Trial Outcomes & Findings for Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet. (NCT NCT03027557)

NCT ID: NCT03027557

Last Updated: 2021-05-25

Results Overview

Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 46 participants
• Primary outcome timeframe: Baseline,one year
• Results posted on: 2021-05-25

Participant Flow

Participant milestones

Measure	Combined Treatment. 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Overall Study STARTED	15	16	15
Overall Study COMPLETED	14	16	15
Overall Study NOT COMPLETED	1	0	0

Reasons for withdrawal

Measure	Combined Treatment. 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Overall Study Adverse Event	1	0	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Combined Treatment. n=15 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.	Total n=46 Participants Total of all reporting groups
Age, Continuous	65.1 years STANDARD_DEVIATION 13.2 • n=15 Participants	65.4 years STANDARD_DEVIATION 8.8 • n=16 Participants	68.0 years STANDARD_DEVIATION 7.0 • n=15 Participants	66.15 years STANDARD_DEVIATION 9.7 • n=46 Participants
Sex: Female, Male Female	14 Participants n=15 Participants	13 Participants n=16 Participants	12 Participants n=15 Participants	39 Participants n=46 Participants
Sex: Female, Male Male	1 Participants n=15 Participants	3 Participants n=16 Participants	3 Participants n=15 Participants	7 Participants n=46 Participants
Race and Ethnicity Not Collected	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Denmark	15 participants n=15 Participants	16 participants n=16 Participants	15 participants n=15 Participants	46 participants n=46 Participants
T-score Lumbar Spine (LS) by Dual X-ray Absorptiometry (DXA)	-1.9 T-score STANDARD_DEVIATION 0.93 • n=15 Participants	-2.0 T-score STANDARD_DEVIATION 0.68 • n=16 Participants	-1.3 T-score STANDARD_DEVIATION 0.85 • n=15 Participants	-1.7 T-score STANDARD_DEVIATION 0.87 • n=46 Participants
T-score TH (by DXA)	-1.4 T-score STANDARD_DEVIATION 0.5 • n=15 Participants	-1.4 T-score STANDARD_DEVIATION 0.6 • n=16 Participants	-1.1 T-score STANDARD_DEVIATION 0.5 • n=15 Participants	-1.3 T-score STANDARD_DEVIATION 0.5 • n=46 Participants
T-score FN (by DXA)	-2.0 T-score STANDARD_DEVIATION 0.7 • n=15 Participants	-1.9 T-score STANDARD_DEVIATION 0.7 • n=16 Participants	-1.7 T-score STANDARD_DEVIATION 0.6 • n=15 Participants	-1.88 T-score STANDARD_DEVIATION 0.6 • n=46 Participants
T-score 1/3 FA (by DXA)	-2.4 T-score STANDARD_DEVIATION 1.2 • n=15 Participants	-2.4 T-score STANDARD_DEVIATION 1.2 • n=16 Participants	-2.8 T-score STANDARD_DEVIATION 0.9 • n=15 Participants	-2.5 T-score STANDARD_DEVIATION 1.1 • n=46 Participants
