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Clinical Trial Results:
Patient and evaluator blinded non-inferiority study on safety, tolerability and lumbar fusion efficacy of a single administration of Osteogrow (rhBMP6 in autologous blood coagulum (ABC) carrier) in adult patients treated by posterolateral lumbar interbody fusion (PLIF) for degenerative disc disease

Summary
EudraCT number	2017-000860-14
Trial protocol	AT
Global end of trial date	13 Mar 2023

Results information
Results version number	v1(current)
This version publication date	11 Feb 2026
First version publication date	11 Feb 2026
Other versions

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

GR-OG-279239-03

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Genera Research Ltd

Sponsor organisation address

Svetonedjeljska 2, Kalinovica, Croatia, 10436 Rakov Potok

Public contact

Slobodan Vukicevic, Genera Research Ltd, +385 (0)16474229, info@genera-research.com

Scientific contact

Slobodan Vukicevic, Genera Research Ltd, +385 (0)16474229, info@genera-research.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

19 Sep 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Mar 2023

Global end of trial reached?

Yes

Global end of trial date

13 Mar 2023

Was the trial ended prematurely?

Main objective of the trial

Evaluate safety and composite endpoint non-inferiority of one of the two doses of Osteogrow+Allograft delivered bilaterally between transverse processes of a single lumbar spine segment in comparison to autologous iliac crest bone graft (with a non-inferiority absolute margin of 10% as patient success at 20 months after surgery)

Protection of trial subjects

Patients were enrolled in three stages, separated by at least 3 months follow-up of patients included in the preceding stage, an interim review of the collected safety data by the Independent Data and Safety Monitoring Board (IDSMB), and a “go/no-go” decision for progression into the next stage based on the IDSMB recommendation. As an additional precaution, the first stage was conducted at a single clinical site. All patients were screened within one month before surgery, operated in a hospital setting and kept in the hospital for at least 10 days (Stage 1 only), or for 5 to 13 days after surgery, depending on the postoperative course. Follow-up visits were performed on the day of hospital discharge and 3 weeks, 6 weeks and 3, 6, 12 and 20 months after surgery. Each visit entailed various clinical assessments, laboratory tests, radiological procedures and/or questionnaires.

Background therapy

PLIF procedure entails lumbar interbody fusion by means of intervertebral cages filled with local (host) bone, and posterior stabilization of the treated spinal segment with pedicle screws.

Evidence for comparator

Autologous bone graft from the iliac crest is considered the gold standard for stimulation of bone formation.

Actual start date of recruitment

25 May 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 143

Worldwide total number of subjects

143

EEA total number of subjects

143

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)

106

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at three centers in Austria, from 26 May 2018 (FPFV) until 13 March 2023 (LPLV)

Screening details

Patients with symptomatic L3-S1 DDD were screened within one month before surgery by medical history, physical exam, clinical laboratory tests, urine drug screen, urine pregnancy test (if applicable), and ECG. Imaging (X-rays, MRI/CT) depended on the availability of recent images. Other procedures were related to the collection of baseline data.

Number of subjects started

162 ^[1]

Number of subjects completed

143

Reason: Number of subjects

Screening failure: 14

Reason: Number of subjects

Surgery cancelled: 3

Reason: Number of subjects

Physician decision: 2

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 162 subjects were assessed for eligibility. Only subjects who were eligible and randomized (N=143) were considered enrolled.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Assessor, Investigator

Blinding implementation details

All patients were blinded to treatment allocation. Investigators who operated on patients were unblinded. Those who performed postoperative physical and neurological examinations were blinded and called blinded evaluators. They were to evaluate adverse events as well, but this could not be confirmed in all cases. Other blinded evaluations included all radiographic measurements or assessments and anti-rhBMP6 antibody tests, which were performed centrally by blinded personnel.

Are arms mutually exclusive

Yes

Standard of Care

Arm description

360 degrees stabilization with intervertebral cages filled with local (host) bone, instrumentation with pedicle screws, and bilateral autologous bone graft from iliac crest in the lateral gutter (approximately 5 cc per side).

Arm type

Standard of Care

Investigational medicinal product name

No investigational medicinal product assigned in this arm

HD OSTEOGROW

Arm description

Standard of Care but with Osteogrow (1 mg rhBMP6 in 5 mL ABC; 0.2 mg/mL), supplemented with allograft (1.3 ± 0.2 g of commercially available human cancellous bone granules, 2-8 mm), implanted into each lateral gutter instead of autologous bone graft, 2 mg rhBMP6 in total

Arm type

Experimental

Investigational medicinal product name

rhBMP6

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for implantation paste

Routes of administration

Implantation

Dosage and administration details

Osteogrow implants were prepared in the operating room using Osteogrow kit (2 mg rhBMP6 in vials, solvent and ancillary items), allograft, and 10 mL of patient’s peripheral blood drawn approximately 60 min before the anticipated time implantation. Osteogrow was implanted into the left and right lateral gutter, one implant per side, after stabilization of the treated spinal level with intervertebral cages filled with local (host) bone and pedicle screws.

LD OSTEOGROW

Arm description

Standard of Care but with Osteogrow (0.5 mg rhBMP6 in 5 mL ABC; 0.1 mg/mL), supplemented with allograft (1.3 ± 0.2 g of commercially available human cancellous bone granules, 2-8 mm), implanted into each lateral gutter instead of autologous bone graft, 1 mg rhBMP6 in total

Arm type

Experimental

Investigational medicinal product name

rhBMP6

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for implantation paste

Routes of administration

Implantation

Dosage and administration details

Osteogrow implants were prepared in the operating room using Osteogrow kit (1 mg rhBMP6 in vials, solvent and ancillary items), allograft, and 10 mL of patient’s peripheral blood drawn approximately 60 min before the anticipated time implantation. Osteogrow was implanted into the left and right lateral gutter, one implant per side, after stabilization of the treated spinal level with intervertebral cages filled with local (host) bone and pedicle screws.

