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Clinical Trial Results:
Uncemented total hip implant and subcutaneous injection of Denosumab for patients with osteoarthritis of the hip. A randomised double blind placebo controlled study on the effects on bone evaluated with DXA, PET/CT, and biochemical markers.

Summary
EudraCT number	2011-001481-18
Trial protocol	SE
Global end of trial date	30 Mar 2017

Results information
Results version number	v1(current)
This version publication date	12 Mar 2020
First version publication date	12 Mar 2020
Other versions
Summary report(s)	Synopsis

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

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Trial information

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Sponsor protocol code

6925

ISRCTN number

US NCT number

NCT01630941

WHO universal trial number (UTN)

Sponsor organisation name

Uppsala University Hospital

Sponsor organisation address

Sjukhusvägen, Uppsala, Sweden, 751 85

Public contact

Hans Mallmin, Uppsala University, 46 186114478, hans.mallmin@akademiska.se

Scientific contact

Hans Mallmin, Uppsala University, 46 186114478, hans.mallmin@akademiska.se

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

03 May 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Mar 2017

Global end of trial reached?

Yes

Global end of trial date

30 Mar 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to study the effect of Denosumab on Bone Mineral Density, Standardised Uptake Value and bone metabolism in patients with total hip arthroplasty. The primary hypothesis is to demonstrate that Denosumab is superior to placebo.

Protection of trial subjects

The patients were informed that there will be 3 PET and 5 DXA assessments which are not clinical praxis. These asssessments were not to result in higher radiation load than normally. However, it has been shown that the radiation level will not give any increased discomfort under normal circumstances. Adverse Events were continuously followed from Baseline until last folloow-up visit after 24 months.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Nov 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 64

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients were recruited at the Dept of Orthopedics, Uppsala University Hospital durign the time period Aug 2012 - Oct 2015.

Screening details

461 patients were pre- screened, of these 64 patients were randomised and 63 patients completed treatment in the study.

Period 1 title

Baseline period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

An authorized research nurse administered 1 ml prefilled syringe of Denosumab or placebo (0.9 % sterile Saline) according to the randomization list without the presence the investigators or other personnel involved in the study. An additional nurse, not involved in the study team, recorded the procedure in the compliance log.

Are arms mutually exclusive

Yes

Denosumab

Arm description

1 ml prefilled syringe of Denosumab, Prolia®, 60 mg/ml

Arm type

Experimental

Investigational medicinal product name

Denosumab, Prolia®, 60 mg/ml

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

1 ml, 60 mg/ml

Placebo

Arm description

0,9% sterile Saline

Arm type

Placebo

Investigational medicinal product name

0,9% saline solution

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

1 ml, 0,9%

Number of subjects in period 1	Denosumab	Placebo
Started	32	32
Completed	32	32

Baseline characteristics

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Reporting group title

Denosumab

Reporting group description

1 ml prefilled syringe of Denosumab, Prolia®, 60 mg/ml

Reporting group title

Placebo

Reporting group description

0,9% sterile Saline

Reporting group values	Denosumab	Placebo	Total
Number of subjects	32	32	64
Age categorical
Units: Subjects
Age continuous
Age 35-65 years
Units: years
arithmetic mean (full range (min-max))	58.4 (47 to 65)	58.8 (48 to 65)	-
Gender categorical
Female/Male
Units: Subjects
Female	20	19	39
Male	12	13	25

Subject analysis set title

Started

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients receiving at least one dose of study medication.

Subject analysis sets values	Started
Number of subjects	64
Age categorical
Units: Subjects
Age continuous
Age 35-65 years
Units: years
arithmetic mean (full range (min-max))	58.6 (47 to 65)
Gender categorical
Female/Male
Units: Subjects
Female	39
Male	25

End points

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Reporting group title

Denosumab

Reporting group description

1 ml prefilled syringe of Denosumab, Prolia®, 60 mg/ml

Reporting group title

Placebo

Reporting group description

0,9% sterile Saline

Subject analysis set title

Started

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients receiving at least one dose of study medication.

Primary: BMD (Bone Mineral Density) in Gruen zone 7

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End point title

BMD (Bone Mineral Density) in Gruen zone 7

End point description

End point type

Primary

End point timeframe

After 12 months

End point values	Denosumab	Placebo
Number of subjects analysed	32	31
Units: g/cm2
arithmetic mean (inter-quartile range (Q1-Q3))
BMD in Gruen zone 7	1.54 (1.46 to 1.63)	1.16 (1.10 to 1.23)

Descriptive statistics

Statistical analysis description

Baseline characteristics and outcome variables were summarized by descriptive statistics.

