Bioequivalence Study of Two Different Formulations of N-acetyl-cysteine (NAC)
Study Details
Study Description
Brief Summary
Study primary Objective:
- To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of N-acetyl-cysteine 600 mg uncoated tablets vs. N-acetyl-cysteine 600 mg film-coated tablets (NAC) in healthy male and female volunteers.
Study secondary objectives:
-
To describe the pharmacokinetic (PK) profile of NAC in plasma after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets;
-
to collect safety and tolerability data after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1 |
Detailed Description
This is single centre, single dose, open, randomised, cross-over, two-stage bioequivalence study to compare two different oral formulations of NAC.
The study has been conducted in healthy volunteers of both genders, in one single dose of both formulations.
The initial 48 subjects were sufficient to satisfy the study objectives on the basis of the ad interim preliminary bioequivalence test. The study was then considered as concluded and the second stage did not take place.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Test - Reference N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose) |
Drug: N-acetylcysteine
The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.
Other Names:
|
Active Comparator: Reference - Test N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose) |
Drug: N-acetylcysteine
The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Cmax of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
Cmax is the maximum concentration level of the drug reached in plasma.
- AUC0-t of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.
Secondary Outcome Measures
- AUC0-∞ of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.
- Tmax of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
time to achieve the maximum concentration level of the drug in plasma.
- t1/2 of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
Half-life (t1/2) is the time to halve the plasma concentration level of the drug.
- Lambda Zeta of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.
- Frel of NAC After Single Dose Administration of Test and Reference [0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)]
Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Informed consent: signed written informed consent before inclusion in the study
-
Sex and age: males and females,18-55 years old, inclusive
-
Body Mass Index (BMI): 18.5-30 kg/m2, inclusive
-
Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, heart rate (HR) 50-90 bpm, measured after 5 min of rest in the sitting position
-
Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
-
Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must be using at least one of the following reliable methods of contraception:
-
Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
-
A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit
-
A male sexual partner who agrees to use a male condom with spermicide
-
A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted.
For all female subjects, pregnancy test result must be negative at screening (serum β-HCG test) and day -1 (urine test).
Exclusion Criteria:
-
Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities
-
Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
-
Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
-
Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
-
Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study
-
Medications: medications, including over the counter (OTC) medications and herbal remedies for 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed
-
Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
-
Blood donation: blood donations for 3 months before this study
-
Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010], caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day)
-
Drug test: positive result at the drug test at screening or day-1
-
Alcohol test: positive alcohol breath test at day -1
-
Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
-
Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Zambon SpA
Investigators
- Principal Investigator: Milko Radicioni, MD, Cross Research SA
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Z7169J02
- CRO-PK-14-286
Study Results
Participant Flow
Recruitment Details | 48 healthy subjects were included in the study, as planned, and received test and reference treatment according to the cross-over design. |
---|---|
Pre-assignment Detail | Subjects were assigned to a sequence of treatments (TR or RT) according to the randomisation list. Randomisation number was given to the subjects on study day -1, Period 1, and was used to assign the treatment sequence according to the randomisation list. The randomisation list was computer-generated by the Contract Research Organisation (CRO) Biometry Unit, using the PLAN procedure of SAS® version 9.3 (TS1M1) (24). The randomisation list was supplied to the Phase I Unit before study start. |
Arm/Group Title | Enrolled Subjects Set |
---|---|
Arm/Group Description | According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule.Two single doses of 600 mg of NAC (one with test and one with reference formulation) were administered to each volunteer in two subsequent study periods (morning of day 1), separated by a wash-out interval of at least 5 days. |
Period Title: Overall Study | |
STARTED | 48 |
COMPLETED | 48 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Enrolled Subjects Set |
---|---|
Arm/Group Description | According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule. Two single doses of 600 mg of NAC (one with test and one with reference formulation) were administered to each volunteer in two subsequent study periods (morning of day 1), separated by a wash-out interval of at least 5 days. |