Number of subjects in period 1	Standard of Care	HD OSTEOGROW	LD OSTEOGROW
Started	62	61	20
Completed	51	52	18
Not completed	11	9	2
Adverse event, serious fatal	3	-	-
Consent withdrawn by subject	2	7	2
Adverse event, non-fatal	2	-	-
Lost to follow-up	4	2	-

Baseline characteristics

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Reporting group title

Standard of Care

Reporting group description

Reporting group title

HD OSTEOGROW

Reporting group description

Reporting group title

LD OSTEOGROW

Reporting group description

Reporting group values	Standard of Care	HD OSTEOGROW	LD OSTEOGROW	Total
Number of subjects	62	61	20	143
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	43	49	15	107
From 65-84 years	19	12	5	36
85 years and over	0	0	0	0
Adults (18-64)	0	0	0	0
Adults	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	57.8 ( 11.7 )	54.5 ( 12.2 )	56.2 ( 13.3 )	-
Gender categorical
Units: Subjects
Female	33	32	10	75
Male	29	29	10	68

Subject analysis set title

Standard of Care (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

HD Osteogrow (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

LD Osteogrow (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

Standard of Care (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Subject analysis set title

HD Osteogrow (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Subject analysis set title

LD Osteogrow (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Subject analysis sets values	Standard of Care (mITT)	HD Osteogrow (mITT)	LD Osteogrow (mITT)	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects	55	56	19	61	61	20
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)	38	46	14	42	49	15
From 65-84 years	17	10	5	19	12	5
85 years and over
Adults (18-64)
Adults
Age continuous
Units: years
arithmetic mean (standard deviation)	57.8 ( 11.7 )	54.6 ( 11.3 )	54.9 ( 12.4 )	57.9 ( 11.9 )	54.5 ( 12.2 )	56.2 ( 13.3 )
Gender categorical
Units: Subjects
Female	29	31	10	32	32	10
Male	26	25	9	29	29	10

End points

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Reporting group title

Standard of Care

Reporting group description

Reporting group title

HD OSTEOGROW

Reporting group description

Reporting group title

LD OSTEOGROW

Reporting group description

Subject analysis set title

Standard of Care (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

HD Osteogrow (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

LD Osteogrow (mITT)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomized subjects who received study treatment, were followed-up for at least 6 months, and had baseline data needed to determine the primary endpoint

Subject analysis set title

Standard of Care (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Subject analysis set title

HD Osteogrow (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Subject analysis set title

LD Osteogrow (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized subjects who received study treatment

Primary: Overall clinical success (OCS) 20 months after surgery

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End point title

Overall clinical success (OCS) 20 months after surgery

End point description

OCS was defined as all of the following: (a) radiographic fusion (no evidence of intervertebral motion with bilateral bony bridging); (b) spinal function improvement (decrease in ODI by ≥15 points); (c) maintenance or improvement in neurological status (equals to neurological success; derived from 11 components); (d) no additional surgical procedures related to the treated spinal level; and (e) no serious implant- or implant/surgical procedure-associated adverse events. To preserve the power of the trial, all comparisons were limited to the main arms (SoC and HD Osteogrow) where missing data on individual components of the OCS were imputed using multiple imputation by chained equations (MICE) or univariate methods as described in the applicable secondary endpoints, and success rates were derived from 20 imputed datasets. No OCS was observed in the LD Osteogrow arm.

End point type

Primary

End point timeframe

Month 20 after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)	1.9	0.2

NI/S of HD Osteogrow vs SoC: OCS at 20 months

Statistical analysis description

Each of the 20 imputed datasets was analysed separately and the results were pooled according to Rubin’s rules. Non-inferiority/superiority (NI/S) was assessed based on the covariate-unadjusted 1-sided 95% CI for the HD Osteogrow - SoC difference in pooled percentages, calculated using Wald’s z statistic for a pair of proportions with non-pooled standard errors.

Comparison groups

HD Osteogrow (mITT) v Standard of Care (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

-1.7

Confidence interval

level

95%

sides

1-sided

lower limit

-5.2

upper limit

Notes
[1] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Secondary: Overall clinical success (OCS) at 6 and 12 months after surgery

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End point title

Overall clinical success (OCS) at 6 and 12 months after surgery

End point description

Please refer to the description of the primary endpoint (OCS 20 months after surgery). In accordance with the planned sequential non-inferiority/superiority (NI/S) testing of HD Osteogrow vs. SoC (NI at month 20 > S at month 20 > S at month 12 > S at month 6), stopping after the first non-rejection of the null hypothesis and leaving the remaining hypotheses non-rejected, the superiority of HD Osteogrow vs. SoC at 12 and 6 months was not tested. No OCS was observed in the LD Osteogrow arm at any time point.

End point type

Secondary

End point timeframe

6 and 12 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Month 6	0.0	1.8
Month 12	2.0	3.7

No statistical analyses for this end point

Secondary: Radiographic fusion (RF) at 6, 12 and 20 months after surgery

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End point title

Radiographic fusion (RF) at 6, 12 and 20 months after surgery

End point description

RF was defined as no evidence of intervertebral motion at the treated spinal level (≤3 mm translation and <5 degrees angular motion on lateral flexion/extension x-rays) with radiographic evidence of bridging trabecular bone (continuous bony connection from the superior to inferior transverse process) on both sides. The latter was assessed by consensus of 3 blinded assessors based on CT scans or lumbar spine x-rays, if a CT scan was not available. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing data on motion and bridging at 6, 12 and 20 months were imputed using multiple imputation by chained equations (MICE) as described in endpoints “no evidence of motion” and “bony bridging”. RF rates shown below were pooled from 20 imputed datasets. No RF was observed in the LD Osteogrow arm.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Month 6	3.8	5.6
Month 12	4.4	6.0
Month 20	6.2	4.2

NI/S of HD Osteogrow vs SoC: RF at month 20

Statistical analysis description

Each of the 20 imputed datasets was analysed separately and the results were pooled according to Rubin’s rules. Exploratory non-inferiority/superiority (NI/S) testing was performed in the same manner as described for the primary endpoint, but with a fixed testing sequence (NI at month 20 > S at month 20 > S at month 12 > S at month 6) stopping after the first non-rejection of the null hypothesis and leaving the remaining hypotheses non-rejected.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

-2

Confidence interval

level

95%

sides

1-sided

lower limit

-9.5

upper limit

Notes
[2] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Secondary: The size of the bone generated between the transverse processes (minimum axial diameter of the bridges)

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End point title

The size of the bone generated between the transverse processes (minimum axial diameter of the bridges)

End point description

For each observed bony bridge, the minimum axial diameter (MAD) of the bridge was measured by three blinded assessors, and the three measurements were averaged. The collected data were summarized for all bridges observed in the mITT dataset and analysed descriptively. In the LD Osteogrow arm, two bridges were observed at month 12 (MAD 6.3 mm for both) and one at month 6 (MAD 4.3 mm).

