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Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Dose Regimens of BIA 5-453

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03099226
Recruitment Status : Completed
First Posted : April 4, 2017
Last Update Posted : April 4, 2017
Sponsor:
Information provided by (Responsible Party):
Bial - Portela C S.A.

Brief Summary:
The purpose of this study was to characterise the plasma and urine pharmacokinetic profile of Etamicastat (BIA 5-453) and its metabolites after three multiple rising dose regimens of Etamicastat (BIA 5-453).

Condition or disease Intervention/treatment Phase
Hypertension Drug: Placebo Drug: BIA 5-453 Phase 1

Detailed Description:

Single centre, double-blind, randomised, placebo-controlled study of three dosage regimens of Etamicastat (BIA 5-453) in 3 groups of 8 hypertensive patients.

In each group, the study consisted of a 10-day multiple-dose period. Progression to the next dose level only occurred if the previous dose level was considered to be safe and well tolerated. An appropriate interval separated the investigation of doses to permit a timely review and evaluation of safety data prior to proceeding to a higher dose level.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomised, Placebo-controlled Study to Evaluate the Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Dose Regimens of Etamicastat (BIA 5-453) in Hypertensive Subjects
Actual Study Start Date : July 15, 2008
Actual Primary Completion Date : April 3, 2009
Actual Study Completion Date : April 3, 2009

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group 1 - BIA 5-453 50 mg or placebo

This study investigated the doses of 50, 100 and 200 mg of Etamicastat (BIA 5-453) during 10 days administered q.d. in the morning under fasting conditions.

On Day 1 and Day 10, patients remained fasted from a minimum of 8 hours before drug administration until after the collection of the 4 hour PK timepoint. Individuals were served a meal following the 4 hour timepoint and had free access to a maximum of 2.5 litres of water per day. However they were not allowed to drink 1 hour before and 1 hour after the dosing except for the 250 mL taken with the IMP at administration.

On other administrations days, patients remained fasted for a minimum of 8 hours before drug administration and the treatments were administered one hour before a standardized breakfast.

The patients were administered between 7:00 and 9:00 o'clock a.m

Drug: Placebo
Placebo blue hard gelatine capsules

Drug: BIA 5-453
Etamicastat (BIA 5-453) blue hard gelatine capsules - 50 Strength (mg)
Other Name: Etamicastat

Experimental: Group 2 - BIA 5-453 100 mg or placebo

This study investigated the doses of 50, 100 and 200 mg of Etamicastat (BIA 5-453) during 10 days administered q.d. in the morning under fasting conditions.

On Day 1 and Day 10, patients remained fasted from a minimum of 8 hours before drug administration until after the collection of the 4 hour PK timepoint. Individuals were served a meal following the 4 hour timepoint and had free access to a maximum of 2.5 litres of water per day. However they were not allowed to drink 1 hour before and 1 hour after the dosing except for the 250 mL taken with the IMP at administration.

On other administrations days, patients remained fasted for a minimum of 8 hours before drug administration and the treatments were administered one hour before a standardized breakfast.

The patients were administered between 7:00 and 9:00 o'clock a.m

Drug: Placebo
Placebo blue hard gelatine capsules

Drug: BIA 5-453
Etamicastat (BIA 5-453) blue hard gelatine capsules - 50 Strength (mg)
Other Name: Etamicastat

Experimental: Group 3 - BIA 5-453 200 mg or placebo

This study investigated the doses of 50, 100 and 200 mg of Etamicastat (BIA 5-453) during 10 days administered q.d. in the morning under fasting conditions.

On Day 1 and Day 10, patients remained fasted from a minimum of 8 hours before drug administration until after the collection of the 4 hour PK timepoint. Individuals were served a meal following the 4 hour timepoint and had free access to a maximum of 2.5 litres of water per day. However they were not allowed to drink 1 hour before and 1 hour after the dosing except for the 250 mL taken with the IMP at administration.

On other administrations days, patients remained fasted for a minimum of 8 hours before drug administration and the treatments were administered one hour before a standardized breakfast.

