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Tolerability, Safety and Pharmacokinetics of Four Single-doses of BIA 6-512 (Trans-resveratrol) and Their Effect on the Levodopa Pharmacokinetics

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ClinicalTrials.gov Identifier: NCT03091543
Recruitment Status : Completed
First Posted : March 27, 2017
Last Update Posted : March 27, 2017
Sponsor:
Information provided by (Responsible Party):
Bial - Portela C S.A.

Brief Summary:
To investigate the effect of four single oral doses of BIA 6-512 (25 mg, 50 mg, 100 mg and 200 mg) on levodopa pharmacokinetics when administered in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg and to assess the tolerability and safety of four single oral doses of BIA 6-512 (25 mg, 50 mg, 100 mg and 200 mg) when administered in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg.

Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: Madopar® HBS 125 Drug: Placebo Drug: BIA 6-512 25 mg dose Drug: BIA 6-512 50 mg dose Drug: BIA 6-512 100 mg dose Drug: BIA 6-512 200 mg dose Phase 1

Detailed Description:
Single centre, double-blind, randomised, placebo-controlled, crossover study with five single-dose treatment periods, with a washout period between doses of 5 days or more. In each of the five consecutive treatment periods, eligible subjects were admitted to the UFH in the day prior to receiving the study medication. On the morning of the dosing day, subjects received BIA 6-512/Placebo concomitantly with Madopar® HBS 125 in fasting conditions (at least 8 hours) and remained in the UFH until at least 24 h post-dose; then, they were discharged and returned for the next period or the follow-up visit. Blood samples for the assay of plasma BIA 6-512, levodopa and 3-O-methyldopa (3-OMD) were taken at the following times: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomised, Crossover, Placebo-controlled Study in Healthy Volunteers to Investigate the Tolerability, Safety and Pharmacokinetics of Four Single-doses of BIA 6-512 (Trans-resveratrol) and Their Effect on the Levodopa Pharmacokinetics When Administered in Combination With a Single-dose of Levodopa/Benserazide 100/25 mg
Actual Study Start Date : May 4, 2004
Actual Primary Completion Date : July 23, 2004
Actual Study Completion Date : July 23, 2004

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sequence A (25 mg - 50 mg - 100 mg - 200 mg - Placebo)
Concomitantly with the BIA 6-512/Placebo dose, subjects will be administered levodopa/benserazide 100/25 mg. All subjects attended to each 5 treatment periods and received a different dose of BIA 6-512 or placebo in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg in each of these treatment periods. The washout period between periods was 5 days or more.
Drug: Madopar® HBS 125
1 capsule of Madopar® HBS 125 (levodopa 100 mg / benserazide 25 mg) in an open label manner, concomitantly with BIA 6-512/Placebo.

Drug: Placebo
2 capsules of placebo

Drug: BIA 6-512 25 mg dose
1 capsule of 25 mg plus 1 capsule of placebo

Drug: BIA 6-512 50 mg dose
2 capsules of 25 mg

Drug: BIA 6-512 100 mg dose
1 capsule of 100 mg plus 1 capsule of placebo

Drug: BIA 6-512 200 mg dose
2 capsules of 100 mg

Experimental: Sequence B (Placebo - 25 mg - 50 mg - 100 mg - 200 mg)
Concomitantly with the BIA 6-512/Placebo dose, subjects will be administered levodopa/benserazide 100/25 mg. All subjects attended to each 5 treatment periods and received a different dose of BIA 6-512 or placebo in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg in each of these treatment periods. The washout period between periods was 5 days or more.
Drug: Madopar® HBS 125
1 capsule of Madopar® HBS 125 (levodopa 100 mg / benserazide 25 mg) in an open label manner, concomitantly with BIA 6-512/Placebo.