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	19 ^[3]	8 ^[4]
Units: Millimeter
arithmetic mean (standard deviation)
Month 6	4.1 ( 2.4 )	3.6 ( 1.6 )
Month 12	4.9 ( 1.9 )	5.2 ( 2.6 )
Month 20	5.0 ( 2.3 )	4.8 ( 3.0 )

Notes
[3] - The total number of bridges in the mITT dataset (19 in month 20, 18 in month 12, and 17 in month 6)
[4] - The total number of bridges in the mITT dataset (8 in month 20, 9 in month 12, and 11 in month 6)

No statistical analyses for this end point

Secondary: Oswestry Disability Index (ODI) over time

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End point title

Oswestry Disability Index (ODI) over time

End point description

ODI (range 0 to 100) is a measure of functional impairment/disability related to lumbar spine problems, derived from the patient’s responses to the ODI questionnaire. Higher ODI values indicate greater disability. Comparisons were limited to the main arms (SoC and HD Osteogrow) where missing ODI values were imputed by visit using multiple imputation by chained equations (MICE); the predictive mean matching was employed with 5 donor values and the following predictor variables: treatment arm, baseline ODI, “no evidence of motion”, SF36 PCS score, ODI Pain score, age, smoking, body mass index, and sex. The mean covariate-adjusted scores pooled from 20 imputed datasets are shown below. Unadjusted mean scores for all arms, based on actual observations only, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Score points
least squares mean (standard error)
Week 3	46.1 ( 2.19 )	45.6 ( 2.16 )
Week 6	38.1 ( 2.38 )	38.1 ( 2.26 )
Month 3	33.3 ( 2.41 )	32.4 ( 2.39 )
Month 6	31.0 ( 2.43 )	29.1 ( 2.37 )
Month 12	30.9 ( 2.98 )	26.6 ( 2.88 )
Month 20	35.3 ( 2.84 )	25.6 ( 2.73 )

Attachments

Longitudinal analysis of ODI scores

ODI over time (main arms): Month 20

Statistical analysis description

Mean ODI values over time were modeled for each of the 20 imputed datasets using GLS-fitted MMRM, a fixed-effect general linear model for repeated measurements with Kenward-Roger adjustment for degrees of freedom, REML estimation of the (co)variance parameters, unstructured covariance pattern, and adjustment for age and baseline value (both interacting with visit). The obtained estimates were pooled and compared between arms at each visit using Wald’s t statistic; 2-sided tests at α=0.05.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.0437 ^[6]

Method

GLS-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

-9.71

Confidence interval

level

95%

sides

2-sided

lower limit

-19.21

upper limit

-0.216

Variability estimate

Standard error of the mean

Dispersion value

4.01

Notes
[5] - Wald’s t statistic (Kenward-Roger scaled Wald’s statistic) is adjusted through both the denominator degrees of freedom and appropriate inflation of the variance-covariance matrix, accounting for small sample sizes and mild deviations from normality of the normalized model residuals. P-values and 95% CIs for mean (pooled) HD Osteogrow-SoC differences were both unadjusted and adjusted for multiplicity using the mvt method. Results for earlier time points are shown in the attachment.
[6] - Wald’s t statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective).

Secondary: Spinal function (ODI) success at 6, 12 and 20 months after surgery

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End point title

Spinal function (ODI) success at 6, 12 and 20 months after surgery

End point description

Spinal function success (SFS), also called ODI success, was an indicator of relevant improvement in spinal function in individual subjects and was defined as a clinically meaningful reduction in ODI of ≥15 points from baseline. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing ODI values were imputed as described for ODI over time. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Month 6	50.8	58.9
Month 12	57.1	61.7
Month 20	49.2	62.4

Attachments

Longitudinal analysis of ODI success rates

NI/S of HD Osteogrow vs SoC: SFS at 20 months

Statistical analysis description

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

13.2

Confidence interval

level

95%

sides

1-sided

lower limit

-3

upper limit

Notes
[7] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Age-adjusted SFS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of SFS over time were modeled for each of the 20 imputed datasets using GEE-estimated logistic regression (unstructured covariance, age interacting with visit), pooled, and compared between arms at each visit on a probability scale (marginal means estimated on a response scale) using Wald’s z statistic (asymptotic normal approximation of the distribution of the relevant test statistic under infinite degrees of freedom); 2-sided tests at α=0.05.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.287 ^[9]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.1511

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0816

upper limit

0.384

Variability estimate

Standard error of the mean

Dispersion value

0.0994

Notes
[8] - P-values and 95% CIs for mean (pooled) HD Osteogrow-SoC differences were both unadjusted and adjusted for multiplicity using the so-called mvt method, a parametric exact method where the critical value for the test statistic is derived from the multivariate t distribution accounting for the estimated means and covariances. Results for earlier time points are shown in the attachment.
[9] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective).

Secondary: Back pain over time

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End point title

Back pain over time

End point description

Back pain was quantified using the ODI Pain score (range 0 to 5), the raw score for the pain question in the ODI questionnaire. Higher scores indicate greater pain. For the main arms (SoC and HD Osteogrow), missing ODI Pain scores were imputed by visit using multiple imputation by chained equations (MICE); the predictive mean matching was employed with 5 donor values and the following predictor variables: treatment arm, baseline ODI Pain score, “no evidence of motion”, any unintended ossification, surgical site swelling, age, smoking, body mass index, and sex. The mean covariate-adjusted scores derived from 20 imputed datasets are shown below. Unadjusted mean scores for all arms, based on actual observations only, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Score points
least squares mean (standard error)
Week 3	1.93 ( 0.133 )	1.87 ( 0.157 )
Week 6	1.79 ( 0.146 )	1.89 ( 0.127 )
Month 3	1.76 ( 0.162 )	1.69 ( 0.148 )
Month 6	1.70 ( 0.174 )	1.83 ( 0.158 )
Month 12	1.98 ( 0.205 )	1.70 ( 0.184 )
Month 20	2.05 ( 0.189 )	1.52 ( 0.171 )

Attachments

Longitudinal analysis of ODI Pain scores

Back pain scores over time (main arms): Month 20

Statistical analysis description

This was an MMRM-based analysis, performed for each of the 20 imputed datasets using GEE estimation with a robust (sandwich) empirical estimator of unstructured covariance and adjustments for age and baseline score that were allowed to vary across visits. The obtained estimates were pooled and compared between arms at each visit using Wald’s z statistic (2-sided tests at α=0.05), with and without adjustment for multiplicity using the mvt method.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.0978 ^[11]

Method

GEE-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

-0.535

Confidence interval

level

95%

sides

2-sided

lower limit

-1.142

upper limit

0.0708

Variability estimate

Standard error of the mean

Dispersion value

0.257

Notes
[10] - MMRM assumed treating ODI Pain scores as numerical outcomes with equidistant items and was performed to obtain easily interpretable results - mean scores and their differences. It also implied equal probability of transition from one score to the other and, therefore, required a sensitivity analysis using a method suitable for handling ordinal outcomes. Results for earlier time points are shown in the attachment.
[11] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective); unadjusted p=0.0375.

