Levodopa Benserazide Generic Formulation Versus the Originator (FARM9X59Y4)

April 9, 2024 updated by: IRCCS San Raffaele Roma

Clinical and Pharmacokinetics Study to Evaluate the Therapeutic Equivalence and Bioequivalence of Levodopa Benserazide Generic Formulation (Teva Italia) Versus the Originator (Madopar®)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00163
        • IRCCS San Raffaele Pisana

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

26 years to 71 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

Out-patients with a diagnosis of idiopathic Parkinson's disease for at least 5 years, receiving L-dopa/benserazide, were enrolled to participate into the study. The patients were recruited within the patient population using the hospitals out-patients clinics.

  • Subject must be ≥30 and ≤75 years of age, of either sex and of any race.
  • Diagnosis of Parkinson's disease
  • Subjects in Hoehn and Yahr stages 2 to 4.
  • Subject must have good response to levodopa (≥30% improvement in the UPDRS score).
  • Subject must have been on a stable regimen of L-dopa for at least 4 month before Screening.
  • A female subject must be postmenopausal, or sterile or use a medically accepted method of contraception.

Fragile population was included in the trial (Elderly 65-74 years and over 75 years).

Exclusion Criteria

  • Atypical Parkinsonism
  • Subjects with very severe motor fluctuations and/or dyskinesias.
  • Significant internal-medicine or psychiatric diseases.
  • Subject's clinical laboratory tests outside the normal ranges.
  • History of previous rhabdomyolysis
  • Subjects in therapy with Catechol-O-methyltransferase-inhibitor.
  • Subjects who participated in any other clinical trial in the 4 months before the screening.
  • Any subject who is pregnant or breastfeeding.
  • Subjects demented or not able to give informed consent to trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Levodopa Benserazide Madopar
Madopar 100+25mg and 200+50mg, tablet, tid e qid, for four weeks
Drug: Levodopa Benserazide Madopar
Madopar 100+25mg and 200+50mg, tablet, tid e qid, for four weeks
Experimental: Levodopa Benserazide Teva Italia
Levodopa Benserazide Teva Italia100+25mg and 200+50mg, tablet, tid e qid, for four weeks
Drug: Levodopa Benserazide Teva Italia
Levodopa benserazide Teva 100+25mg and 200+50mg, tablet, tid e qid, for four weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in bioequivalence in the total Area Under the Curve (AUC-t) between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
AUC-t: area under the curve within first and last observed point
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
Change in therapeutic equivalence measured with the Unified Parkinson's Disease rating scale part III between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
A difference of -3 points on the UPDRS motor score be the margin for non-inferiority
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in Patient Clinical Global Impression - Global Improvement scale between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
Change in bioequivalence in minimum concentration (Cmin) between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
Change in bioequivalence in time to maximum concentration (Tmax) after the last dose between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
Change in bioequivalence in the half life (t 1/2) after the last dose between the generic levodopa/benserazide and the originator.
Time Frame: end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)
end of maintenance period 1 and maintenance period 2 (each period of 4 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele Roma

Collaborators

Agenzia Italiana del Farmaco

Investigators

  • Principal Investigator: FABRIZIO STOCCHI, PROFESSOR, IRCCS San Raffaele

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (Actual)

December 1, 2015

Study Completion (Actual)

December 1, 2015

Study Registration Dates

First Submitted

March 31, 2016

First Submitted That Met QC Criteria

April 14, 2016

First Posted (Estimated)

April 18, 2016

Study Record Updates

Last Update Posted (Actual)

April 10, 2024

Last Update Submitted That Met QC Criteria

April 9, 2024

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RP 13/12

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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