Drug: Placebo
2 capsules of placebo

Drug: BIA 6-512 25 mg dose
1 capsule of 25 mg plus 1 capsule of placebo

Drug: BIA 6-512 50 mg dose
2 capsules of 25 mg

Drug: BIA 6-512 100 mg dose
1 capsule of 100 mg plus 1 capsule of placebo

Drug: BIA 6-512 200 mg dose
2 capsules of 100 mg

Experimental: Sequence C (200 mg - Placebo - 25 mg - 50 mg - 100 mg)
Concomitantly with the BIA 6-512/Placebo dose, subjects will be administered levodopa/benserazide 100/25 mg. All subjects attended to each 5 treatment periods and received a different dose of BIA 6-512 or placebo in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg in each of these treatment periods. The washout period between periods was 5 days or more.
Drug: Madopar® HBS 125
1 capsule of Madopar® HBS 125 (levodopa 100 mg / benserazide 25 mg) in an open label manner, concomitantly with BIA 6-512/Placebo.

Drug: Placebo
2 capsules of placebo

Drug: BIA 6-512 25 mg dose
1 capsule of 25 mg plus 1 capsule of placebo

Drug: BIA 6-512 50 mg dose
2 capsules of 25 mg

Drug: BIA 6-512 100 mg dose
1 capsule of 100 mg plus 1 capsule of placebo

Drug: BIA 6-512 200 mg dose
2 capsules of 100 mg

Experimental: Sequence D (100 mg - 200 mg - Placebo - 25 mg - 50 mg)
Concomitantly with the BIA 6-512/Placebo dose, subjects will be administered levodopa/benserazide 100/25 mg. All subjects attended to each 5 treatment periods and received a different dose of BIA 6-512 or placebo in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg in each of these treatment periods. The washout period between periods was 5 days or more.
Drug: Madopar® HBS 125
1 capsule of Madopar® HBS 125 (levodopa 100 mg / benserazide 25 mg) in an open label manner, concomitantly with BIA 6-512/Placebo.

Drug: Placebo
2 capsules of placebo

Drug: BIA 6-512 25 mg dose
1 capsule of 25 mg plus 1 capsule of placebo

Drug: BIA 6-512 50 mg dose
2 capsules of 25 mg

Drug: BIA 6-512 100 mg dose
1 capsule of 100 mg plus 1 capsule of placebo

Drug: BIA 6-512 200 mg dose
2 capsules of 100 mg

Experimental: Sequence E (50 mg - 100 mg - 200 mg - Placebo - 25 mg)
Concomitantly with the BIA 6-512/Placebo dose, subjects will be administered levodopa/benserazide 100/25 mg. All subjects attended to each 5 treatment periods and received a different dose of BIA 6-512 or placebo in combination with a single-dose of controlled release levodopa/benserazide 100/25 mg in each of these treatment periods. The washout period between periods was 5 days or more.
Drug: Madopar® HBS 125
1 capsule of Madopar® HBS 125 (levodopa 100 mg / benserazide 25 mg) in an open label manner, concomitantly with BIA 6-512/Placebo.

Drug: Placebo
2 capsules of placebo

Drug: BIA 6-512 25 mg dose
1 capsule of 25 mg plus 1 capsule of placebo

Drug: BIA 6-512 50 mg dose
2 capsules of 25 mg

Drug: BIA 6-512 100 mg dose
1 capsule of 100 mg plus 1 capsule of placebo

Drug: BIA 6-512 200 mg dose
2 capsules of 100 mg




Primary Outcome Measures :
  1. Maximum observed plasma drug concentration (Cmax) post-dose - Levodopa [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of Levodopa following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  2. Time of occurrence of Cmax (tmax) - Levodopa [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of Levodopa following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  3. Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t), calculated by the linear trapezoidal rule - Levodopa [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of Levodopa following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  4. Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞), calculated from AUC0-t + (Clast/λz), where Clast is the last quantifiable concentration and λz the apparent terminal rate constant - Levodopa [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of Levodopa following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  5. Apparent terminal half-life, calculated from ln 2/λz (t1/2) - Levodopa [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of Levodopa following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  6. Maximum observed plasma drug concentration (Cmax) post-dose - BIA 6-512 [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of BIA 6-512 following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  7. Time of occurrence of Cmax (tmax) - BIA 6-512 [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of BIA 6-512 following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  8. Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t), calculated by the linear trapezoidal rule - BIA 6-512 [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of BIA 6-512 following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  9. Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞), calculated from AUC0-t + (Clast/λz), where Clast is the last quantifiable concentration and λz the apparent terminal rate constant - BIA 6-512 [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of BIA 6-512 following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  10. Apparent terminal half-life, calculated from ln 2/λz (t1/2) - BIA 6-512 [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of BIA 6-512 following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg


Secondary Outcome Measures :
  1. Maximum observed plasma drug concentration (Cmax) post-dose - 3-OMD [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of 3-O-methyldopa (3-OMD) following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  2. Time of occurrence of Cmax (tmax) - 3-OMD [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of 3-O-methyldopa (3-OMD) following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  3. Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t), calculated by the linear trapezoidal rule - 3-OMD [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of 3-O-methyldopa (3-OMD) following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  4. Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞), calculated from AUC0-t + (Clast/λz), where Clast is the last quantifiable concentration and λz the apparent terminal rate constant - 3-OMD [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of 3-O-methyldopa (3-OMD) following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg

  5. Apparent terminal half-life, calculated from ln 2/λz (t1/2) - 3-OMD [ Time Frame: pre-dose, ¼, ½, 1, 1½, 2, 3, 4, 6, 9, 12, 16 and 24 hours post-dose. ]
    Pharmacokinetic parameters of 3-O-methyldopa (3-OMD) following oral administration of single-doses of Madopar® HBS 125 concomitantly with placebo or BIA 6-512 25 mg, 50 mg, 100 mg and 200 mg



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or female subjects aged between 18 and 45 years, inclusive.
  • Subjects of body mass index (BMI) between 19 and 30 kg/m2, inclusive.
  • Subjects who were healthy as determined by pre-study medical history, physical examination (including neurological examination), and 12-lead ECG.
  • Subjects who had clinical laboratory tests within normal reference values.
  • Subjects who were negative for HBsAg, anti-HCVAb and HIV-1 and HIV-2 Ab tests at screening.
  • Subjects who had negative for alcohol and drugs of abuse at screening and each admission to each treatment period.
  • Subjects who were non-smokers or who smoked less than 10 cigarettes or equivalent per day.
  • Subjects who were able and willing to give written informed consent.
  • (If female) She was not of childbearing potential by reason of surgery or, if of childbearing potential, she used one of the following methods of contraception: double barrier, intrauterine device or abstinence.
  • (If female) She had a negative pregnancy test at screening and admission to each treatment period.

Exclusion Criteria:

  • Subjects who did not conform to the above inclusion criteria, OR
  • Subjects who had a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders.
  • Subjects who had a clinically relevant surgical history.
  • Subjects who had a clinically relevant family history.
  • Subjects who had a history of relevant atopy.
  • Subjects who had a history of relevant drug hypersensitivity.
  • Subjects who had a history of alcoholism or drug abuse.
  • Subjects who consumed more than 21 units of alcohol a week.
  • Subjects who had a significant infection or known inflammatory process on screening and/or first admission.
  • Subjects who had acute gastrointestinal symptoms at the time of screening and/or first admission (e.g., nausea, vomiting, diarrhoea, heartburn).
  • Subjects who had used prescription or over-the-counter medication within 2 weeks of first admission.
  • Subjects who had used any investigational drug and/or participated in any clinical trial within 4 months of their first admission.
  • Subjects who had donated and/or received any blood or blood products within the previous 4 months prior to screening.
  • Subjects who were vegetarians, vegans and/or have medical dietary restrictions.
  • Subjects who cannot communicate reliably with the investigator.
  • Subjects who were unlikely to co-operate with the requirements of the study.
  • Subjects who were unwilling or unable to give written informed consent.
  • (If female) She was pregnant or breast-feeding.
  • (If female) She was of childbearing potential and she did not use an approved effective contraceptive method or she used oral contraceptives.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03091543


Locations
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Portugal
Human Pharmacology Unit (UFH)
S. Mamede do Coronado, Portugal, 4745-457
Sponsors and Collaborators
Bial - Portela C S.A.

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Responsible Party: Bial - Portela C S.A.
ClinicalTrials.gov Identifier: NCT03091543     History of Changes
Other Study ID Numbers: BIA-6512-101
First Posted: March 27, 2017    Key Record Dates
Last Update Posted: March 27, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Resveratrol
Levodopa
Benserazide
Benserazide, levodopa drug combination
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Antioxidants
Protective Agents
Enzyme Inhibitors