Back pain scores (ordinal regression): Month 20

Statistical analysis description

ODI Pain scores were also modelled in each imputed dataset using GEE-estimated ordinal logistic regression (GEE estimation with category-exchangeability structure and robust standard errors, visit and arm interactions, and with an independent adjustment for age at each visit; adjustment for baseline was not meaningful). The obtained age-adjusted estimates on the latent variable scale were pooled and compared between arms in the same way as described above for MMRM.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.0347 ^[13]

Method

GEE-fitted ordinal regression

Parameter type

Mean difference (final ranked values)

Point estimate

-0.9377

Confidence interval

level

95%

sides

2-sided

lower limit

-1.823

upper limit

-0.0525

Variability estimate

Standard error of the mean

Dispersion value

0.376

Notes
[12] - A latent variable is a virtual random continuous variable underlying the ordinal response, i.e., the observed scores are considered to be a categorized manifestation of some underlying continuous response. Positive estimates on the latent variable scale reflect greater odds of higher scores (for ODI Pain score this means worse condition), while negative estimates indicate greater odds of lower scores (better condition). Results were consistent with those obtained via MMRM except for month 20.
[13] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective).

Secondary: Back pain relief success (BPRS) over time

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End point title

Back pain relief success (BPRS) over time

End point description

BPRS was an indicator of relevant reduction in back pain in individual subjects and was defined as a clinically meaningful reduction in ODI Pain score of ≥1 point from baseline. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing ODI Pain scores were imputed as described for back pain over time. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of patients
number (not applicable)
Month 6	69.4	58.9
Month 12	64.5	61.6
Month 20	61.5	72.8

Attachments

Longitudinal analysis of back pain relief success

Age-adjusted BPRS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of BPRS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2905 ^[14]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.1442

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0753

upper limit

0.364

Variability estimate

Standard error of the mean

Dispersion value

0.093

Notes
[14] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective).

NI/S of HD Osteogrow vs SoC: BPRS at 20 months

Statistical analysis description

Each of the 20 imputed datasets was analysed separately and unadjusted BPRS rates were pooled according to Rubin’s rules. Exploratory non-inferiority/superiority (NI/S) testing was performed in the same manner as described for radiographic fusion.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[15]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

11.3

Confidence interval

level

95%

sides

1-sided

lower limit

-3.7

upper limit

Notes
[15] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Secondary: Leg pain over time

Top of page

End point title

Leg pain over time

End point description

Leg pain was quantified using the LLQ Pain score (range 0 to 100), the score for the pain domain of the American Academy of Orthopedic Surgeons Lower Limb Questionnaire (LLQ questions 3 to 5). Higher scores indicate less pain. For the main arms (SoC and HD Osteogrow), missing LLQ Pain scores were imputed by visit using multiple imputation by chained equations (MICE); the predictive mean matching was employed with 5 donor values and the following predictor variables: treatment arm, baseline LLQ Pain score, any unintended ossification, “no evidence of motion”, neurological success, age, smoking, body mass index, and sex. The mean covariate-adjusted scores derived from 20 imputed datasets are shown below. Unadjusted mean scores for all arms, based on actual observations only, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Score points
least squares mean (standard error)
Week 3	64.0 ( 2.90 )	65.7 ( 2.84 )
Week 6	71.4 ( 2.79 )	71.5 ( 2.87 )
Month 3	72.0 ( 2.79 )	72.7 ( 2.76 )
Month 6	65.8 ( 3.02 )	70.5 ( 2.96 )
Month 12	63.0 ( 3.63 )	73.1 ( 3.58 )
Month 20	62.6 ( 3.16 )	80.2 ( 3.06 )

Attachments

Longitudinal analysis of LLQ Pain scores

Leg pain scores over time (main arms): Month 20

Statistical analysis description

LLQ Pain scores were modelled and compared between the main arms in the same manner as described for ODI over time.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.0003 ^[17]

Method

GLS-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

17.609

Confidence interval

level

95%

sides

2-sided

lower limit

7.195

upper limit

28.02

Variability estimate

Standard error of the mean

Dispersion value

4.3756

Notes
[16] - Results for earlier time points are shown in the attachment.
[17] - Wald’s t statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective).

Secondary: Leg pain relief success (LPRS) over time

Top of page

End point title

Leg pain relief success (LPRS) over time

End point description

LPRS was an indicator of relevant reduction in leg pain in individual subjects and was defined as a clinically meaningful increase in LLQ Pain score of ≥15 points from baseline. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing LLQ Pain scores were imputed as described for leg pain over time. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of patients
number (not applicable)
Month 6	54.4	56.5
Month 12	49.1	56.2
Month 20	46.2	77.4

Attachments

Longitudinal analysis of leg pain relief success

Age-adjusted LPRS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of LPRS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0021 ^[18]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.3142

Confidence interval

level

95%

sides

2-sided

lower limit

0.0954

upper limit

0.533

Variability estimate

Standard error of the mean

Dispersion value

0.0927

Notes
[18] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective).

NI/S of HD Osteogrow vs SoC: LPRS at 20 months

Statistical analysis description

Each of the 20 imputed datasets was analysed separately and unadjusted LPRS rates were pooled according to Rubin’s rules. Exploratory non-inferiority/superiority (NI/S) testing was performed in the same manner as described for radiographic fusion.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[19]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

31.2

Confidence interval

level

95%

sides

1-sided

lower limit

upper limit

Notes
[19] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

NI/S of HD Osteogrow vs SoC: LPRS at 12 months

Statistical analysis description

Same as for the LPRS analysis at 20 months.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

superiority

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

7.1

Confidence interval

level

95%

sides

1-sided

lower limit

-9.5

upper limit

Secondary: Quality of life (QoL): Physical component summary (PCS) scores over time

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End point title

Quality of life (QoL): Physical component summary (PCS) scores over time

End point description

General health status and patient satisfaction with their health were assessed by measuring health-related QoL using the 36-Item Short Form Health Survey (SF36). The SF36 PCS score is an indicator of overall physical health (a score of 50 is a norm; values <50 or >50 are below or above the norm, respectively). For the main arms (SoC and HD Osteogrow), missing PCS scores were imputed by visit using multiple imputation by chained equations (MICE); the predictive mean matching was employed with 5 donor values and the following predictor variables: treatment arm, ODI, “no evidence of motion”, neurological success, baseline PCS score, age, smoking, body mass index, and sex. The mean covariate-adjusted scores derived from 20 imputed datasets are shown below. Unadjusted mean scores for all arms, based on actual observations only, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Score points
least squares mean (standard error)
Week 3	32.3 ( 0.97 )	32.2 ( 0.95 )
Week 6	34.3 ( 0.92 )	35.5 ( 0.95 )
Month 3	37.7 ( 1.04 )	36.6 ( 1.04 )
Month 6	36.8 ( 1.14 )	38.5 ( 1.12 )
Month 12	38.2 ( 1.40 )	40.5 ( 1.46 )
Month 20	36.9 ( 1.52 )	42.1 ( 1.45 )

Attachments

Longitudinal analysis of PCS scores

PCS scores over time: Month 20

Statistical analysis description

PCS scores were modelled and compared between the main arms in the same manner as described for ODI over time.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.0421 ^[21]

Method

GLS-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

5.119

Confidence interval

level

95%

sides

2-sided

lower limit

0.976

upper limit

9.26

Variability estimate

Standard error of the mean

Dispersion value

2.09

Notes
[20] - Results for earlier time points are shown in the attachment.
[21] - Wald’s t statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective).

