A Randomized Phase 3 Study to Evaluate Two Formulations of Romosozumab in Postmenopausal Women With Osteoporosis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02016716
• Collaborator: (none)
• Enrollment: 294
• Locations: 12
• Arms: 4
• Actual Duration (Months): 12.2
• Patients Per Site: 24.5
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

The purpose of this study is to compare 2 formulations of romosozumab (AMG 785) on bone mineral density (BMD) in postmenopausal women with osteoporosis.

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal Osteoporosis	Drug: Romosozumab 90 mg/mL; Drug: Placebo 90 mg/mL; Drug: Romosozumab 70 mg/mL; Drug: Placebo 70 mg/mL	Phase 3

Detailed Description

Upon confirmation of eligibility, participants were randomized in a 22:5:22:5 ratio to the following treatment groups:

• Romosozumab 90 mg/mL

• Placebo 90 mg/mL

• Romosozumab 70 mg/mL

• Placebo 70 mg/mL

After completing a 6-month treatment period, participants entered a 3-month follow-up period with an end of study (EOS) at month 9.

For the analysis of efficacy endpoints, the 2 placebo groups were combined into a single placebo group. For safety analyses, the data for placebo were presented separately for each group.

Study Design

• Study Type: Interventional
• Actual Enrollment: 294 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Multiple-dose Phase 3 Study to Evaluate the Noninferiority of Romosozumab at a 90 mg/mL Concentration Compared With a 70 mg/mL Concentration in Postmenopausal Women With Osteoporosis
• Actual Study Start Date: Dec 3, 2013
• Actual Primary Completion Date: Sep 8, 2014
• Actual Study Completion Date: Dec 8, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Romosozumab 90 mg/mL Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous (SC) 1.17 mL injections of a 90 mg/mL solution, for 6 months.	Drug: Romosozumab 90 mg/mL; Administered as 2 SC injections of a 90 mg/mL concentration in a 1.17 mL crystal zenith resin prefilled syringe (PFS).; Other Names: AMG 785 EVENITY™
Experimental: Placebo 90 mg/mL Participants received matching placebo administered as 2 subcutaneous injections of 1.17 mL every month for 6 months.	Drug: Placebo 90 mg/mL; Placebo administered as 2 SC injections with the 1.17 mL crystal zenith resin PFS.
Experimental: Romosozumab 70 mg/mL Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1.0 mL injections of a 70 mg/mL solution, for 6 months.	Drug: Romosozumab 70 mg/mL; Administered as 3 SC injections of a 70 mg/mL concentration in a 1.0 mL glass PFS.; Other Names: AMG 785 EVENITY™
Placebo Comparator: Placebo 70 mg/mL Participants received matching placebo administered as 3 subcutaneous injections of 1.0 mL every month for 6 months.	Drug: Placebo 70 mg/mL; Placebo administered as 3 SC injections with the 1.0 mL glass PFS.

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine [Baseline and month 6]

   Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA).

Secondary Outcome Measures

1. Percent Change From Baseline in Total Hip BMD [Baseline and month 6]

   Total hip BMD was measured using DXA. The analysis was based on an ANCOVA model adjusted for treatment and baseline total hip BMD T-score.

2. Percent Change From Baseline in Femoral Neck BMD [Baseline and month 6]

   Femoral neck BMD was measured using DXA. The analysis was based on an ANCOVA model adjusted for treatment and baseline femoral neck BMD T-score.

3. Percent Change From Baseline in N-Terminal Propeptide Type 1 Procollagen (P1NP) [Baseline, month 1, month 3, and month 6]

4. Percent Change From Baseline in Serum C-Telopeptide (CTX) [Baseline, month 1, month 3, and month 6]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Postmenopausal women with osteoporosis at high risk for fracture defined as

• BMD T-score ≤ -2.50 at the lumbar spine, total hip, or femoral neck AND

• a history of fragility fracture or at least 2 other risk factors

Exclusion Criteria:

• BMD T score < -3.50 at the total hip or femoral neck.

• History of hip fracture.

• History of metabolic or bone disease (except osteoporosis).

• Use of agents affecting bone metabolism.

• Vitamin D insufficiency.

• History of solid organ or bone marrow transplants.

• Hyper- or hypocalcemia.

• Hyper- or hypothyroidism.

