Download PDF

Clinical Trial Results:
A Multicenter, Double-blind, Randomized Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis

Summary
EudraCT number	2013-001279-19
Trial protocol	CZ PL DK
Global end of trial date	09 Jul 2015

Results information
Results version number	v1(current)
This version publication date	15 Jul 2016
First version publication date	15 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

20120187

ISRCTN number

US NCT number

NCT02157948

WHO universal trial number (UTN)

Sponsor organisation name

Amgen, Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ-Medical Info - Clinical Trials, Amgen (Europe) GmbH, MedinfoInternational@amgen.com

Scientific contact

IHQ-Medical Info - Clinical Trials, Amgen (Europe) GmbH, MedinfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study are to evaluate 1. whether the efficacy of denosumab (60 mg subcutaneously every 6 months) manufactured by the proposed process referred to as CP4 is not inferior to that of denosumab manufactured by the currently approved commercial process referred to as CP2 based on the change in lumbar spine bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at 12 months in postmenopausal women with osteoporosis; 2. whether the efficacy of denosumab CP4 (60 mg subcutaneously every 6 months) is equivalent to that of denosumab CP2 based on the change in lumbar spine BMD by DXA at 12 months in postmenopausal women with osteoporosis.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and the informed consent form were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and written approval was received by Amgen before recruitment of subjects and shipment of Amgen investigational product (IP). All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 May 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 167

Country: Number of subjects enrolled

Denmark: 142

Country: Number of subjects enrolled

United States: 52

Country: Number of subjects enrolled

Canada: 33

Worldwide total number of subjects

394

EEA total number of subjects

309

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

135

From 65 to 84 years

257

85 years and over

Subject disposition

Top of page

Recruitment details

This study was conducted at 21 centers in Poland, Denmark, United States (US), and Canada. The first subject enrolled on 05 May 2014 and the last subject enrolled on 03 July 2014.

Screening details

Ambulatory postmenopausal women 55 years or older with a BMD value equivalent to a T-score of ≤ 2.5 at lumbar spine, total hip, or femoral neck were eligible to enroll. Five hundred and forty-seven subjects were screened; 394 were enrolled and 153 did not meet eligibility criteria.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Denosumab CP2

Arm description

Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

Arm type

Active comparator

Investigational medicinal product name

Denosumab CP2

Investigational medicinal product code

Other name

Prolia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once every 6 months

Denosumab CP4

Arm description

Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

Arm type

Experimental

Investigational medicinal product name

denosumab CP4

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once every 6 months

Number of subjects in period 1	Denosumab CP2	Denosumab CP4
Started	197	197
Received Treatment	196	196
Completed	188	188
Not completed	9	9
Consent withdrawn by subject	4	5
Protocol specified criteria	2	1
Lost to follow-up	3	2
Decision by sponsor	-	1

Baseline characteristics

Top of page

Reporting group title

Denosumab CP2

Reporting group description

Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

Reporting group title

Denosumab CP4

Reporting group description

Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

Reporting group values	Denosumab CP2	Denosumab CP4	Total
Number of subjects	197	197	394
Age categorical
Units: Subjects
< 65 years	65	70	135
≥ 65 years	132	127	259
Age continuous
Units: years
arithmetic mean (standard deviation)	68 ± 6.8	68.3 ± 7.3	-
Gender categorical
Units: Subjects
Female	197	197	394
Male	0	0	0
Race
Units: Subjects
White	190	195	385
Asian	4	1	5
Native Hawaiian or Other Pacific Islander	2	1	3
Other	1	0	1
Lumbar Spine Bone Mineral Density (BMD) T-score
The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
Units: T-score
arithmetic mean (standard deviation)	-2.75 ± 0.91	-2.75 ± 0.75	-
Serum Type I collagen C-telopeptide (CTX-1)
Units: ng/mL
arithmetic mean (standard deviation)	0.48 ± 0.333	0.501 ± 0.269	-
Serum Procollagen type 1 N-terminal (P1NP)
Units: µg/L
arithmetic mean (standard deviation)	62 ± 31.7	64.5 ± 32.8	-

End points

Top of page

Reporting group title

Denosumab CP2

Reporting group description

Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

Reporting group title

Denosumab CP4

Reporting group description

Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

Primary: Percent Change from Baseline in Lumbar Spine BMD

Top of page

End point title

Percent Change from Baseline in Lumbar Spine BMD

End point description

Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The primary efficacy analysis subset included all randomized subjects who had a baseline lumbar spine DXA BMD measurement and at least 1 postbaseline lumbar spine DXA BMD measurement. Postbaseline BMD values obtained at the early termination visit were carried forward as the month-12 value.

End point type

Primary

End point timeframe

Baseline and Month 12

End point values	Denosumab CP2	Denosumab CP4
Number of subjects analysed	187 ^[1]	188 ^[2]
Units: percent change
arithmetic mean (standard deviation)	5.78 ± 3.44	5.73 ± 3.08

Notes
[1] - Subjects with a non-missing baseline and at least 1 non-missing postbaseline measurement
[2] - Subjects with a non-missing baseline and at least 1 non-missing postbaseline measurement

Non-inferiority Testing

Statistical analysis description

The treatment comparison was analyzed using the analysis of covariance (ANCOVA) model including treatment, baseline BMD value, machine type, and machine type-by-baseline BMD value interaction. The effect of denosumab CP4 on lumbar spine BMD at 12 months relative to the effect of denosumab CP2 was estimated by the least-squares mean of the treatment difference (denosumab CP4 – denosumab CP2) and the corresponding 2-sided 95% confidence interval (CI).