Secondary: PCS success (PCSS; meaningful improvement in physical health) at 6, 12 and 20 months after surgery

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End point title

PCS success (PCSS; meaningful improvement in physical health) at 6, 12 and 20 months after surgery

End point description

PCSS was an indicator of relevant improvement in physical health in individual subjects and was defined as a clinically meaningful increase in PCS score of ≥5 points from baseline. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing PCS scores were imputed as described for PCS scores over time. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms at all time points, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of patients
number (not applicable)
Month 6	61.4	63.4
Month 12	59.5	66.4
Month 20	54.9	76.7

Attachments

Longitudinal analysis of PCS success rates

NI/S of HD Osteogrow vs SoC: PCSS at 20 months

Statistical analysis description

Each of the 20 imputed datasets was analysed separately and PCSS rates were pooled according to Rubin’s rules. Exploratory non-inferiority/superiority (NI/S) testing was performed in the same manner as described for radiographic fusion.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[22]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

21.8

Confidence interval

level

95%

sides

1-sided

lower limit

6.2

upper limit

Notes
[22] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

NI/S of HD Osteogrow vs SoC: PCSS at 12 months

Statistical analysis description

Same as for the PCSS analysis at 20 months.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

Confidence interval

level

95%

sides

1-sided

lower limit

-9.6

upper limit

Age-adjusted PCSS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of PCSS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0395 ^[23]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.2299

Confidence interval

level

95%

sides

2-sided

lower limit

0.00845

upper limit

0.451

Variability estimate

Standard error of the mean

Dispersion value

0.0937

Notes
[23] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective).

Secondary: Quality of life (QoL): Mental component summary (MCS) scores over time

Top of page

End point title

Quality of life (QoL): Mental component summary (MCS) scores over time

End point description

General health status and patient satisfaction with their health were assessed by measuring health-related QoL using the 36-Item Short Form Health Survey (SF36). The SF36 MCS score is an indicator of overall mental health (a score of 50 is a norm; values <50 or >50 are below or above the norm, respectively). For the main arms (SoC and HD Osteogrow), missing MCS scores were imputed by visit using multiple imputation by chained equations (MICE); the predictive mean matching was employed with 5 donor values and the following predictor variables: treatment arm, ODI, ODI Pain score, LLQ Pain score, baseline MCS score, age, smoking, body mass index, and sex. The mean covariate-adjusted scores derived from 20 imputed datasets are shown below. Unadjusted mean scores for all arms, based on actual observations only, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Score points
least squares mean (standard error)
Week 3	36.6 ( 1.76 )	36.5 ( 1.70 )
Week 6	41.2 ( 1.71 )	38.9 ( 1.73 )
Month 3	40.6 ( 1.85 )	40.1 ( 1.87 )
Month 6	40.2 ( 1.86 )	40.4 ( 1.85 )
Month 12	39.2 ( 1.97 )	43.1 ( 1.99 )
Month 20	37.7 ( 1.98 )	41.8 ( 1.90 )

Attachments

Longitudinal analysis of MCS scores

MCS scores over time: Month 20

Statistical analysis description

MCS scores were modelled and compared between the main arms in the same manner as described for ODI over time.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.3344 ^[25]

Method

GLS-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

4.116

Confidence interval

level

95%

sides

2-sided

lower limit

-2.62

upper limit

10.86

Variability estimate

Standard error of the mean

Dispersion value

2.8

Notes
[24] - Results for earlier time points are shown in the attachment.
[25] - Wald’s t statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at 6, 12 and 20 months as they were most relevant from a clinical perspective).

Secondary: MCS success (MCSS; meaningful improvement in mental health) at 6, 12 and 20 months after surgery

Top of page

End point title

MCS success (MCSS; meaningful improvement in mental health) at 6, 12 and 20 months after surgery

End point description

MCSS was an indicator of relevant improvement in mental health in individual subjects and was defined as a clinically meaningful increase in MCS score of ≥3 points from baseline. All comparisons were limited to the main arms (SoC and HD Osteogrow) where missing PCS scores were imputed as described for PCS scores over time. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms at all time points, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of patients
number (not applicable)
Month 6	54.6	55.8
Month 12	43.5	55.7
Month 20	53.1	51.2

Attachments

Longitudinal analysis of MCS success rates

NI/S of HD Osteogrow vs SoC: MCSS at 20 months

Statistical analysis description

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

-1.9

Confidence interval

level

95%

sides

1-sided

lower limit

-19.4

upper limit

Notes
[26] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Age-adjusted MCSS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of MCSS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9999 ^[27]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

-0.005

Confidence interval

level

95%

sides

2-sided

lower limit

-0.256

upper limit

0.246

Variability estimate

Standard error of the mean

Dispersion value

0.106

Notes
[27] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective).

Secondary: Neurological success (NS) over time

Top of page

End point title

Neurological success (NS) over time

End point description

NS was a component of overall clinical success and was defined as maintenance or improvement in neurological status, i.e., no worsening in the American Spinal Injury Association (ASIA) motor and sensory scores for lower extremities, patellar and Achilles reflexes, and straight leg raise test results (all on both sides, left and right), with no new permanent neurological deficit related to treated spinal level. For the main arms (SoC, HD Osteogrow), missing binary data on NS (Yes/No) were imputed by visit using MICE, based on logistic regression and the following predictor variables: treatment arm, “no evidence of motion”, any unintended ossification, ODI, SF36 PCS score, age, smoking, BMI, and sex. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms (based on the number of subjects who completed the visit; those with missing data counted as non-success), interpreted as observed probabilities, are shown in the attachment.

End point type

Secondary

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Week 3	43.4	40.0
Week 6	36.8	52.6
Month 3	34.1	46.1
Month 6	49.9	38.8
Month 12	38.2	29.3
Month 20	50.0	39.1

Attachments

Longitudinal analysis of neurological success rate

NI/S of HD Osteogrow vs SoC: NS at 20 months

Statistical analysis description

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

-10.9

Confidence interval

level

95%

sides

1-sided

lower limit

-27.2

upper limit

Notes
[28] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Age-adjusted NS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of NS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6283 ^[29]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

-0.1056

Confidence interval

level

95%

sides

2-sided

lower limit

-0.341

upper limit

0.1302

Variability estimate

Standard error of the mean

Dispersion value

0.099

Notes
[29] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective); unadjusted p=0.2859.

