Osteoporosis
Conditions
Brief summary
This study will evaluate the bioequivalence of alendronate in combination with vitamin D compared to alendronate alone and the bioequivalence of vitamin D in combination with alendronate compared to vitamin D alone. This was an open-label, randomized, 2-part, crossover study. Each participant participated in one part of the study only (i.e., each participant participated only in Part I or only in Part II). Participants entered the study sequentially within each part of the study. A washout of at least 12 days separated each treatment period within each part of the study.
Interventions
DRUGalendronate sodium+vitamin D combination
A single dose tablet of 70mg alendronate sodium+5600 IU vitamin D combination tablet in one treatment period of each sequence.
A single dose tablet of 70mg alendronate in one treatment period of each sequence.
DIETARY_SUPPLEMENTComparator: Vitamin D
Two tablets of 2800 IU vitamin D, totaling 5600 IU, in one treatment period of each sequence.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or nonpregnant female age 18 to 85 years * female of childbearing potential on appropriate method of contraception and not nursing * Body Mass Index (BMI) less than or equal to 30 kg/m2 * subject is in good health
Exclusion criteria
* mental or legal incapacitation * received bisphosphonate treatment within 3 months of enrollment. * unable to sit or stand upright for at least 2 hours * unwilling to refrain from consumption of alcohol or caffeinated products from 24 hours prior and 36 hours after study drug administration * unwilling to limit alcohol consumption to no more than 2 drinks per day * unwilling to limit caffeinated products to the equivalent of 4 cups of coffee per day or equivalent. * unwilling to refrain from smoking during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Urinary Excretion of Alendronate | Day 1-2 across the 36 hour urinary collection period (Periods 1 and 2) | Bioequivalence was demonstrated by measuring the total urinary excretion of alendronate which was determined over a 36-hour period following single dose administration of 70-mg alendronate+5600 International Units (IU) vitamin D combination tablet and 70mg alendronate tablet alone. 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 on Days 1 and 2. |
| Part II: AUC (Area Under the Plasma Concentration-time Curve) of Vitamin D | Day 1 across the 80-hour plasma collection period (Period 1 and 2) | The serum vitamin D pharmacokinetic parameter was calculated following the treatment of 70mg alendronate+5600 IU vitamin D combination tablet and 5600 IU vitamin D tablet on Day 1: area under the plasma concentration-time curve (AUC0-80hr). Serum samples for determination of vitamin D concentrations were obtained at -2 and 0 hrs predose on Day 1 and at 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72 and 80 hours post dose for each treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part II : Maximum Concentration (Cmax) of Vitamin D | Day 1 across the 80-hour plasma collection period (Periods 1 and 2) | Serum vitamin D pharmacokinetic parameter was calculated for the following: maximum concentration of drug observed in serum (Cmax). Serum samples for determination of vitamin D concentrations were obtained at -2 and 0 hrs predose on Day 1 and at 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72 and 80 hours post dose for each treatment period. |
Participant flow
Pre-assignment details
This was a randomized, 2-part, crossover study. Each participant participated in one part of the study only (i.e., each participant participated only in Part I or only in Part II). A washout of at least 12 days separated each treatment period within each part of the study. 318 participants were enrolled (251 in Part 1 and 67 in Part 2).
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Alendronate+vitamin D combo, then alendronate: In Period 1 participants received a single dose of 70mg alendronate+5600 IU vitamin D combination tablet, and in Period 2 a single dose of 70mg alendronate tablet. A washout of at least 12 days separated each treatment period.
Alendronate, then alendronate+vitamin D combo: In Period 1 participants received 70mg alendronate tablet, and in Period 2 a single dose of 70mg alendronate+5600 IU vitamin D combination tablet. A washout of at least 12 days separated each treatment period. | 251 |
| Part 2 Alendronate+vitamin D combo, then vitamin D: In Period 1 participants received a single dose of 70mg alendronate+5600 IU vitamin D combination tablet, and in Period 2 a single dose of 5600 IU vitamin D, administered as 2 x 2800 IU tablets. A washout of at least 12 days separated each treatment period.