The patients were administered between 7:00 and 9:00 o'clock a.m

Drug: BIA 5-453
Etamicastat (BIA 5-453) blue hard gelatine capsules - 50 Strength (mg)
Other Name: Etamicastat




Primary Outcome Measures :
  1. Cmax: Maximum observed plasma concentration (Plasma results on Day 1) [ Time Frame: D1 pre-dose, and H0.5 , 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  2. tmax: time to reach maximum plasma concentration (Plasma results on Day 1) [ Time Frame: D1 pre-dose, and H0.5 , 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  3. AUC0-t: Area under the plasma concentration-time curve from time zero to last measurable plasma concentration (Plasma results on Day 1) [ Time Frame: D1 pre-dose, and H0.5 , 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  4. AUC0-24: AUC from time zero to 24h-post dose (Plasma results on Day 1) [ Time Frame: D1 pre-dose, and H0.5 , 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  5. Cmax: Maximum observed plasma concentration (Plasma results on Day 10) [ Time Frame: D10 pre-dose, and H0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12,16, 24, 48 and 72 h post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  6. tmax: time to reach maximum plasma concentration (Plasma results on Day 10) [ Time Frame: D10 pre-dose, and H0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12,16, 24, 48 and 72 h post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  7. AUC0-t: Area under the plasma concentration-time curve from time zero to last measurable plasma concentration (Plasma results on Day 10) [ Time Frame: D10 pre-dose, and H0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12,16, 24, 48 and 72 h post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  8. AUC0-24: AUC from time zero to 24h-post dose (Plasma results on Day 10) [ Time Frame: D10 pre-dose, and H0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12,16, 24, 48 and 72 h post-dose ]
    Plasma pharmacokinetic parameters (SD) following single and repeated doses of 50, 100, and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  9. C max : Maximum excretion rate (Urine results on Day 1) [ Time Frame: D1 pre-dose, and 0-4, 4-8, 8-12, 12-24 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  10. tmax : Time of Maximum Excretion Rate (Urine results on Day 1) [ Time Frame: D1 pre-dose, and 0-4, 4-8, 8-12, 12-24 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  11. AURC(0-tlast) : Area Under the Urine Excretion Curve from time zero to last time (Urine results on Day 1) [ Time Frame: D1 pre-dose, and 0-4, 4-8, 8-12, 12-24 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  12. AmtCUM : Cumulative Amount of Drug excreted in urine (Urine results on Day 1) [ Time Frame: D1 pre-dose, and 0-4, 4-8, 8-12, 12-24 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  13. C max : Maximum excretion rate (Urine results on Day 10) [ Time Frame: D10 pre-dose, and 0-4, 4-8, 8-12, 12-24, 24-48, 48 72 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  14. tmax : Time of Maximum Excretion Rate (Urine results on Day 10) [ Time Frame: D10 pre-dose, and 0-4, 4-8, 8-12, 12-24, 24-48, 48 72 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  15. AURC(0-tlast) : Area Under the Urine Excretion Curve from time zero to last time (Urine results on Day 10) [ Time Frame: D10 pre-dose, and 0-4, 4-8, 8-12, 12-24, 24-48, 48 72 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects

  16. AmtCUM : Cumulative Amount of Drug excreted in urine (Urine results on Day 10) [ Time Frame: D10 pre-dose, and 0-4, 4-8, 8-12, 12-24, 24-48, 48 72 h post-dose ]
    Urine pharmacokinetic parameters (SD) following single and repeated doses of 100 and 200 mg of Etamicastat (BIA 5-453) in hypertensive subjects



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 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. A signed and dated informed consent form before any study-specific screening procedure is performed.
  2. Male patients aged between 18 and 65 years (inclusive)
  3. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive)
  4. Patients with essential hypertension, without previous treatment (but in which treatment was justified), defined at the selection visit as blood pressure (BP) after 10 minutes of rest in supine position of

    • diastolic blood pressure (DBP) ≥ 90 mmHg and/or,
    • systolic blood pressure (SBP) ≥ 140 mmHg
  5. Patients with essential hypertension, with previous treatment, defined at the end of the screening period (i.e. after 3 weeks wash-out of antihypertensive treatment(s) and before D-1) as blood pressure (BP) after 10 minutes of rest in supine position of