Volumetric Bone Mineral Density (vBMD) LS	96.4 mg/cm^3 STANDARD_DEVIATION 28.1 • n=15 Participants	99.7 mg/cm^3 STANDARD_DEVIATION 24.0 • n=16 Participants	94.2 mg/cm^3 STANDARD_DEVIATION 25.4 • n=15 Participants	96.9 mg/cm^3 STANDARD_DEVIATION 25.1 • n=46 Participants
vBMD distal forearm	183.5 mg/cm^3 STANDARD_DEVIATION 32.0 • n=15 Participants	194.9 mg/cm^3 STANDARD_DEVIATION 37.6 • n=16 Participants	181.4 mg/cm^3 STANDARD_DEVIATION 35.5 • n=15 Participants	192.6 mg/cm^3 STANDARD_DEVIATION 34.6 • n=46 Participants
Cortical width	1.23 mm STANDARD_DEVIATION 0.5 • n=15 Participants	1.19 mm STANDARD_DEVIATION 0.5 • n=16 Participants	1.14 mm STANDARD_DEVIATION 0.4 • n=15 Participants	1.2 mm STANDARD_DEVIATION 0.4 • n=46 Participants
Nephrolithiasis	0 Participants n=15 Participants	3 Participants n=16 Participants	1 Participants n=15 Participants	4 Participants n=46 Participants
Nephrocalcinosis	2 Participants n=15 Participants	1 Participants n=16 Participants	3 Participants n=15 Participants	6 Participants n=46 Participants
Pancreas calcifications	0 Participants n=15 Participants	1 Participants n=16 Participants	2 Participants n=15 Participants	3 Participants n=46 Participants
Fracture by Vertebral Fracture Assessment (VFA)	1 Participants n=15 Participants	3 Participants n=16 Participants	2 Participants n=15 Participants	6 Participants n=46 Participants
Body Mass Index	27.7 kg/m^2 STANDARD_DEVIATION 3.5 • n=15 Participants	27.4 kg/m^2 STANDARD_DEVIATION 4.8 • n=16 Participants	28.4 kg/m^2 STANDARD_DEVIATION 3.9 • n=15 Participants	27.8 kg/m^2 STANDARD_DEVIATION 4.0 • n=46 Participants
Ionized Calcium	1.39 mmol/l STANDARD_DEVIATION 0.08 • n=15 Participants	1.39 mmol/l STANDARD_DEVIATION 0.078 • n=16 Participants	1.39 mmol/l STANDARD_DEVIATION 0.08 • n=15 Participants	1.39 mmol/l STANDARD_DEVIATION 0.06 • n=46 Participants
P-Parathyroid Hormone (PTH)	12.1 pmol/l STANDARD_DEVIATION 6.2 • n=15 Participants	13.1 pmol/l STANDARD_DEVIATION 6.4 • n=16 Participants	11.2 pmol/l STANDARD_DEVIATION 4.3 • n=15 Participants	12.1 pmol/l STANDARD_DEVIATION 5.7 • n=46 Participants
Agatston Score	4.9 units on a scale n=15 Participants	10.1 units on a scale n=16 Participants	55.7 units on a scale n=15 Participants	15.5 units on a scale n=46 Participants
U-Calcium	338 mg/d n=15 Participants	276 mg/d n=16 Participants	314 mg/d n=15 Participants	284 mg/d n=46 Participants
U-Phosphorous	28.5 mmol/d n=15 Participants	32.2 mmol/d n=16 Participants	35.2 mmol/d n=15 Participants	32.0 mmol/d n=46 Participants
P-Phosphorous	0.77 mmol/l STANDARD_DEVIATION 0.15 • n=15 Participants	0.77 mmol/l STANDARD_DEVIATION 0.16 • n=16 Participants	0.79 mmol/l STANDARD_DEVIATION 0.12 • n=15 Participants	0.78 mmol/l STANDARD_DEVIATION 0.14 • n=46 Participants
Major Depression Inventory score	5 MDI-points n=15 Participants	5 MDI-points n=16 Participants	5 MDI-points n=15 Participants	5 MDI-points n=46 Participants