Vitamin D, then alendronate+vitamin D combo: In Period 1 participants received a single dose of 5600 IU vitamin D, administered as 2 x 2800 IU tablets, and in Period 2 a single dose of 70mg alendronate+5600 IU vitamin D combination tablet. A washout of at least 12 days separated each treatment period. | 67 |
| Total | 318 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Adverse Event | 0 | 1 | 0 | 0 |
| Period 1 | Lost to Follow-up | 1 | 2 | 0 | 0 |
| Period 1 | positive drug screen or personal reasons | 0 | 3 | 0 | 4 |
| Period 1 | Protocol Violation | 0 | 0 | 1 | 0 |
| Period 1 | Withdrawal by Subject | 8 | 6 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 0 | 1 | 1 |
| Period 2 | Positive Drug Screen or Personal Reasons | 1 | 0 | 0 | 0 |
| Period 2 | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1 | Part 2 | Total |
|---|---|---|---|
| Age, Customized Between 18 and 78 years | 251 participants | 67 participants | 318 participants |
| Sex: Female, Male Female | 132 Participants | 29 Participants | 161 Participants |
| Sex: Female, Male Male | 119 Participants | 38 Participants | 157 Participants |
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 | 21 / 302 | 12 / 241 | 9 / 65 |
| serious Total, serious adverse events | 0 / 302 | 0 / 241 | 0 / 65 |
Outcome results
Primary
Part 1: Urinary Excretion of Alendronate
Bioequivalence was demonstrated by measuring the total urinary excretion of alendronate which was determined over a 36-hour period following single dose administration of 70-mg alendronate+5600 International Units (IU) vitamin D combination tablet and 70mg alendronate tablet alone. 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 on Days 1 and 2.
Time frame: Day 1-2 across the 36 hour urinary collection period (Periods 1 and 2)
Population: 220 participants of the 251 enrolled in Part 1 were included in the statistical analysis. 31 participants were excluded: 23 were enrolled but did not complete both study periods and 8 participants had incomplete urine profiles in one or both periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate+Vitamin D Combo | Part 1: Urinary Excretion of Alendronate | 133.6 μg | Standard Deviation 189.2 |
| Alendronate | Part 1: Urinary Excretion of Alendronate | 132.2 μg | Standard Deviation 273.4 |
90% CI: [0.92, 1.11]
Primary
Part II: AUC (Area Under the Plasma Concentration-time Curve) of Vitamin D
The serum vitamin D pharmacokinetic parameter was calculated following the treatment of 70mg alendronate+5600 IU vitamin D combination tablet and 5600 IU vitamin D tablet on Day 1: area under the plasma concentration-time curve (AUC0-80hr). Serum samples for determination of vitamin D concentrations were obtained at -2 and 0 hrs predose on Day 1 and at 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72 and 80 hours post dose for each treatment period.
Time frame: Day 1 across the 80-hour plasma collection period (Period 1 and 2)
Population: 60 participants of the 67 enrolled in Part 2 were included in the statistical analysis. 7 participants that were enrolled, but did not complete both study periods were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate+Vitamin D Combo | Part II: AUC (Area Under the Plasma Concentration-time Curve) of Vitamin D | 490.2 ng*hr/mL | Standard Deviation 259.6 |
| Alendronate | Part II: AUC (Area Under the Plasma Concentration-time Curve) of Vitamin D | 518.7 ng*hr/mL | Standard Deviation 269.8 |
Comparison: Least squares mean ratio for AUC 0-80 hr for vitamin D following administration of combination tablet and vitamin D alone. No correction for endogenous Vitamin D concentration pre-treatment was made in the analysis.90% CI: [0.89, 1]
Secondary
Part II : Maximum Concentration (Cmax) of Vitamin D
Serum vitamin D pharmacokinetic parameter was calculated for the following: maximum concentration of drug observed in serum (Cmax). Serum samples for determination of vitamin D concentrations were obtained at -2 and 0 hrs predose on Day 1 and at 2, 3, 5, 7, 9, 12, 16, 24, 36, 48, 72 and 80 hours post dose for each treatment period.
Time frame: Day 1 across the 80-hour plasma collection period (Periods 1 and 2)
Population: 60 participants of the 67 enrolled in Part 2 were included in the statistical analysis. 7 participants that were enrolled, but did not complete both study periods were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alendronate+Vitamin D Combo | Part II : Maximum Concentration (Cmax) of Vitamin D | 12.2 ng/ml | Standard Deviation 5.6 |
| Alendronate | Part II : Maximum Concentration (Cmax) of Vitamin D | 13.0 ng/ml | Standard Deviation 5.9 |
Comparison: Least squares mean ratio for Cmax for vitamin D following administration of combination tablet and vitamin D alone.~No correction for endogenous Vitamin D concentration pre-treatment was made in the analysis.90% CI: [0.88, 1]