A Study of the Bioequivalence of 70 mg Alendronate and 70 mg Alendronate in Combination With 2800 IU Vitamin D

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00806416
• Collaborator: (none)
• Enrollment: 244
• Arms: 4
• Duration (Months): 8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis	Drug: alendronate sodium (+) cholecalciferol; Drug: Comparator: alendronate; Dietary Supplement: Comparator: cholecalciferol (Vitamin D)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 244 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 2-Part, Open-Label, Randomized, Crossover Study to Evaluate the Bioequivalence of the 70 mg Alendronate/2800 IU Vitamin D3 Final Market Combination Tablet to a 70 mg Alendronate Marketed Tablet, and the Relative Bioavailability of Vitamin D3
• Study Start Date: May 1, 2003
• Actual Primary Completion Date: Aug 1, 2003
• Actual Study Completion Date: Jan 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1 alendronate/vitamin D combination then alendronate	Drug: alendronate sodium (+) cholecalciferol; 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.; Drug: Comparator: alendronate; 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.
Experimental: Sequence 2 alendronate then alendronate/vitamin D combination	Drug: alendronate sodium (+) cholecalciferol; 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.; Drug: Comparator: alendronate; 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.
Experimental: Sequence 3 alendronate/vitamin D combination then vitamin D	Drug: alendronate sodium (+) cholecalciferol; 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.; Dietary Supplement: Comparator: 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.
Experimental: Sequence 4 vitamin D then alendronate/vitamin D combination	Drug: alendronate sodium (+) cholecalciferol; 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.; Dietary Supplement: Comparator: 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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Organon and Co
• ClinicalTrials.gov Identifier: NCT00806416
• Other Study ID Numbers: 0217A-226; 2008_596
• First Posted: Dec 10, 2008
• Last Update Posted: Feb 8, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Osteoporosis; Vitamin D; Cholecalciferol; Alendronate

Study Results

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 Detail	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).

Arm/Group Title	Alendronate/Vitamin D Combination Then Alendronate	Alendronate Then Alendronate/Vitamin D Combination	Alendronate/Vitamin D Combination Then Vitamin D	Vitamin D Then Alendronate/Vitamin D Combination
Arm/Group Description	70 mg alendronate/2800-IU (international unit) vitamin D3 (cholecalciferol) combination tablet; 70 mg alendronate tablet	70 mg alendronate tablet; 70 mg alendronate/2800-IU vitamind D3 comination tablet	70 mg alendronate/2800-IU vitamind D3 combination tablet; 2800-IU vitamin D3 tablet	2800-IU vitamin D3 tablet; 70 mg alendronate/2800-IU vitamin D3 comination tablet
Period Title: Period 1 - Part I
STARTED	107	107	0	0
COMPLETED	104	103	0	0
NOT COMPLETED	3	4	0	0
Period Title: Period 1 - Part I
STARTED	104	103	0	0
COMPLETED	104	103	0	0
NOT COMPLETED	0	0	0	0
Period Title: Period 1 - Part I
STARTED	0	0	14	16
COMPLETED	0	0	14	14
NOT COMPLETED	0	0	0	2
Period Title: Period 1 - Part I
STARTED	0	0	14	14
COMPLETED	0	0	14	14
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Part I	Part II	Total
Arm/Group Description	70 mg alendronate/2800-IU vitamin D3 combination tablet; 70 mg alendronate tablet	2800-IU vitamin D3 tablet; 70 mg alendronate/2800-IU vitamin D3 comination tablet	Total of all reporting groups
Overall Participants	214	30	244
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	41.6	35.2	40.8
Sex: Female, Male (Count of Participants)
Female	119 55.6%	14 46.7%	133 54.5%
Male	95 44.4%	16 53.3%	111 45.5%
Height (Centimeters) [Mean (Full Range) ]
Mean (Full Range) [Centimeters]	167.2	170.4	167.5
Weight (Kilograms) [Mean (Full Range) ]
Mean (Full Range) [Kilograms]	72.8	71.2	72.6

Outcome Measures

1. Primary Outcome

Title	Part 1: The Total Urinary Excretion of Alendronate With Alendronate/Vitamin D Combination Tablet Relative to Alendronate Tablet
Description	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).

Outcome Measure Data

Analysis Population Description

Two hundred-seven (207) subjects (excluding 7 that were enrolled but did not complete both study periods) were included in the statistical analysis.

Arm/Group Title	Alendronate/Vitamin D Combination	Alendronate
Arm/Group Description	70 mg alendronate/2800-IU vitamin D3 combination tablet	70 mg alendronate tablet
Measure Participants	207	207
Least Squares Mean (Standard Deviation) [micrograms (μg)]	197.5 (329.1)	191.9 (522.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alendronate/Vitamin D Combination, Alendronate
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Administration of a 70 mg alendronate/2800 IU vitamin D3 final market combination tablet and the 70 mg alendronate market tablet, the GMR of the combination tablet/alendronate only tablet are contained within [0.80,1.25].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least square mean ratio
	Estimated Value	1.03
	Confidence Interval	() 90%; 0.91 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Part II : The Pharmacokinetic Parameters AUC0-120 hr of Vitamin D in Combination Tablet Relative to Vitamin D Tablet
Description	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).