Comparison groups

Denosumab v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

≤ 0.05 ^[2]

Method

ANCOVA

Parameter type

geometric mean ratio

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

1.44

Notes
[1] - Analysis of covariance (ANCOVA) with treatment group and baseline value were used to test the null-hypoth of no difference between Denosumab and placebo with respect to each continuous outcome variable.To control the overall type I error, the primary variables were tested in a hierarchical fashion starting with ‘BMD Gruen zone 7.
[2] - If p-value was less than 0.05, test for sum of all Gruen zones was done at 0.05 level.

Adverse events

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Timeframe for reporting adverse events

From Baseline visit until last follow up visit after 24 months.

Adverse event reporting additional description

An AE can be any unfavorable, unintended clinical sign, symptom, medical complaint or clinically relevant change in laboratory variables or clinical tests. The Investigator will assess the maximum intensity of the AE and judge the possible relationship between the AE and the investigational product as well as any concomitant medications.

Assessment type

Systematic

Dictionary name

Not coded

Dictionary version

Reporting group title

Denosumab

Reporting group description

Active treatment

Reporting group title

Placebo

Reporting group description

Comparison

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.

Serious adverse events	Denosumab	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 32 (9.38%)	4 / 24 (16.67%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cyst
Additional description: Patient no 1227. Placebo patient (female). Arachnoid cyst 3 weeks after second dose of study med.Resolved after 8 months.
subjects affected / exposed ^[2]	0 / 1 (0.00%)	1 / 1 (100.00%)
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
Implant loosening
Additional description: Placebo pt no 1118. Implant loosening at one month after second dose, resolved after one day. Second implant loosening 2.5 months after second dose, resolved after 3.5 months. Denosumab pt no 1119. Implant loosening six months after second dose.
subjects affected / exposed ^[3]	1 / 1 (100.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Gynecological bleeding
Additional description: Placebo patient no 1111. 5 months after second dose of study medication. Resolved after 17 days.
subjects affected / exposed ^[4]	0 / 1 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Perimyocardit
Additional description: Placebo patient 1111 (female). Six and a half months after second dose of study medication. Resolved after two days.
subjects affected / exposed ^[5]	0 / 1 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eye disorder
Additional description: Patient 1134 (female). Denosumab patient experiencing elevated pressure anterior chamber right eye three weeks after second dose of study med. Resolved after 3,5 months.
subjects affected / exposed ^[6]	1 / 1 (100.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Myoma
Additional description: Placebo patient no 1111. Six months after second dose of study medication. Resolved after 13 days.
subjects affected / exposed ^[7]	0 / 1 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
Additional description: Patient no 1124 (female). Placebo patient, osteoarhritis 7 months after the second dose of study med. Resolved after 4 months.
subjects affected / exposed ^[8]	0 / 1 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis reactive
Additional description: Patient no 1205. Denomsumab patient. Worsening of her hip arthritis right side (ie unaffected hip) three months after first dose of study med.
subjects affected / exposed ^[9]	1 / 1 (100.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Notes
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: One patient experienced the same event twice causing prolonged hospitalisation.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Only one patient exposed, but not possible to fill in 0 in the other treatment group.

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

Non-serious adverse events	Denosumab	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 32 (0.00%)	0 / 24 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

13 Feb 2012

The study is avaluable after 24 months. Schedule of event updated and clarified. PIC is completed at visit 1 instead of visit 0. Clarification of BMI. Exclusion crit 9: persons suffering from claustrophobia are not suitable for PET scanning. Section 11 Assessment of efficacy: Additional text "Investigators decision".

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

http://www.ncbi.nlm.nih.gov/pubmed/31589776

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Clinical trials

Clinical Trial Results:
Uncemented total hip implant and subcutaneous injection of Denosumab for patients with osteoarthritis of the hip. A randomised double blind placebo controlled study on the effects on bone evaluated with DXA, PET/CT, and biochemical markers.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: BMD (Bone Mineral Density) in Gruen zone 7

Primary: BMD (Bone Mineral Density) in Gruen zone 7

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Uncemented total hip implant and subcutaneous injection of Denosumab for patients with osteoarthritis of the hip. A randomised double blind placebo controlled study on the effects on bone evaluated with DXA, PET/CT, and biochemical markers.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: BMD (Bone Mineral Density) in Gruen zone 7

Primary: BMD (Bone Mineral Density) in Gruen zone 7

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Uncemented total hip implant and subcutaneous injection of Denosumab for patients with osteoarthritis of the hip. A randomised double blind placebo controlled study on the effects on bone evaluated with DXA, PET/CT, and biochemical markers.