Levodopa Benserazide Generic Formulation Versus the Originator
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      The trial was an experimental two-centers, randomized, double-blind, two-sequence,
      non-inferiority cross-over study.

      Screened subjects already treated with Levodopa/Benserazide (LDB) (Madopar®) who agreed to
      participate in the study entered a 4 weeks period if not on stable regimen of Madopar®
      (run-in period). Following the run-in period, there were two maintenance periods of 4 weeks
      each, for a total duration of 8 weeks.

      Patients were assigned randomly (1:1) by a computerized randomization system to one of two
      formulation sequences maintaining the dose stabilized during the run in:

        -  generic-originator

        -  originator-generic At the end of maintenance period 1, the patients in each formulation
           group underwent an overnight switch to the same dose of the alternative formulation. The
           dose was kept stable during the whole length of trial. Clinical evaluations were
           performed at the end of each period. The tablets were encapsulated to maintain the
           blindness.

      A pharmacokinetic study with a fixed dose (100+25 mg) was performed in a sub-population of 14
      subjects.

      Population: out-patients with a diagnosis of idiopathic Parkinson's disease for at least 5
      years, receiving L-dopa/benserazide.

      The total duration of the trial was approximately 8 weeks for patient divided in two
      maintenance periods of 4 weeks each.
    

Detailed description: 
      The trial was an experimental two-centers, randomized, double-blind, two-sequence,
      non-inferiority cross-over study.

      Population: out-patients with a diagnosis of idiopathic Parkinson's disease (PD) for at least
      5 years, receiving Levodopa, were enrolled to participate into the study. The study was
      performed in hospital setting using the facilities of the clinical trial centre in both sites
      involved in the study. The patients were recruited within the patient population using the
      hospitals out-patients clinics. Recruitment timing lasted 18 months.

      Screened subjects who agreed to participate in the study, taking Levodopa/Benserazide LDB
      (Madopar®) entered a 4 weeks period with stable regimen of Madopar® (run-in period). The
      formulations of levodopa admitted in the trial were: Madopar® 100+25; and 200+50 (1/2 or 1
      tablet). Following the run-in period, there were two key phases of the study: two maintenance
      periods (4 weeks each), for a total duration of 8 weeks. Patients were assigned randomly
      (1:1) by a computerized randomization system to one of two formulation sequences maintaining
      the dose stabilized during the run in:

        -  generic-originator

        -  originator-generic At the end of maintenance period 1, the patients in each formulation
           group underwent an overnight switching to the same dose of the alternative formulation.
           The dose was kept stable during the whole length of trial. Clinical evaluations were
           performed at the end of each period (see flow chart enclosed). The tablets were
           encapsulated to maintain the blindness. A pharmacokinetic study with a fixed dose
           (100+25 mg) was performed in a sub-population of 14 subjects. The drugs was administered
           orally. In case of prolonged, not tolerable akinetic periods during the study, the
           patients could be rescued with an extra dose of levodopa. Any antiparkinsonian treatment
           modification or supplementation of antiparkinsonian drugs was not allowed during the
           study. Any other drug not specific for Parkinson's disease was evaluated by the
           investigators and allowed only if necessary and if not interfering with the study drugs.

      The random allocation of patients to one of the two treatment groups was centrally managed by
      the coordinating centre, according to an automatically generated randomization list provided
      by the team responsible for the data collection monitoring and statistical analysis. An
      allocation ratio of 1:1 was assumed when generating the list. Patients eligible to enter the
      randomization procedure was sequentially assigned to the lowest randomization sequence number
      not yet assigned to any study subject. For each randomization number, a sealed envelope
      containing the randomization code was prepared by the team that generated the randomization
      list. Unblinding was permitted only if strictly necessary. In case it was essential to know
      the treatment assigned to a patient due to serious unexpected adverse events, the envelope
      containing the patient's randomization code could be open. In such cases, a detailed report
      on the timing, the causes and the patient's randomization number would have been issued by
      the person responsible for the trial and archived by the coordinating centre.

      Mechanical blinding (encapsulation) was used to ensure the double-blind nature of the study.
      Because the patients enrolled in the trial received levodopa/benserazide in different doses,
      over-encapsulation of tablets permitted blinding of most oral dosage forms: ½ tablet, several
      small tablets, capsules of different sizes or colors. Each capsule was then be placed in a
      narrow opaque tube and identified as "Treatment 1" and "Treatment 2" before administration to
      the patient. The patient, the investigator, Medical Monitor and Clinical Monitor remained
      blinded, whereas the site pharmacist and a nurse who administered study medication were not
      blind throughout this part of the study.

      No interim analysis was planned for this protocol. Amendments: no amendments were presented
      during the study.
    

Intervention name(s): Levodopa Benserazide Madopar; Levodopa Benserazide Teva Italia
Intervention type(s): Drug; Drug
Intervention description(s): Madopar 100+25mg and 200+50mg, tablet, tid e qid, for four weeks; Levodopa benserazide Teva 100+25mg and 200+50mg, tablet, tid e qid, for four weeks
Intervention MeSH terms: Levodopa; Benserazide; Benserazide, levodopa drug combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Parkinson; Therapeutic Equivalence; Levodopa