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.

Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Lumbar Spine Bone Mineral Density	0.030 g/cm^2 Standard Error 0.009	0.042 g/cm^2 Standard Error 0.009	-0.016 g/cm^2 Standard Error 0.007

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.

Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Total Hip Bone Mineral Density	0.027 g/cm^2 Standard Error 0.006	0.021 g/cm^2 Standard Error 0.003	-0.013 g/cm^2 Standard Error 0.006

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.

Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Femoral Neck Bone Mineral Density	0.023 g/cm^2 Standard Error 0.006	0.020 g/cm^2 Standard Error 0.005	-0.007 g/cm^2 Standard Error 0.006

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group did not provide results for this analysis as he/she experienced a wrist fracture prior to the final scan.

Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=15 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in 1/3 Forearm Bone Mineral Density	0.005 g/cm^2 Standard Error 0.003	0.005 g/cm^2 Standard Error 0.003	-0.005 g/cm^2 Standard Error 0.004

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.

Percentage change of Bone Mineral Density after one year of treatment from baseline.

Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in Lumbar Spine Bone Mineral Density	3.6 % change Standard Error 1.1	5.1 % change Standard Error 1.1	-1.8 % change Standard Error 0.8

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.

Percentage change of Bone Mineral Density after one year of treatment from baseline.

Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in Total Hip Bone Mineral Density	3.45 % change Standard Error 0.72	2.64 % change Standard Error 0.41	-1.50 % change Standard Error 0.72

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.

Percentage change of Bone Mineral Density after one year of treatment from baseline.

Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in Femoral Neck Bone Mineral Density	3.70 % change Standard Error 0.98	3.03 % change Standard Error 0.86	-0.78 % change Standard Error 0.9

PRIMARY outcome

Timeframe: Baseline,one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group did not provide results for this analysis as he/she experienced a wrist fracture prior to the final scan.

Percentage change of Bone Mineral Density after one year of treatment from baseline.

Measured with Dual-energy X-ray absorptiometry (DXA)-scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=15 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in 1/3 Forearm Bone Mineral Density	0.94 % change Standard Error 0.7	0.88 % change Standard Error 0.5	-0.91 % change Standard Error 0.7

SECONDARY outcome

Timeframe: Baseline, one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. Another scan could not be included due to a technical problems with the image analysis.

Measured at baseline and after one year by QCT.

Outcome measures

Measure	Combined Treatment. n=13 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Volumetric BMD for the Lumbar Spine.	4.93 mg/cm^3 Standard Error 2.15	5.35 mg/cm^3 Standard Error 1.91	-2.56 mg/cm^3 Standard Error 1.6

SECONDARY outcome

Timeframe: Monthly up to one year.

Blood samples were acquired once every 4 weeks for safety-purposes.

Outcome measures

Measure	Combined Treatment. n=210 p-calcium measurements 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=240 p-calcium measurements 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=224 p-calcium measurements 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Mean P-calcium During Treatment.	1.28 mmol/l Standard Error 0.007	1.38 mmol/l Standard Error 0.006	1.40 mmol/l Standard Error 0.004

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

p-CTX, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)	-48.7 % change Interval -73.2 to -15.8	-58.2 % change Interval -76.7 to -44.3	11.8 % change Interval 1.96 to 40.0

SECONDARY outcome

Timeframe: Baseline, one year

Population: Some participant from the combined and placebo groups could not be included in the analysis because they had coronary stents.

Simultaneously with QCT-measurements coronary calcification was be assessed. Agatston score is a score based on the extent of coronary artery calcification calculated on the amount of plaque observed in a CT scan. A score of zero indicates absence of coronary calcium, 1-10: minimal calcification, 11-100 mild calcification, 101-400 moderate calcification, >400 severe calcification.

Thus the score increases with increasing level of calcification in the coronary vessels.

Outcome measures

Measure	Combined Treatment. n=12 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=13 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Median Agatstons Score Final	5.0 score on a scale Interval 0.0 to 78.1	24.3 score on a scale Interval 0.7 to 602.1	117.8 score on a scale Interval 6.8 to 182.6

SECONDARY outcome

Timeframe: Patients with nephrolithiasis at one year reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

Number of subjects w. renal stones at final scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Patients With Nephrolithiasis Final Scan.	0 Participants	3 Participants	1 Participants

SECONDARY outcome

Timeframe: Patients with pancreas-calcifications at one year reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.

By QCT.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Patients With Pancreas-calcifications Final Scan.	0 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: 2 weeks after termination of medication.

Measured from effect on s-calcium and PTH weeks after termination of IMP

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Patients with vertebral fractures at one year reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.

Number of participants with vertebral fractures as assessed by VFA at final scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Vertebral Fracture Assessment - Final Scan	1 Participants	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline, 6 mths, one year.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final collection of MDI-questionnaires.

Major Depression Inventory (MDI)-score, Baseline, 6 months, one year (week 52)., change between baseline and 1 year reported.

The Major Depression Inventory (MDI) is a mood questionnaire developed by the World Health Organization. To calculate the total score, a sum of ten individual items (each with an individual score between 0-5, with 0 indicating absence of a symptom and 5 indicating constant presence of a given symptom) is used. A higher score signifies deeper depression with 50 being the maximum score.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change MDI-score	0.0 MDI-score Interval -4.0 to 1.0	-0.5 MDI-score Interval -4.5 to 1.0	0.0 MDI-score Interval -3.0 to 0.0

SECONDARY outcome

Timeframe: Monthly up to one year.