Outcome Measure Data

Analysis Population Description

Twenty-eight (28) subjects (excluding 2 that were enrolled but did not complete both study periods) were included in the statistical analysis.

Arm/Group Title	Alendronate/Vitamin D Combination	Vitamin D
Arm/Group Description	70 mg alendronate/2800-IU vitamin D3 combination tablet	2800-IU vitamin D3 tablet
Measure Participants	28	28
Least Squares Mean (Standard Deviation) [ng*hr/mL]	296.4 (375.5)	337.9 (344.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alendronate/Vitamin D Combination, Alendronate
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Administration of a 70 mg alendronate/2800 IU vitamin D3 final market combination tablet and a tablet containing 2800 IU vitamin D3, the geometric mean ratio (GMR) for AUC0-120 hr and Cmax, corrected for predose concentration, of the combination tablet/2800 IU vitamin D3 only tablet were contained within [0.80,1.25].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least square mean ratio for AUC0-120 hr
	Estimated Value	0.88
	Confidence Interval	() 90%; 0.81 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Part II : The Pharmacokinetic Parameters Cmax of Vitamin D in Combination Tablet Relative to Vitamin D Tablet
Description	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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alendronate/Vitamin D Combination	Vitamin D
Arm/Group Description	70 mg alendronate/2800-IU vitamin D3 combination tablet	2800-IU vitamin D3 tablet
Measure Participants	28	28
Least Squares Mean (Standard Deviation) [ng/mL]	5.9 (3.3)	6.6 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alendronate/Vitamin D Combination, Alendronate
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Administration of a 70 mg alendronate/2800 IU vitamin D3 final market combination tablet and a tablet containing 2800 IU vitamin D3, the geometric mean ratio (GMR) for AUC0-120 hr and Cmax, corrected for predose concentration, of the combination tablet/2800 IU vitamin D3 only tablet were contained within [0.80,1.25].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least-squares mean for Cmax
	Estimated Value	0.89
	Confidence Interval	() 90%; 0.84 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	214 subjects were enrolled in Part I of the study & 30 subjects were enrolled in Part II. All 214 subjects in the Alendronate arm & 210 subjects from Part I and 30 subjects from Part II in the Alendronate/Vitamin D Combination are included in the analysis for safety. The 30 Vitamin D arm subjects that were enrolled in Part II are included.
Arm/Group Title	Alendronate/Vitamin D Combination		Alendronate		Vitamin D
Arm/Group Description	70 mg alendronate/2800-IU vitamin D3 combination tablet		70 mg alendronate tablet		2800-IU vitamin D3 tablet
All Cause Mortality
	Alendronate/Vitamin D Combination		Alendronate		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Alendronate/Vitamin D Combination		Alendronate		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/240 (0%)		0/214 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Alendronate/Vitamin D Combination		Alendronate		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/240 (22.9%)		39/214 (18.2%)		9/30 (30%)
Eye disorders
Conjunctivitis	1/240 (0.4%)		0/214 (0%)		1/30 (3.3%)
Keratoconjunctivitis Sicca	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Gastrointestinal disorders
Abdominal Pain	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Abdominal Pain Upper	2/240 (0.8%)		3/214 (1.4%)		0/30 (0%)
Constipation	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Diarrhoea	9/240 (3.8%)		6/214 (2.8%)		1/30 (3.3%)
Dyspepsia	3/240 (1.3%)		4/214 (1.9%)		0/30 (0%)
Flatulence	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Intestinal Functional Disorder	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Loose Stools	1/240 (0.4%)		2/214 (0.9%)		0/30 (0%)
Nausea	4/240 (1.7%)		4/214 (1.9%)		1/30 (3.3%)
Retching	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Vomiting	5/240 (2.1%)		3/214 (1.4%)		0/30 (0%)
General disorders
Chest Pain	2/240 (0.8%)		2/214 (0.9%)		0/30 (0%)
Pain	3/240 (1.3%)		1/214 (0.5%)		0/30 (0%)
Rigors	2/240 (0.8%)		0/214 (0%)		0/30 (0%)
Injury, poisoning and procedural complications
Contusion	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Excoriation	2/240 (0.8%)		0/214 (0%)		0/30 (0%)
Injury	0/240 (0%)		0/214 (0%)		1/30 (3.3%)
Soft Tissue Injury	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Investigations
Body Temperature Increased	0/240 (0%)		1/214 (0.5%)		0/30 (0%)
Haemoglobin Decreased	1/240 (0.4%)		0/214 (0%)		1/30 (3.3%)
White Blood Cells Urine Positive	0/240 (0%)		0/214 (0%)		1/30 (3.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Back Pain	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Muscle Cramp	0/240 (0%)		0/214 (0%)		1/30 (3.3%)
Nervous system disorders
Dizziness	3/240 (1.3%)		1/214 (0.5%)		0/30 (0%)
Headache	30/240 (12.5%)		20/214 (9.3%)		3/30 (10%)
Somnolence	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Reproductive system and breast disorders
Haematospermia	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Menstruation Irregular	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal Pain	1/240 (0.4%)		1/214 (0.5%)		0/30 (0%)
Rhinitis	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Sinus Congestion	1/240 (0.4%)		0/214 (0%)		0/30 (0%)
Vascular disorders
Hot Flush	0/240 (0%)		1/214 (0.5%)		0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.