Overall Participants | 48 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
48
100%
|
>=65 years |
0
0%
|
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
42.6
(8.6)
|
Sex: Female, Male (Count of Participants) | |
Female |
25
52.1%
|
Male |
23
47.9%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
0
0%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
0
0%
|
White |
47
97.9%
|
More than one race |
0
0%
|
Unknown or Not Reported |
1
2.1%
|
Region of Enrollment (participants) [Number] | |
Switzerland |
48
100%
|
Outcome Measures
Title | Cmax of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | Cmax is the maximum concentration level of the drug reached in plasma. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Mean (Standard Deviation) [ng/mL] |
2804.38
(899.47)
|
3215.63
(1382.02)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Test, Reference |
---|---|---|
Comments | ||
Type of Statistical Test | Equivalence | |
Comments | The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function. | |
Statistical Test of Hypothesis | p-Value | 0.0136 |
Comments | p value for treatment effect | |
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric means ratio |
Estimated Value | 89.81 | |
Confidence Interval |
(2-Sided) 94.12% 82.82 to 97.40 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | AUC0-t of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Mean (Standard Deviation) [ng/mL*h] |
10637.87
(3100.94)
|
11773.11
(3775.43)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Test, Reference |
---|---|---|
Comments | ||
Type of Statistical Test | Equivalence | |
Comments | The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function. | |
Statistical Test of Hypothesis | p-Value | 0.0047 |
Comments | ||
Method | ANOVA | |
Comments | p value for treatment effect | |
Method of Estimation | Estimation Parameter | Geometric means ratio |
Estimated Value | 90.79 | |
Confidence Interval |
(2-Sided) 94.12% 85.25 to 96.69 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | AUC0-∞ of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Mean (Standard Deviation) [ng/mL*h] |
12586.17
(3577.24)
|
13739.43
(4190.59)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Test, Reference |
---|---|---|
Comments | ||
Type of Statistical Test | Equivalence | |
Comments | The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function. | |
Statistical Test of Hypothesis | p-Value | 0.0095 |
Comments | p value for treatment effect | |
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric means ratio |
Estimated Value | 91.86 | |
Confidence Interval |
(2-Sided) 94.12% 86.45 to 97.61 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Tmax of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | time to achieve the maximum concentration level of the drug in plasma. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Median (Full Range) [hours] |
1.00
|
1.00
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Test, Reference |
---|---|---|
Comments | ||
Type of Statistical Test | Equivalence | |
Comments | The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function. | |
Statistical Test of Hypothesis | p-Value | 0.5050 |
Comments | ||
Method | Friedman test | |
Comments |
Title | t1/2 of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | Half-life (t1/2) is the time to halve the plasma concentration level of the drug. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Mean (Standard Deviation) [hours] |
14.11
(4.16)
|
13.59
(2.69)
|
Title | Lambda Zeta of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves. |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Test | Reference |
---|---|---|
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. |
Measure Participants | 48 | 48 |
Mean (Standard Deviation) [1/h] |
0.05
(0.01)
|
0.05
(0.01)
|
Title | Frel of NAC After Single Dose Administration of Test and Reference |
---|---|
Description | Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) |
Time Frame | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) |
Outcome Measure Data
Analysis Population Description |
---|
PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results. |
Arm/Group Title | Enrolled Subjects Set |
---|---|
Arm/Group Description | According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule. |
Measure Participants | 48 |
Mean (Standard Deviation) [percentage] |
92.82
(18.05)
|
Adverse Events
Time Frame | From the beginning of screening days ( day -21 ) up to Final Visit (Day 2). | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Test - Reference | Reference - Test | ||
Arm/Group Description | N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose) N-acetylcysteine: The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose) N-acetylcysteine: The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h. | ||
All Cause Mortality |
||||
Test - Reference | Reference - Test | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/48 (0%) | 0/48 (0%) | ||
Serious Adverse Events |
||||
Test - Reference | Reference - Test | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/48 (0%) | 0/48 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Test - Reference | Reference - Test | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 4/48 (8.3%) | 2/48 (4.2%) | ||
Gastrointestinal disorders | ||||
Nausea | 1/48 (2.1%) | 1 | 1/48 (2.1%) | 1 |
Abdominal discomfort | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
Vomiting | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 |
Nervous system disorders | ||||
Dizziness | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 |
Headache | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Isabella Salerio, PhD |
---|---|
Organization | Zambon S.p.A. |
Phone | +3902665241 |
clinicaltrials@zambongroup.com |
- Z7169J02
- CRO-PK-14-286