Secondary: Incidence of adverse events (AEs) and treatment-emergent adverse events (TEAEs)

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End point title

Incidence of adverse events (AEs) and treatment-emergent adverse events (TEAEs)

End point description

AEs were collected at each post-screening visit. TEAEs were defined as any AEs that occurred after the start of study treatment, i.e., after placement of an implant (Osteogrow or autologous bone graft [ABG]) into the lateral gutter. Each AE/TEAE was categorized by seriousness, severity, outcome, and relationship to each the implant (Osteogrow or ABG) and surgical procedure (SP; surgery on Day 0). Categorization was to be performed by a blinded evaluator, but this could not be confirmed for all events. The categories shown in endpoint values are not mutually exclusive but include all events that met the criteria for a given category, e.g., deaths were also counted as serious TEAEs, or “implant- and SP-related AEs” were also counted as both implant-related and SP-related AEs. Consequently, implant-related SAEs were equivalent to the SAE component of overall clinical success (implant- or implant/surgical procedure-associated SAEs).

End point type

Secondary

End point timeframe

From screening until the end of observation (up to 20 months after surgery)

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61	61	20
Units: Percentage of subjects
number (confidence interval 95%)
Any adverse event (AE)	98.4 (91.3 to 99.7)	90.2 (80.2 to 95.4)	90.0 (69.9 to 97.2)
Any treatment-emergent AE (TEAE)	98.4 (91.3 to 99.7)	90.2 (80.2 to 95.4)	85.0 (64.0 to 94.8)
Serious TEAEs	54.1 (41.7 to 66.0)	31.1 (20.9 to 43.6)	25.0 (11.2 to 46.9)
Severe TEAEs	44.3 (32.5 to 56.7)	19.7 (11.6 to 31.3)	10.0 (2.8 to 30.1)
Any implant-related AEs	4.9 (1.7 to 13.5)	6.6 (2.6 to 15.7)	5.0 (0.9 to 23.6)
Any surgical procedure-related AEs	52.5 (40.2 to 64.5)	45.9 (34.0 to 58.3)	40.0 (21.9 to 61.3)
Implant and procedure-related AEs	3.3 (0.9 to 11.2)	6.6 (2.6 to 15.7)	5.0 (0.9 to 23.6)
Surgical procedure-related SAEs	13.1 (6.8 to 23.8)	11.5 (5.7 to 21.8)	15.0 (5.2 to 36.0)
Non-TEAEs	6.6 (2.6 to 15.7)	3.3 (0.9 to 11.2)	15.0 (5.2 to 36.0)

Any adverse events (main arms)

Statistical analysis description

Wilson’s 95% CIs were calculated for within-arm percentages to avoid a negative lower bound and provide a more accurate estimate in the case of low fraction of events. The comparison was limited to the main arms; the 95% CI for the SoC - HD Osteogrow difference in percentages was calculated using the Miettinen-Nurminen method to provide a more accurate and conservative estimate in the case of low event fraction or small differences between the arms. CIs were not adjusted for multiplicity.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other ^[30]

Method

Parameter type

Difference in percentages

Point estimate

8.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

18.5

Notes
[30] - The difference is statistically significant if the CI does not include zero.

Any TEAEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

8.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

18.5

Serious TEAEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events. Three subjects in the SoC arm died (4.9%; 95%CI: 1.7% to 13.5%) vs. none in the Osteogrow arms (0%; 95%CI: not calculated).

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

39.2

Severe TEAEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

24.6

Confidence interval

level

95%

sides

2-sided

lower limit

8.1

upper limit

Implant-related AEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events. Implant-related AEs were serious in one subject in the SoC arm (1.6%; 95%CI: 0.3% to 8.7%) vs. none in the Osteogrow arms (0%; 95%CI: not calculated).

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

7.9

Surgical procedure-related AEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.1

upper limit

23.9

Implant- and procedure-related AEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

-3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-12.9

upper limit

5.5

Surgical procedure-related SAEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.7

upper limit

14.1

Non-TEAEs (main arms)

Statistical analysis description

Same as for analysis of any adverse events.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentages

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

12.9

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Incidence

Top of page

End point title

Additional surgical procedures related to the treated spinal level (ASP): Incidence

End point description

Additional surgical procedures related to the treated spinal level included all minor or major subsequent procedures in the area of the surgical wound or the treated spinal segment, regardless of whether they were triggered by complications of PLIF surgery or unsatisfactory therapeutic response to PLIF surgery. All comparisons were limited to the main arms (SoC and HD Osteogrow).

End point type

Secondary

End point timeframe

From surgery (Day 0) until the end of observation (up to 20 months after surgery)

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)	LD Osteogrow (mITT)	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	55	56	19	61	61	20
Units: Percentage of subjects
number (not applicable)	14.5	8.9	5.3	14.8	11.5	5.0

ASP (main arms): Incidence, mITT

Statistical analysis description

Logistic regression with treatment arm as the only categorical covariate.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3566

Method

Regression, Logistic

Confidence interval

ASP (main arms): Incidence, SAF

Statistical analysis description

Logistic regression with treatment arm as the only categorical covariate.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5912

Method

Regression, Logistic

Confidence interval

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Number of additional procedures

Top of page

End point title

Additional surgical procedures related to the treated spinal level (ASP): Number of additional procedures

End point description

End point type

Secondary

End point timeframe

From surgery (Day 0) until the end of observation (up to 20 months after surgery)

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)	LD Osteogrow (mITT)	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	55	56	19	61	61	20
Units: Percentage of subjects	10	6	2	11	10	2

ASP (main arms): Number of procedures, mITT

Statistical analysis description

The average number of additional procedures per arm was calculated for all arms (termed procedure-per-patient ratio: 0.182 vs. 0.107 and 0.105 in the SoC vs. HD and LD Osteogrow arms, respectively) and compared between the main arms using a Poisson generalized linear model (GLM). The fitted model was tested for overdispersion and was found appropriate.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3013

Method

Poisson GLM

Confidence interval

ASP (main arms): Number of procedures, SAF

Statistical analysis description

The average number of additional procedures per arm was calculated for all arms (termed procedure-per-patient ratio: 0.180 vs. 0.164 and 0.100 in the SoC vs. HD and LD Osteogrow arms, respectively) and compared between the main arms using a negative binomial GLM because the Poisson GLM did not pass the criteria for overdispersion.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.8557

Method

Negative binomial GLM

Confidence interval

Notes
[31] - Negative binomial GLM

Secondary: Pelvic/hip pain over time

Top of page

End point title

Pelvic/hip pain over time

End point description

Data on postoperative pelvic/hip pain, a proxy for iliac crest pain, were collected from hospital discharge onwards. Pain was quantified using the HOOS Pain score (range 0 to 100), the score for the pain domain of the Hip Dysfunction and Osteoarthritis Outcome Score questionnaire (questions P1 to P10). Higher HOOS Pain scores indicate less pain. As for other endpoints, all comparisons were limited to the main arms (SoC and HD Osteogrow).