• Hyper- or hypoparathyroidism.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Gainesville	Georgia	United States	30501
2	Research Site	Bethesda	Maryland	United States	20817
3	Research Site	Brno		Czechia	602 00
4	Research Site	Klatovy		Czechia	339 01
5	Research Site	Uherske Hradiste		Czechia	686 01
6	Research Site	Gdynia		Poland	81-384
7	Research Site	Gliwice		Poland	44-100
8	Research Site	Katowice		Poland	40-040
9	Research Site	Kraków		Poland	31-501
10	Research Site	Swidnik		Poland	21-040
11	Research Site	Warszawa		Poland	01-192
12	Research Site	Wroclaw		Poland	50-088

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02016716
• Other Study ID Numbers: 20120156; 2013-000434-35
• First Posted: Dec 20, 2013
• Last Update Posted: Nov 8, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Amgen: Postmenopausal Osteoporosis
• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	This study was conducted at 11 centers: 7 in Poland, 2 in the Czech Republic, and 2 in the United States. The first participant enrolled on 03 December 2013 and the last participant enrolled on 07 March 2014.
Pre-assignment Detail	Eligible participants were randomized in a 22:5:22:5 ratio to receive romosozumab 90 mg/mL placebo 90 mg/mL romosozumab 70 mg/mL placebo 70 mg/mL For efficacy analyses the 2 placebo groups were combined, for safety analyses the data were reported separately.

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Period Title: Overall Study
STARTED	53	118	123
Received Study Treatment	53	118	123
COMPLETED	47	110	117
NOT COMPLETED	6	8	6

Baseline Characteristics

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL	Total
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.	Total of all reporting groups
Overall Participants	53	118	123	294
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.4 (8.0)	67.4 (7.1)	67.7 (7.6)	67.7 (7.5)
Age, Customized (Count of Participants)
< 65 years	23 43.4%	46 39%	46 37.4%	115 39.1%
≥ 65 years	30 56.6%	72 61%	77 62.6%	179 60.9%
Sex: Female, Male (Count of Participants)
Female	53 100%	118 100%	123 100%	294 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.8%	6 5.1%	9 7.3%	17 5.8%
Not Hispanic or Latino	51 96.2%	112 94.9%	114 92.7%	277 94.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	2 1.7%	0 0%	2 0.7%
Black (or African American)	0 0%	1 0.8%	0 0%	1 0.3%
White	53 100%	115 97.5%	123 100%	291 99%
Lumbar Spine Bone Mineral Density (BMD) T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-2.842 (1.033)	-2.965 (0.960)	-3.029 (0.687)	-2.970 (0.871)
Total Hip BMD T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-2.057 (0.634)	-1.819 (0.673)	-1.828 (0.649)	-1.866 (0.660)
Femoral Neck BMD T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-2.304 (0.517)	-2.139 (0.611)	-2.018 (0.593)	-2.118 (0.595)
Serum Procollagen Type 1 N-telopeptide (P1NP) (μg/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [μg/L]	49.0	53.0	50.0	51.0
Serum Type 1 Collagen C-telopeptide (CTX) (ng/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ng/L]	426.5	440.0	402.0	426.0

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine
Description	Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA).
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and a month 6 lumbar spine DXA BMD measurement

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Measure Participants	46	110	117
Least Squares Mean (95% Confidence Interval) [percent change]	0.8	9.6	9.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romosozumab 70 mg/mL, Romosozumab 90 mg/mL
	Comments	The primary hypothesis was that the mean percent change from baseline in lumbar spine BMD at month 6 in participants receiving romosozumab 210 mg QM using the 90 mg/mL concentration would not be inferior to that in participants receiving romosozumab 210 mg QM using the 70 mg/mL concentration.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was claimed if the lower bound of the 1-sided 97.5% CI (or the lower bound of 2-sided 95% CI) of the mean difference between the 2 romosozumab groups was > -2.0%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -1.5 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on ANCOVA model adjusting for treatment, and baseline lumbar spine BMD T-score.

2. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD
Description	Total hip BMD was measured using DXA. The analysis was based on an ANCOVA model adjusted for treatment and baseline total hip BMD T-score.
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and month 6 hip DXA BMD measurement.

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Measure Participants	46	110	116
Least Squares Mean (95% Confidence Interval) [percent change]	-0.0	3.9	3.4

3. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck BMD
Description	Femoral neck BMD was measured using DXA. The analysis was based on an ANCOVA model adjusted for treatment and baseline femoral neck BMD T-score.
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and month 6 femoral neck DXA BMD measurement.

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Measure Participants	46	110	116
Least Squares Mean (95% Confidence Interval) [percent change]	-0.5	3.1	2.6

4. Secondary Outcome

Title	Percent Change From Baseline in N-Terminal Propeptide Type 1 Procollagen (P1NP)
Time Frame	Baseline, month 1, month 3, and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and at least one postbaseline measurement for P1NP, and with available data at each time point.

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Measure Participants	51	115	120
Month 1	2.000	96.296	97.435
Month 3	-9.601	23.960	16.216
Month 6	-12.500	-2.885	-3.604

5. Secondary Outcome

Title	Percent Change From Baseline in Serum C-Telopeptide (CTX)
Time Frame	Baseline, month 1, month 3, and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and at least one postbaseline measurement for CTX and with available data at each time point.