All participants filled in questionnaires regarding symptoms related to the treatment.

Results are reported in the Adverse Events section.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, one year

Population: Data were not collected

Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, one year.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 4 patients did not provide data for the analysis due to errors in the technique of the obtained images.

Measured at baseline and after one year at the distal non-dominant antebrachii.

Outcome measures

Measure	Combined Treatment. n=12 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=14 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Cortical Width.	-0.04 mm Standard Error 0.1	0.02 mm Standard Error 0.08	0.04 mm Standard Error 0.05

SECONDARY outcome

Timeframe: Baseline, one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 5 patients did not provide data for the analysis due to errors in the technique of the obtained images.

Measured at baseline and after one year by QCT.

Outcome measures

Measure	Combined Treatment. n=12 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=13 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Change in Volumetric BMD for the Distal Forearm.	1.0 mg/cm^3 Standard Error 2.1	9.6 mg/cm^3 Standard Error 3.7	-1.1 mg/cm^3 Standard Error 4.6

SECONDARY outcome

Timeframe: Baseline, one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. Another scan could not be included due to a technical problems with the image analysis.

Measured at baseline and after one year by QCT.

Outcome measures

Measure	Combined Treatment. n=13 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in Volumetric BMD for the Lumbar Spine.	6.18 % change Standard Error 3.14	5.66 % change Standard Error 1.85	-2.94 % change Standard Error 1.96

SECONDARY outcome

Timeframe: Baseline, one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 5 patients did not provide data for the analysis due to errors in the technique of the obtained images.

Measured at baseline and after one year by QCT.

Outcome measures

Measure	Combined Treatment. n=12 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=13 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=14 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percentage Change in Volumetric BMD for the Distal Forearm.	0.53 % change Standard Error 1.2	5.2 % change Standard Error 1.0	-0.74 % change Standard Error 2.6

SECONDARY outcome

Timeframe: Monthly up to one year.

Blood samples were acquired once every 4 weeks for safety-purposes.

Outcome measures

Measure	Combined Treatment. n=211 p-PTH measurements 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=240 p-PTH measurements 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=225 p-PTH measurements 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Mean p-PTH During Treatment.	12.0 pmol/l Interval 11.1 to 12.9	13.4 pmol/l Interval 12.7 to 14.2	9.9 pmol/l Interval 9.5 to 10.4

SECONDARY outcome

Timeframe: Monthly up to one year.

Blood samples were acquired once every 4 weeks for safety-purposes.

Outcome measures

Measure	Combined Treatment. n=211 p-phosphate measurements 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=240 p-phosphate measurements 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=225 p-phosphate measurements 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Mean p-Phosphate During Treatment.	0.83 pmol/l Standard Error 0.013	0.76 pmol/l Standard Error 0.012	0.083 pmol/l Standard Error 0.011

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

p-P1NP, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP).	-63.1 % change Interval -66.9 to -57.2	-66.1 % change Interval -75.9 to -55.4	17.8 % change Interval -11.0 to 31.5

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

p-osteocalcin, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in P-osteocalcin.	-60.0 % change Interval -69.8 to -36.9	-58.9 % change Interval -66.9 to -49.0	7.0 % change Interval -0.9 to 36.9

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

S-Bone specific alkaline phosphatase, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP).	-40.0 % change Interval -46.3 to -24.1	-46.3 % change Interval -51.5 to -38.4	9.7 % change Interval -7.9 to 32.5

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

P-Trap5b, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b).	-27.8 % change Interval -34.1 to -2.3	-36.7 % change Interval -51.8 to -16.4	2.3 % change Interval -4.9 to 19.6

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

P-Sclerostin, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in p-Sclerostin.	10.0 % change Interval 3.1 to 21.1	6.5 % change Interval 0.9 to 15.9	4.8 % change Interval -2.3 to 13.9

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

P-FGF23 , change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23).	35.8 % change Interval 0.0 to 52.9	20.4 % change Interval -13.6 to 58.2	28.0 % change Interval -25.9 to 64.7

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

P-25-vitD , change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Changes in p-25-vitamin D	22.1 nmol/l Interval 13.3 to 32.6	16.0 nmol/l Interval 4.1 to 22.0	21.2 nmol/l Interval 8.2 to 30.5

SECONDARY outcome

Timeframe: Change from baseline at 48 weeks reported.