End point type

Secondary

End point timeframe

Hospital discharge, weeks 3 and 6, and months 3, 6, 12 and 20

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	59 ^[32]	61 ^[33]	19 ^[34]
Units: Score points
arithmetic mean (standard deviation)
Discharge	74.5 ( 21.8 )	68.1 ( 26.5 )	62.4 ( 23.4 )
Week 3	70.4 ( 24.7 )	69.7 ( 25.3 )	66.1 ( 22.8 )
Week 6	74.9 ( 22.5 )	73.1 ( 24.7 )	72.2 ( 26.4 )
Month 3	71.9 ( 25.5 )	70.9 ( 27.0 )	69.9 ( 26.1 )
Month 6	71.8 ( 25.6 )	73.5 ( 27.6 )	69.7 ( 28.0 )
Month 12	66.5 ( 27.9 )	79.4 ( 22.6 )	68.7 ( 29.0 )
Month 20	67.1 ( 24.6 )	80.3 ( 22.2 )	71.6 ( 20.8 )

Attachments

Longitudinal analysis of HOOS Pain scores

Notes
[32] - 59, 57, 55, 54, 54, 50 and 51 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively
[33] - 61, 59, 58, 55, 56, 50 and 52 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively
[34] - 19, 17, 18, 19, 18, 19 and 18 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively

HD Osteogrow vs SoC: Pelvic/hip pain at 20 months

Statistical analysis description

Exploratory superiority testing was based on the 1-sided 95% CI for the HD Osteogrow - SoC difference in mean unadjusted HOOS Pain scores, calculated using a t-test with Welch–Satterthwaite adjustment for degrees of freedom. The lower limit of this CI >0 indicated superiority. A fixed testing sequence (starting at month 20 and continuing backward until discharge) was applied, stopping after the first non-rejection of the null hypothesis and leaving the remaining hypotheses non-rejected.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

13.2

Confidence interval

level

95%

sides

1-sided

lower limit

5.5

upper limit

HD Osteogrow vs SoC: Pelvic/hip pain at 12 months

Statistical analysis description

The same as described for pelvic/hip pain at 20 months.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

12.9

Confidence interval

level

95%

sides

1-sided

lower limit

4.3

upper limit

HD Osteogrow vs SoC: Pelvic/hip pain at 6 months

Statistical analysis description

The same as described for pelvic/hip pain at 20 months.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.7

Confidence interval

level

95%

sides

1-sided

lower limit

-6.7

upper limit

HOOS Pain scores over time (main arms): Month 20

Statistical analysis description

HOOS Pain scores over time were modeled for the main arms using GLS-fitted MMRM, a fixed-effect general linear model for repeated measurements with Kenward-Roger adjustment for degrees of freedom, REML estimation of the (co)variance parameters, unstructured covariance pattern, and adjustment for age, allowing the adjustments to vary at each time point. The obtained estimates were compared between arms at each visit using Wald’s t statistic; 2-sided tests at α=0.05.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.0455 ^[36]

Method

GLS-fitted MMRM

Parameter type

Mean difference (final values)

Point estimate

9.611

Confidence interval

level

95%

sides

2-sided

lower limit

0.197

upper limit

19.03

Variability estimate

Standard error of the mean

Dispersion value

4.75

Notes
[35] - Wald’s t statistic (Kenward-Roger scaled Wald’s statistic) is adjusted through both the denominator degrees of freedom and appropriate inflation of the variance-covariance matrix, accounting for small sample sizes and mild deviations from normality of the normalized model residuals. P-values and 95% CIs for mean HD Osteogrow-SoC differences were both unadjusted and adjusted for multiplicity using the mvt method. Results for earlier time points are shown in the attachment.
[36] - Wald’s t statistic unadjusted for multiplicity; p=0.1785 after mvt correction for 7 tests.

Secondary: Anti-rhBMP antibodies

Top of page

End point title

Anti-rhBMP antibodies

End point description

Anti-rhBMP6 antibodies were measured at screening and 3, 6, 12 and 20 months after surgery using a validated indirect enzyme-linked immunosorbent assay. Test results were reported as positive, negative, or indeterminate. At least one postoperative test result was available for 58 (95%), 57 (93%) and 19 (95%) subjects in the SoC, HD Osteogrow and LD Osteogrow arms, respectively. The endpoint values shown below are percentages of subjects tested positive for anti-rhBMP6 antibodies, calculated based on the total number subjects tested at each time point. No subject had an indeterminate test result.

End point type

Secondary

End point timeframe

3, 6, 12 and 20 months after surgery

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	60 ^[37]	59 ^[38]	20 ^[39]
Units: Percentage of subjects
number (not applicable)
Screening	0.0	0.0	0.0
Month 3	0.0	0.0	0.0
Month 6	0.0	0.0	0.0
Month 12	0.0	0.0	0.0
Month 20	0.0	0.0	0.0

Notes
[37] - 60, 52, 54, 49 and 47 subjects had data at screening and months 3, 6, 12 and 20, respectively
[38] - 59, 53, 51, 48 and 48 subjects had data at screening and months 3, 6, 12 and 20, respectively
[39] - : 20, 18, 17, 18 and 18 subjects had data at screening and months 3, 6, 12 and 20, respectively

No statistical analyses for this end point

Secondary: Operative time

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End point title

Operative time

End point description

Operative time was defined as the time from the first surgical incision to closure of the surgical wound.

End point type

Secondary

End point timeframe

Day of surgery (Day 0)

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61	61	20
Units: Minutes
arithmetic mean (standard deviation)	198.4 ( 68.9 )	169.1 ( 155.0 )	165.4 ( 60.4 )

Operative time (main arms)

Statistical analysis description

Operative time was compared between the main arms using the Monte-Carlo (permutation) version of the Welch t-test (9999 samples, seed=1000).

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0072

Method

Permutation Welch two-sample t-test

Parameter type

Mean difference (final values)

Point estimate

29.18

Confidence interval

level

95%

sides

2-sided

lower limit

7.64

upper limit

50.82

Variability estimate

Standard error of the mean

Dispersion value

11.132

Secondary: Intraoperative blood loss

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End point title

Intraoperative blood loss

End point description

Intraoperative blood loss was estimated using the Lopez-Pikado equation, based on hematocrit before surgery and on postoperative day 5, blood transfusions during surgery and up to day 5, and sex, age, body weight and height of the subject.

End point type

Secondary

End point timeframe

Day of surgery (Day 0)

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61	61	20
Units: Milliliters
arithmetic mean (standard deviation)	1425.2 ( 482.2 )	1318.3 ( 473.2 )	1361.5 ( 445.2 )

Intraoperative blood loss (main arms)

Statistical analysis description

Blood loss was compared between the main arms using the Monte-Carlo (permutation) version of the Welch t-test (9999 samples, seed=1000).

