Osteoporosis
Conditions
Brief summary
This study will evaluate the bioequivalence of alendronate in combination with vitamin D (cholecalciferol) compared to alendronate alone and the bioequivalence of vitamin D in combination with alendronate compared to vitamin D alone.
Interventions
A single dose tablet of 70 mg alendronate/2800 IU (international unit) vitamin D in one treatment period of each sequence. There will be a 12 day interval between each treatment period.
A single dose table of 70 mg alendronate in one treatment period of each sequence. There will be a 12 day interval between each treatment period.
DIETARY_SUPPLEMENTComparator: cholecalciferol (Vitamin D)
A single dose tablet of 2800 IU vitamin D in one treatment period of each sequence. There will be a 12 day interval between each treatment period.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or nonpregnant female age 18 to 65 years * Female of childbearing potential on appropriate method of contraception and not nursing * BMI (body mass index) less than or equal to 30 kg/m2 * Subject is in good health * Willing to limit direct sunlight and apply sunscreen if in the sun more than 1 hour
Exclusion criteria
* mental or legal incapacitation * received bisphosphonate treatment within 3 months of screening * unable to sit or stand upright for at least 2 hours
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: The Total Urinary Excretion of Alendronate With Alendronate/Vitamin D Combination Tablet Relative to Alendronate Tablet | On Day 1 across the 36-hour urinary collection period (Periods 1 and 2). | Urinary excretion of alendronate was determined over a 36-hour period following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 70 mg alendronate alone tablet. Urine for each treatment period was collected at -2 to 0 hours predose, 0 to 8, 8 to 24, and 24 to 36 hours postdose. |
| Part II : The Pharmacokinetic Parameters AUC0-120 hr of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | On Day 1 across the 120-hour plasma collection period (Periods 1 and 2). | Serum vitamin D3 pharmacokinetic parameter AUC0-120 hr (area under the serum concentration-time curve) after treatment on Day 1was calculated following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 2800-IU vitamin D3 tablet. Serum for each treatment period was collected at -24, -18, -12, -6, and 0 hours predose, and 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose. |
| Part II : The Pharmacokinetic Parameters Cmax of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | On Day 1 across the 120-hour plasma collection period (Periods 1 and 2). | Serum vitamin D3 pharmacokinetic parameter Cmax (maximum concentration observed in serum) after treatmen on Day 1was calculated following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 2800-IU vitamin D3 tablet. Serum for each treatment period was collected at -24, -18, -12, -6, and 0 hours predose, and 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose. |
Participant flow
Recruitment details
Participants were recruited from the following clinical research organizations: Thomas Jefferson University, Division of Clinical Pharmacology, Philadelphia, PA; Clinical Pharmacology Associates, Miami, FL; and Northwest Kinetics, Tacoma, WA, between May 2003 and July 2003.
Pre-assignment details
A total of 244 participants were enrolled in the study (214 participants were enrolled in Part I and 30 participants were enrolled in Part II).
Participants by arm
| Arm | Count |
|---|---|
| Part I 70 mg alendronate/2800-IU vitamin D3 combination tablet; 70 mg alendronate tablet | 214 |
| Part II 2800-IU vitamin D3 tablet; 70 mg alendronate/2800-IU vitamin D3 comination tablet | 30 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 - Part I | Adverse Event | 0 | 1 | 0 | 0 |
| Period 1 - Part I | Lost to Follow-up | 0 | 2 | 0 | 0 |
| Period 1 - Part I | Withdrawal by Subject | 3 | 1 | 0 | 0 |
| Period 1 - Part II | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Part II | Total | Part I |
|---|---|---|---|
| Age, Continuous | 35.2 years | 40.8 years | 41.6 years |
| Height | 170.4 Centimeters | 167.5 Centimeters | 167.2 Centimeters |
| Sex: Female, Male Female | 14 Participants | 133 Participants | 119 Participants |
| Sex: Female, Male Male | 16 Participants | 111 Participants | 95 Participants |
| Weight | 71.2 Kilograms | 72.6 Kilograms | 72.8 Kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 240 | 39 / 214 | 9 / 30 |
| serious Total, serious adverse events | 0 / 240 | 0 / 214 | 0 / 30 |
Outcome results
Primary
Part 1: The Total Urinary Excretion of Alendronate With Alendronate/Vitamin D Combination Tablet Relative to Alendronate Tablet
Urinary excretion of alendronate was determined over a 36-hour period following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 70 mg alendronate alone tablet. Urine for each treatment period was collected at -2 to 0 hours predose, 0 to 8, 8 to 24, and 24 to 36 hours postdose.
