stable dose of LD for 2 months and not have a history of motor fluctuations or dyskinesias.

Lazabemide+LD vs. Placebo+LD

Lazabemide (100, 200 or 400mg/d) or matching placebo. Within each active-treatment group, subjects randomised to receive either 4 or 6 weeks of active medication, followed respectively by either 4 or 2 weeks of placebo.

During study use of antidepressants, sedative hypnotics and amphetamines not permitted, but anticholinergics and antihistamines at stable dose allowed.

Italy/Germany ⁽¹⁸⁾

Patients with early idiopathic PD, who had never been treated with any kind of antiparkinsonian drugs.

Selegiline+Lisuride vs. Placebo+Lisuride

All patients received lisuride for 3-4 week dose titration period, where lisuride dose increased gradually to optimal dose according to physician and patient’s judgement. This was followed by 3-month double-blind phase of selegiline (5mg bid) or placebo administered with lisuride. After which all patients received selegiline for a further 3 months.

Longer-Term Efficacy Trials

France ⁽¹⁹⁾

Patients with untreated PD in Hoehn & Yahr stage <2.5 in the absence of any other previous anti-PD treatment. Patients who had received previous anti-PD treatment of short duration were accepted for study after obligatory wash-out period of 1 month.

Selegiline vs. Placebo

Selegiline or matching placebo started immediately at 10mg/d and maintained constant until day 90. If patient and physician satisfied with results, treatment could be continued after day 90 indefinitely.

Any dissatisfaction or need for active treatment (with LD) could justify withdrawal from the study.

PSG TEMPO ⁽²⁰⁾

Patients aged >35 who had the presence of ³ 2 of the cardinal signs of PD and who disease severity was not greater than Hoehn & Yahr stage III.

Rasagiline vs. Placebo

Rasagiline (1 or 2mg/d) or matching placebo. Started with 1-week titration period when all subjects on active treatment received 1mg/d of rasagiline. After 1-week, subjects assigned to 2mg/d of rasagiline took the maintenance dosage for the remaining 25-week period.

Subjects could be treated with anticholinergics, but other anti-PD medications were not permitted. Some antidepressants and sympathomimetics were not permitted. Addition of or change of anticholinergic therapy was not allowed during study.

Swedish PSG ⁽²¹⁾

Patients aged ≤75 years with previously untreated idiopathic PD.

Selegiline (±LD) vs. Placebo (±LD)

Selegiline at 10mg/d or matching placebo.

Regimen continued until patient reached level of clinical disability sufficient to warrant initiation of LD therapy (this was primary endpoint of monotherapy part of trial). Study continued in double-blind manner for 7 years or until patient needed additional dopaminergic therapy.

UK Middlesex ⁽²²⁾

Newly diagnosed, untreated clinical idiopathic PD patients aged ≥65 years, with Hoehn & Yahr stage I-III.

Selegiline vs. Placebo

(54 weeks or until LD)

Selegiline at 10mg/d or matching placebo.

Endpoint was reaching Hoehn & Yahr stage IV, which was set as indication for LD replacement therapy.

PSG Lazabemide 3 ⁽²³⁾

Patients who had idiopathic PD for <7 years and who were in Hoehn & Yahr stage I or II. Subjects excluded if taking any PD medication – specifically if treated within 6 weeks with LD or dopamine agonists or within 2 months with MAOBI.

Lazabemide vs. Placebo

(52/54 weeks or until LD)

Lazabemide (25, 50, 100 or 200mg/d) or matching placebo. Within each active-treatment group, subjects randomised to receive either 52 or 54 weeks of active medication, followed respectively by either 4 or 2 weeks of placebo.

Primary endpoint of study was need for LD.

The use of antidepressants, hypnotics and amphetamines not permitted during study.

USA (Bromocriptine) ⁽²⁴⁾

PD patients in Hoehn & Yahr stage I-III. All had ³ 2 of resting tremor, bradykinesia or cog-wheel rigidity. Patients were on no medication at time of baseline evaluation and could have received no selegiline during the preceding 60 days or other anti-PD therapy for ≥30 days prior to entry.

Selegiline+Bromocriptine vs. Placebo+Bromocriptine

Patients initiated on 10mg/d of selegiline or matching placebo. On 3^rd day, patients were started on bromocriptine (5mg), which could be titrated up or down during study as deemed clinically appropriate.

Could receive supplemental doses of LD once a total daily bromocriptine dose of 20mg had been achieved.

USA (Levodopa) ⁽²⁴⁾

PD patients in Hoehn & Yahr stage I-III. All had ³ 2 of resting tremor, bradykinesia or cog-wheel rigidity. Patients were on no medication at time of baseline evaluation and could have received no selegiline during the preceding 60 days or other anti-PD therapy for ≥30 days prior to entry.

Selegiline+LD vs.

Placebo+LD

Patients initiated on 10mg/d of selegiline or matching placebo. On 3^rd day, patients were started on LD (25/100), which could be titrated up or down during study as deemed clinically appropriate.

Italy ⁽²⁵⁾

PD patients diagnosed <2 years, who had not taken any of the study drugs for >4 months.

Selegiline (±LD) vs. LD

Drug doses increased slowly over 2-4 weeks until clinical efficacy reached or adverse effects occurred. Maximum doses were 750mg/d LD and 10mg/d selegiline.

Patients randomised to selegiline could have LD added if necessary. In cases of non-tolerance, assigned drug was substituted with another, at discretion of treating neurologist.

California ⁽²⁶⁾

Patients aged 30-80 years with early, untreated PD for <5 years.

Selegiline vs. Placebo

(3 years or until LD, then wash-out).

Selegiline at 5mg 2xdaily or matching placebo.

Endpoint of study was 3 years follow-up or need for LD.

Norway-Denmark ⁽²⁷⁾

PD patients with Hoehn & Yahr stage I-III. Patients either de novo or could have received LD for <6 months.

Selegiline+LD vs. Placebo+LD

Selegiline (10mg/d) or matching placebo given in morning. If patients had been taking LD, a 2-week wash-out performed before admission to study. Standard formulation of LD and benserazide; dose increased until an optimal dosage reached.

Endpoint of study was 5 years follow-up or need for additional medication. Additional drugs given when disease control required >6 doses of standard LD within 24 hour period.

SELEDO ⁽²⁸⁾

PD patients aged ≤75, with Hoehn & Yahr stage I-III. Patients either de novo or could have received LD for £ 12 months and the dose had been constant for previous 4 weeks.

Selegiline+LD vs. Placebo+LD

Selegiline (10mg/d) or matching placebo. LD dose titrated individually until a stable improved stage reached. The LD dose titrated in this way was kept constant over at least a 3-month period.

Pre-treatment and comedication with amantadine and anticholinergic agents accepted. Beta-blockers and antihypertensives allowed and no restrictions on other drugs for concomitant disorders.

Finland ^(29-31)

Patients aged <80 years with de novo, idiopathic PD (Hoehn & Yahr stage I-III) who had not been treated with anti-PD treatment apart from anticholinergic drugs for <3 months (in which case there was a 2-week wash-out period).

Selegiline (±LD) vs. Placebo (±LD)

Selegiline at 10mg/d or matching placebo.

Endpoint for monotherapy part of study was need for LD. For combined therapy part of study, time until additional dopaminergic therapy was an efficacy measure.

DATATOP ^(32-34)

Patients with idiopathic PD for <5 years in Hoehn & Yahr stage I or II. Patients excluded if they were taking any medications for their PD or had previously been treated with selegiline.

Selegiline vs. Placebo (until LD)

(± tocopherol in each arm)

Selegiline at 10mg/d or matching placebo.

Need for LD was primary endpoint of trial. Once endpoint reached, treatments withdrawn in blinded fashion, then 30 days later a final assessment was done.

UK-PDRG ^(4,35,36)

Untreated PD patients of any age with incapacity, which in view of clinician concerned was sufficient to merit dopaminergic treatment. Patients who had previously received anticholinergic drugs and those who had been considered based on uncertain or incomplete evidence to be intolerant of LD were also eligible. Patients known to have failed to respond to dopaminergic drugs were excluded.

Selegiline+LD vs. LD

(until selegiline arm closed)

Selegiline patients were started with 5mg selegiline for 1 week followed by an increase to 5mg 2xdaily for 3 weeks. LD then added in same way as LD arm. LD patients were treated with 62.5mg 3xdaily, which was then increased to 125mg 3xdaily and maintained for 3 months.

Additional anti-parkinsonian drugs allowed during the trial. If patient unable to tolerate trial drug or failed to improve based on clinician’s judgement, they could be re-randomised to one of the other two arms of the trial or withdrawn.