Arm/Group Title	Placebo	Romosozumab 70 mg/mL	Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo (either administered as 2 subcutaneous (SC) injections of 1.17 mL or 3 SC injections of 1.0 mL) every month for 6 months.	Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.	Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
Measure Participants	51	115	120
Month 1	0.282	-23.158	-21.456
Month 3	-5.687	-11.219	-5.473
Month 6	-8.120	-25.780	-17.305

Adverse Events

Time Frame	Adverse events are reported from the first dose of study drug until 90 days after last dose (9 months overall).
Adverse Event Reporting Description	One participant was randomized to the placebo group but incorrectly received 1 dose of romosozumab 70 mg/mL and was included in the romosozumab 70 mg/mL group for analysis of adverse events. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo 70 mg		Placebo 90 mg/mL		Romosozumab 70 mg/mL		Romosozumab 90 mg/mL
Arm/Group Description	Participants received matching placebo administered as 3 subcutaneous injections of 1.0 mL every month for 6 months.		Participants received matching placebo administered as 2 subcutaneous injections of 1.17 mL every month for 6 months.		Participants received 210 mg romosozumab monthly, administered as 3 subcutaneous 1 mL injections of a 70 mg/mL solution, for 6 months.		Participants received 210 mg romosozumab monthly, administered as 2 subcutaneous 1.17 mL injections of a 90 mg/mL solution, for 6 months.
All Cause Mortality
	Placebo 70 mg		Placebo 90 mg/mL		Romosozumab 70 mg/mL		Romosozumab 90 mg/mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo 70 mg		Placebo 90 mg/mL		Romosozumab 70 mg/mL		Romosozumab 90 mg/mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/26 (15.4%)		2/26 (7.7%)		7/119 (5.9%)		3/123 (2.4%)
Blood and lymphatic system disorders
Coagulopathy	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Cardiac disorders
Atrial fibrillation	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Cardiac failure	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Endocrine disorders
Hyperthyroidism	0/26 (0%)		0/26 (0%)		0/119 (0%)		1/123 (0.8%)
Gastrointestinal disorders
Abdominal pain	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Appendicitis noninfective	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Gastritis	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Mesenteric artery embolism	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
General disorders
Death	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
Infections and infestations
Appendicitis perforated	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Sepsis	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Injury, poisoning and procedural complications
Carbon monoxide poisoning	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Femoral neck fracture	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Humerus fracture	0/26 (0%)		1/26 (3.8%)		0/119 (0%)		0/123 (0%)
Overdose	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Patella fracture	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
Musculoskeletal and connective tissue disorders
Spinal deformity	0/26 (0%)		1/26 (3.8%)		0/119 (0%)		0/123 (0%)
Spinal osteoarthritis	0/26 (0%)		1/26 (3.8%)		0/119 (0%)		0/123 (0%)
Vertebral lesion	0/26 (0%)		1/26 (3.8%)		0/119 (0%)		0/123 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
Basal cell carcinoma	0/26 (0%)		0/26 (0%)		0/119 (0%)		1/123 (0.8%)
Medullary thyroid cancer	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
Uterine cancer	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Nervous system disorders
Ischaemic stroke	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Polyneuropathy	0/26 (0%)		1/26 (3.8%)		0/119 (0%)		0/123 (0%)
Retrograde amnesia	1/26 (3.8%)		0/26 (0%)		0/119 (0%)		0/123 (0%)
Surgical and medical procedures
Umbilical hernia repair	0/26 (0%)		0/26 (0%)		1/119 (0.8%)		0/123 (0%)
Vascular disorders
Arterial rupture	0/26 (0%)		0/26 (0%)		0/119 (0%)		1/123 (0.8%)
Other (Not Including Serious) Adverse Events
	Placebo 70 mg		Placebo 90 mg/mL		Romosozumab 70 mg/mL		Romosozumab 90 mg/mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		5/26 (19.2%)		24/119 (20.2%)		38/123 (30.9%)
General disorders
Asthenia	0/26 (0%)		2/26 (7.7%)		4/119 (3.4%)		4/123 (3.3%)
Injection site erythema	0/26 (0%)		0/26 (0%)		2/119 (1.7%)		7/123 (5.7%)
Injection site pain	0/26 (0%)		0/26 (0%)		7/119 (5.9%)		3/123 (2.4%)
Infections and infestations
Nasopharyngitis	3/26 (11.5%)		0/26 (0%)		9/119 (7.6%)		19/123 (15.4%)
Upper respiratory tract infection	1/26 (3.8%)		2/26 (7.7%)		1/119 (0.8%)		2/123 (1.6%)
Urinary tract infection	0/26 (0%)		1/26 (3.8%)		1/119 (0.8%)		7/123 (5.7%)
Injury, poisoning and procedural complications
Fall	2/26 (7.7%)		0/26 (0%)		2/119 (1.7%)		2/123 (1.6%)
Musculoskeletal and connective tissue disorders
Bone pain	0/26 (0%)		2/26 (7.7%)		2/119 (1.7%)		2/123 (1.6%)
Nervous system disorders
Headache	3/26 (11.5%)		0/26 (0%)		2/119 (1.7%)		2/123 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.