Time frame: On Day 1 across the 36-hour urinary collection period (Periods 1 and 2).
Population: Two hundred-seven (207) subjects (excluding 7 that were enrolled but did not complete both study periods) were included in the statistical analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate/Vitamin D Combination | Part 1: The Total Urinary Excretion of Alendronate With Alendronate/Vitamin D Combination Tablet Relative to Alendronate Tablet | 197.5 micrograms (μg) | Standard Deviation 329.1 |
| Alendronate | Part 1: The Total Urinary Excretion of Alendronate With Alendronate/Vitamin D Combination Tablet Relative to Alendronate Tablet | 191.9 micrograms (μg) | Standard Deviation 522.2 |
Comparison: If the true geometric mean ratio (GMR) for total urinary excretion of alendronate of 70 mg alendronate/vitamin D3 combination tablet with respect to alendronate alone is 1.00 then a sample size =208 provided 99% probability of yielding a 90% CI for the total urinary excretion GMR within the interval of \[0.80, 1.25\]. These calculations were based on the observed-pooled within-subject standard deviation (log scale) of 0.521 obtained from earlier Phase 1 studies.90% CI: [0.91, 1.17]
Primary
Part II : The Pharmacokinetic Parameters AUC0-120 hr of Vitamin D in Combination Tablet Relative to Vitamin D Tablet
Serum vitamin D3 pharmacokinetic parameter AUC0-120 hr (area under the serum concentration-time curve) after treatment on Day 1was calculated following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 2800-IU vitamin D3 tablet. Serum for each treatment period was collected at -24, -18, -12, -6, and 0 hours predose, and 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose.
Time frame: On Day 1 across the 120-hour plasma collection period (Periods 1 and 2).
Population: Twenty-eight (28) subjects (excluding 2 that were enrolled but did not complete both study periods) were included in the statistical analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate/Vitamin D Combination | Part II : The Pharmacokinetic Parameters AUC0-120 hr of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | 296.4 ng*hr/mL | Standard Deviation 375.5 |
| Alendronate | Part II : The Pharmacokinetic Parameters AUC0-120 hr of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | 337.9 ng*hr/mL | Standard Deviation 344.2 |
Comparison: If the true GMRs for AUC and Cmax for 70 mg alendronate/vitamin D3 combination tablet with respect to 2800 IU vitamin D3 alone were 1.00 then a sample size=28 provided \>99% probability of yielding a 90% CI for both AUC(0-120 hr) and Cmax GMRs within the interval of \[0.80, 1.25\]. The within-subject standard deviation of 0.14 ln ng•hr/mL for AUC(0-120 hr) (ng•hr/mL) and 0.14 ng/mL for Cmax was obtained from another phase 1 study.90% CI: [0.81, 0.95]
Primary
Part II : The Pharmacokinetic Parameters Cmax of Vitamin D in Combination Tablet Relative to Vitamin D Tablet
Serum vitamin D3 pharmacokinetic parameter Cmax (maximum concentration observed in serum) after treatmen on Day 1was calculated following single-dose administration of a 70 mg alendronate/2800-IU vitamin D3 combination tablet or 2800-IU vitamin D3 tablet. Serum for each treatment period was collected at -24, -18, -12, -6, and 0 hours predose, and 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose.
Time frame: On Day 1 across the 120-hour plasma collection period (Periods 1 and 2).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate/Vitamin D Combination | Part II : The Pharmacokinetic Parameters Cmax of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | 5.9 ng/mL | Standard Deviation 3.3 |
| Alendronate | Part II : The Pharmacokinetic Parameters Cmax of Vitamin D in Combination Tablet Relative to Vitamin D Tablet | 6.6 ng/mL | Standard Deviation 3.1 |
Comparison: If the true GMR ratios for AUC and Cmax for 70 mg alendronate/vitamin D3 combination tablet with respect to 2800 IU vitamin D3 alone were 1.00 then a sample of N=28 provided \>99% probability of yielding a 90% CI for both AUC0-120 hr and Cmax GMRs within the interval of \[0.80, 1.25\]. The within-subject standard deviation of 0.14 ln ng•hr/mL for AUC0-120 hr (ng•hr/mL) and 0.14 ng/mL for Cmax was obtained from another phase 1 study.90% CI: [0.84, 0.95]