Comparison groups

Denosumab CP2 v Denosumab CP4

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.001 ^[4]

Method

ANCOVA

Parameter type

Difference from CP2

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.57

Notes
[3] - The lower bound of the 2-sided 95% CI of the between-group difference (denosumab CP4 – denosumab CP2) in percent change from baseline in lumbar spine BMD at 12 months was compared with the non-inferiority margin of -1.44% for assessing non-inferiority.
[4] - One-sided p-value based on the prespecified non-inferiority margin of -1.44% for lumbar spine

Equivalence Testing

Statistical analysis description

Comparison groups

Denosumab CP2 v Denosumab CP4

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

equivalence ^[5]

P-value

< 0.001 ^[6]

Method

ANCOVA

Parameter type

Difference from CP2

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.57

Notes
[5] - The lower and upper bounds of the same 2-sided 95% CI of the between-group difference were compared with the equivalence margin of ±1.44% for assessing equivalence.
[6] - Two-sided p-value based on the prespecified equivalence margin of ±1.44% for lumbar spine.

Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

Top of page

End point title

Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

End point description

The bone turnover marker (BTM) efficacy analysis subset includes all randomized subjects who had a baseline measurement and at least one post baseline measurement.

End point type

Secondary

End point timeframe

Baseline, month 1, month 6 and month 12

End point values	Denosumab CP2	Denosumab CP4
Number of subjects analysed	197	197
Units: percent change
median (inter-quartile range (Q1-Q3))
Month 1 (n = 195, 193)	-86.39 (-90.65 to -78.45)	-88.05 (-91.12 to -80.79)
Month 6 (n = 191, 189)	-76.46 (-85.58 to -60.58)	-79.48 (-87.06 to -66.86)
Month 12 (n = 187, 188)	-71.34 (-83.33 to -47.13)	-75.44 (-85.88 to -61.9)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

Top of page

End point title

Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

End point description

The bone turnover marker (BTM) efficacy analysis subset includes all randomized subjects who had a baseline measurement and at least one post baseline measurement.

End point type

Secondary

End point timeframe

Baseline and month 1, month 6 and month 12

End point values	Denosumab CP2	Denosumab CP4
Number of subjects analysed	197	197
Units: percent change
median (inter-quartile range (Q1-Q3))
Month 1 (N = 195, 193)	-29.59 (-38.06 to -20.02)	-29.86 (-38.8 to -20.9)
Month 6 (n = 192, 190)	-76.63 (-82.9 to -66.69)	-77.74 (-85.02 to -70.31)
Month 12 (n = 186, 188)	-71.44 (-77.64 to -57.35)	-72.08 (-80.24 to -62.4)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

12 Months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Denosumab CP4

Reporting group description

Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

Reporting group title

Denosumab CP2

Reporting group description

Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

Serious adverse events	Denosumab CP4	Denosumab CP2
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 196 (3.06%)	13 / 196 (6.63%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign ovarian tumour
subjects affected / exposed	1 / 196 (0.51%)	0 / 196 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incision site haematoma
subjects affected / exposed	1 / 196 (0.51%)	0 / 196 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary contusion
subjects affected / exposed	1 / 196 (0.51%)	0 / 196 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 196 (0.51%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Cholecystectomy
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 196 (0.00%)	2 / 196 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 196 (0.00%)	2 / 196 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 196 (0.51%)	0 / 196 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 196 (0.00%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 196 (0.51%)	0 / 196 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 196 (0.51%)	1 / 196 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Denosumab CP4	Denosumab CP2
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 196 (18.37%)	25 / 196 (12.76%)
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	15 / 196 (7.65%)	11 / 196 (5.61%)
occurrences all number	21	11
Infections and infestations
Nasopharyngitis
subjects affected / exposed	21 / 196 (10.71%)	15 / 196 (7.65%)
occurrences all number	24	16

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

30 May 2014

- Reference was removed for the possibility of informed consent for eligible subjects being provided by a legally acceptable representative. - The protocol was updated to state that the comparison between denosumab CP2 and CP4, in terms of the change from baseline in lumbar spine BMD, was being performed using noninferiority testing in addition to equivalence testing to conform to guidance received from the US FDA. - Minor clarifications were made to the exclusion criteria, and other administrative changes were made where necessary. Typographic and formatting errors were corrected throughout the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
A Multicenter, Double-blind, Randomized Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change from Baseline in Lumbar Spine BMD

Primary: Percent Change from Baseline in Lumbar Spine BMD

Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multicenter, Double-blind, Randomized Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change from Baseline in Lumbar Spine BMD

Primary: Percent Change from Baseline in Lumbar Spine BMD

Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Double-blind, Randomized Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis