L-Dopa supplemented by a peripheral decarboxylase inhibitor is considered the most potent therapeutic regimen prolonging active life in Parkinsonian patients. The long-term benefit of therapy is limited by adverse effects, such as dyskinesia and on-off phenomena, which can be mitigated by the concomitant administration of dopamine agonists, such as bromocriptine. In order to quantify the beneficial impact of early combination therapy, a controlled clinical trial (PRADO:PRA vi-del1 +DOpa) in patients with early Parkinson's disease was carried out, whereby L-Dopa monotherapy (in a fixed combination with benserazide (DoBe) was being compared with the same combination plus bromocriptine (DoBeBro). Patients were recruited and treated by 101 practising neurologists in the Federal Republic of Germany and in Hungary. 'Twenty seven clinical university centers cross-checked the patients at regular intervals. The trial started with 3 months of DoBe monotherapy (median dose of 375 mg L-Dopa for both randomized groups) followed by gradual substitution of DoBe by bromocriptine over 3 months in one of the groups (250 mg L-Dopa/10 mg bromocriptine). The target medication was maintained from study months 6 to 54.

The aim of this multicenter randomized prospective study in patients with early Parkinson's disease is to differentiate over a 4-year period between levodopa/benserazide monotherapy and the corresponding combination with bromocriptine by the assessment of motorial side effects, therapeutical benefit and fine motorial skills. Although there is circumstantial evidence, that partial substitution of levodopa by bromocriptine carries benefit in preventing late levodopa-specific side effects and delaying the declining therapeutical benefit, so far no knowledge has been available how levodopa and the corresponding combination with bromocriptine would compare on a long-term basis. Such study appears all the more important since there are experimental findings consistent with a neurotoxic effect of levodopa on the one hand and some 'protective' impact of bromocriptine on the other. As to the practical procedure of the comparison, all patients were first treated with a levodopa monotherapy for 3 months. This was a platform for the consecutive randomized splitting of the patients into two groups receiving either continuing levodopa therapy or combination therapy, based upon at least 40 +/- 10% substitution of levodopa by bromocriptine. The investigation methods included, besides the usual clinical rating scales (Webster, Zung, Hoehn and Yahr), an apparative test series, the so-called 'MLS', which allowed a sensitive and reliable assessment of fine motorial skills. The results of the first 3 months of treatment with levodopa monotherapy before the consecutive splitting into the two treatment regimens demonstrate that the randomization was successful and that there were no significant differences, that potentially might interfere with the drug-specific evaluation afterwards. The results of the substitution phase show that combined treatment permitted a mean reduction of the levodopa dosage by 40%, without deterioration of therapeutic response. In addition, feasibility of the overall approach based upon a sophisticated interplay between the practising neurologists (101) and the centers (27) was demonstrated.