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

S-1,25-vitD, change from baseline at 48 weeks.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Changes in s-1,25-vitamin D	7.5 pmol/l Interval -4.0 to 35.0	4.5 pmol/l Interval -15.0 to 25.5	26.0 pmol/l Interval 14.0 to 36.0

SECONDARY outcome

Timeframe: Baseline, one year

Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.

Number of subjects w. renal calcifications at final scan.

Outcome measures

Measure	Combined Treatment. n=14 Participants 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 Participants 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 Participants 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Patients With Nephrocalcinosis, Final Scan.	2 Participants	1 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Monthly up to one year.

Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.

Outcome measures

Outcome data not reported

Adverse Events

Combined Treatment.

Serious events: 2 serious events

Other events: 13 other events

Deaths: 0 deaths

Denosumab Monotherapy

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Measure	Combined Treatment. n=15 participants at risk 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 participants at risk 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 participants at risk 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Cardiac disorders Angina, Unstable	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Blood and lymphatic system disorders Polycythaemia Vera	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Nervous system disorders Epilepsy	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.2% 1/16 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Gastrointestinal disorders Inflammatory Bowel Disease	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Gastrointestinal disorders Gastritis	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Skin and subcutaneous tissue disorders Erysipelas	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.

Other adverse events

Measure	Combined Treatment. n=15 participants at risk 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily.	Denosumab Monotherapy n=16 participants at risk 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily.	Placebo n=15 participants at risk 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Skin and subcutaneous tissue disorders Leg edema	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	12.5% 2/16 • Number of events 7 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Respiratory, thoracic and mediastinal disorders Coughing	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	25.0% 4/16 • Number of events 9 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	13.3% 2/15 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Respiratory, thoracic and mediastinal disorders Dyspnea	13.3% 2/15 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	12.5% 2/16 • Number of events 6 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Nervous system disorders Paraesthesia, hands	40.0% 6/15 • Number of events 36 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	18.8% 3/16 • Number of events 15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	26.7% 4/15 • Number of events 20 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Nervous system disorders Paraesthesia, feet	26.7% 4/15 • Number of events 17 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	18.8% 3/16 • Number of events 27 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	13.3% 2/15 • Number of events 23 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Nervous system disorders Headache	13.3% 2/15 • Number of events 4 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.2% 1/16 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
General disorders Fatigue	6.7% 1/15 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.2% 1/16 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	13.3% 2/15 • Number of events 5 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Ear and labyrinth disorders Dizziness	6.7% 1/15 • Number of events 3 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	25.0% 4/16 • Number of events 7 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	20.0% 3/15 • Number of events 17 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Gastrointestinal disorders Nausea	46.7% 7/15 • Number of events 18 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	56.2% 9/16 • Number of events 21 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	26.7% 4/15 • Number of events 5 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Gastrointestinal disorders Abdominal pain	13.3% 2/15 • Number of events 6 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	12.5% 2/16 • Number of events 6 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Gastrointestinal disorders Gastroenteritis	20.0% 3/15 • Number of events 5 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	13.3% 2/15 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Renal and urinary disorders Cystitis	13.3% 2/15 • Number of events 2 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.2% 1/16 • Number of events 5 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	40.0% 6/15 • Number of events 14 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	37.5% 6/16 • Number of events 17 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	20.0% 3/15 • Number of events 20 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Musculoskeletal and connective tissue disorders Back pain	6.7% 1/15 • Number of events 12 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.2% 1/16 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	6.7% 1/15 • Number of events 1 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Endocrine disorders Hypocalcaemia	40.0% 6/15 • Number of events 33 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/16 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	0.00% 0/15 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.
Infections and infestations Upper respiratory tract infection	33.3% 5/15 • Number of events 12 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	37.5% 6/16 • Number of events 20 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.	26.7% 4/15 • Number of events 5 • Adverse events were collected for each participant from baseline until two weeks after treatment-cessation, up to 1 year. Adverse events were collected at each visit using a adverse event questionnaire as well as assessment by a study-physician.

Additional Information

Professor Peter Vestergaard

Aalborg University Hospital

Phone: +45 97 66 36 00

Email: p.vestergaard@rn.dk

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place