    • diastolic blood pressure (DBP) ≥ 90 mmHg and/or,
    • systolic blood pressure (SBP) ≥ 140 mmHg
  6. Naive or patients taking any class of antihypertensive treatment including (but not limited to) one of the following authorised treatments: B-blockers, diuretics, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), calcium channel blockers. Patients observed a wash-out for their antihypertensive treatments of approximately 3 weeks.
  7. Laboratory tests within the normal range of the laboratory (haematology, biochemistry and urinalysis) or considered as not clinically significant by the investigator.
  8. Electrocardiogram recording on a 12-lead ECG without any clinically significant abnormality
  9. Covered by National Health Insurance
  10. Once clinical eligibility had been established, patients conducted 24 h ambulatory blood pressure monitoring (ABPM) at the end of the screening period, and after treatment wash-out for patients already treated. They had to meet the following off-treatment criteria for mean 24 h ambulatory blood pressure measurements to be included in the study:

    • Average daytime ambulatory systolic/diastolic BP ≥ 135 / 85 mm Hg and/or
    • Ambulatory night-time systolic/diastolic BP ≥ 120 / 70 mm Hg.

Exclusion Criteria:

Criteria associated with hypertension, associated risk factors, and target organ damage:

  1. Severe hypertension (SBP≥180 mm Hg and/or DBP≥110 mm Hg) at any time during the study from screening period to end of study visit or in the medical history, malignant hypertension
  2. Secondary hypertension (including known renovascular hypertension, pheochromocytoma)
  3. Any recent history of coronary artery disease (in the previous 6 months) and including myocardial infarction, or precordial pain suggesting angina pectoris and coronary revascularisation
  4. Any recent history of cardiac failure (in the previous 6 months)
  5. Any recent history of cerebrovascular stroke or transient ischemia (in the previous 6 months)
  6. Any known aortic or mitral valve stenosis or hypertrophic obstructive myocardiopathy
  7. Any known severe ocular complication of hypertension (stage III or IV retinopathy),
  8. Any history of ventricular rhythm disorders (torsades de pointes, ventricular tachycardia, polymorphic ventricular extra-systoles except isolated extra-systoles), auricular disorders (fibrillation or flutter).
  9. Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of Etamicastat (BIA 5-453)
  10. Presence or history of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, haematological, neurological or psychiatric disease.
  11. Frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month).

    Criteria associated with patient characteristic:

  12. History or presence of drug dependence.
  13. Patients smoking more than 10 cigarettes per day
  14. History of alcoholism within 1 year before day 1. Consumption of more than 50 g of ethanol per day (12.5 cL glass of 10° [10%] wine = 12 g; 4 cL of aperitif, 42° [42%] whiskey = 17 g; 25 cL glass of 3° [3%] beer = 7.5 g; 25 cL glass of 6° [6%] beer = 15 g
  15. Participation in a drug trial within 3 months preceding the selection visit.
  16. Positive result from the hepatitis serology for hepatitis B (HBs Ag) and/or hepatitis C (HCV Ab).
  17. Positive result for HIV1+2 serology.
  18. Positive Urine Drug Screen (UDS) (amphetamines, benzodiazepines, ecstasy, cocaine, opiates).
  19. Loss of greater than 400 mL or blood donation within the last 3 months.

    Criteria associated with concomitant diseases:

  20. Patients taking one of the following treatments: aldosterone antagonists, nitrite derivatives.
  21. Presence or history of any allergic or unusual reaction to drugs.
  22. Excessive consumption of beverages containing xanthine bases (more than six cups or glasses per day) or inability to stop consumption during the hospitalization.

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): NCT03099226


Locations
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France
Biotrial
Rennes, France, F-35000
Sponsors and Collaborators
Bial - Portela C S.A.
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Responsible Party: Bial - Portela C S.A.
ClinicalTrials.gov Identifier: NCT03099226    
Other Study ID Numbers: BIA-5453-201HT
First Posted: April 4, 2017    Key Record Dates
Last Update Posted: April 4, 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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Hypertension
Vascular Diseases
Cardiovascular Diseases