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2528

Method

Permutation Welch two-sample t-test

Parameter type

Mean difference (final values)

Point estimate

107.46

Confidence interval

level

95%

sides

2-sided

lower limit

-77.11

upper limit

287.62

Variability estimate

Standard error of the mean

Dispersion value

92.518

Secondary: Number of hospital days

Top of page

End point title

Number of hospital days

End point description

End point type

Secondary

End point timeframe

From the day of surgery (Day 0) until the end of observation (up to 20 months)

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61	61	20
Units: Days
arithmetic mean (standard deviation)
Initial postoperative hospital stay	8.8 ( 3.5 )	8.3 ( 3.1 )	8.6 ( 4.7 )
All hospital stays during follow-up	22.6 ( 18.9 )	20.2 ( 15.1 )	15.6 ( 11.2 )

Postoperative hospital stay (main arms)

Statistical analysis description

The length of postoperative hospital stay was compared between the main arms using the Monte-Carlo (permutation) version of the Welch t-test (9999 samples, seed=1000).

Comparison groups

HD Osteogrow (SAF) v Standard of Care (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3428

Method

Permutation Welch two-sample t-test

Parameter type

Mean difference (final values)

Point estimate

0.562

Confidence interval

level

95%

sides

2-sided

lower limit

-0.627

upper limit

1.704

Variability estimate

Standard error of the mean

Dispersion value

0.598

All hospital stays during follow-up (main arms)

Statistical analysis description

The same as described above for postoperative hospital stay.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4267

Method

Permutation Welch two-sample t-test

Parameter type

Mean difference (final values)

Point estimate

2.499

Confidence interval

level

95%

sides

2-sided

lower limit

-3.661

upper limit

8.644

Variability estimate

Standard error of the mean

Dispersion value

3.149

Other pre-specified: “No evidence of motion” at the treated spinal level

Top of page

End point title

“No evidence of motion” at the treated spinal level

End point description

“No evidence of motion” (NEoM) at the treated spinal level was a component of radiographic fusion and defined as ≤3 mm translation and <5 degrees angular motion on lateral flexion/extension x-rays. Motion was measured with FXA™ software. For the main arms (SoC, HD Osteogrow), missing binary data on NEoM (Yes/No) at 6, 12 and 20 months were imputed by visit using MICE, based on logistic regression and the following predictor variables: treatment arm, bridging on either side, ODI, neurological success, SF36 PCS score, age, smoking, BMI, and sex. As NEoM was used as a predictor for some other variables, data for earlier time points were imputed by carrying backward the first postoperative value. The endpoint values shown below are estimated marginal means (EM means) from the model described in the statistical analysis section. The observed NEoM rates in all arms, based on the total number of actual observations and interpreted as observed probabilities, are shown in the attachment.

End point type

Other pre-specified

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Unitless (range 0 to 1)
number (confidence interval 95%)
Month 6	0.958 (0.818 to 0.992)	0.942 (0.812 to 0.985)
Month 12	0.956 (0.774 to 0.994)	0.900 (0.776 to 0.966)
Month 20	0.970 (0.787 to 0.997)	0.942 (0.808 to 0.987)

Attachments

Longitudinal analysis of no evidence of motion

“No evidence of motion”: Month 20

Statistical analysis description

Probabilities of “no evidence of motion” were modeled for each of the 20 imputed datasets using GEE-estimated logistic regression (unstructured covariance, age and baseline value interacting with visit), pooled, and compared between arms at each visit on a probability scale (marginal means estimated on a response scale) using Wald’s z statistic (asymptotic normal approximation of the distribution of the relevant test statistic under infinite degrees of freedom); 2-sided tests at α=0.05.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

= 0.888 ^[41]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

-0.0283

Confidence interval

level

95%

sides

2-sided

lower limit

-0.133

upper limit

0.0768

Variability estimate

Standard error of the mean

Dispersion value

0.0441

Notes
[40] - P-values and 95% CIs for mean (pooled) HD Osteogrow - SoC differences were both unadjusted and adjusted for multiplicity using the so-called mvt method, a parametric exact method where the critical value for the test statistic is derived from the multivariate t distribution accounting for the estimated means and covariances. Results for earlier time points are shown in the attachment.
[41] - Wald’s z statistic with mvt correction for 3 tests.

Other pre-specified: Bony bridging on at least one side

Top of page

End point title

Bony bridging on at least one side

End point description

Bony bridging was defined as radiographic evidence of continuous bony connection from the superior to inferior transverse process. It was assessed separately for the left/right side by consensus of 3 blinded assessors. Bilateral bridging was required to claim the radiographic fusion, yet any bridging was also of interest. For the main arms (SoC, HD Osteogrow), missing data at 6, 12 or 20 months were imputed separately for each side using MICE, by logistic regression and the following predictor variables: treatment arm, “no evidence of motion”, ODI, neurological success, SF36 PCS score, age, smoking, BMI, and sex. The presence of unilateral or bilateral bridging was passively imputed thereafter by logical conjunction of the data for each side. The endpoint values are estimated marginal means (EM means) from the model described in the statistical analysis section. The observed bridging rates in all arms, based on the total number of actual observations, are shown in the attachment.

End point type

Other pre-specified

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Unitless (range 0 to 1)
arithmetic mean (standard error)
Month 6	0.265 ( 0.0595 )	0.158 ( 0.0518 )
Month 12	0.347 ( 0.0762 )	0.159 ( 0.0545 )
Month 20	0.360 ( 0.0717 )	0.148 ( 0.0525 )

Attachments

Longitudinal analysis bridging on at least 1 side

Bridging on at least one side: Month 20

Statistical analysis description

Probabilities of at least unilateral bridging were modeled for each of the 20 imputed datasets using GEE-estimated logistic regression (unstructured covariance; age interacting with visit), pooled, and compared between arms at each visit on a probability scale (marginal means estimated on a response scale) using Wald’s z statistic (asymptotic normal approximation of the distribution of the relevant test statistic under infinite degrees of freedom); 2-sided tests at α=0.05.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.045 ^[43]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

-0.211

Confidence interval

level

95%

sides

2-sided

lower limit

-0.419

upper limit

-0.00366

Variability estimate

Standard error of the mean

Dispersion value

0.0885

Notes
[42] - P-values and 95% CIs for mean (pooled) HD Osteogrow-SoC differences were both unadjusted and adjusted for multiplicity as described for “no evidence of motion”. Results for earlier time points are shown in the attachment.
[43] - Wald’s z statistic with mvt correction for 3 tests.

Other pre-specified: Bilateral bony bridging

Top of page

End point title

Bilateral bony bridging

End point description

Bilateral bony bridging, defined as radiographic evidence of continuous bony connection from the superior to inferior transverse process on both sides, was a component of radiographic fusion. For the main arms (SoC, HD Osteogrow), missing data at 6, 12 or 20 months were imputed as described for “bony bridging on at least one side”. The resulting data on bilateral bridging were used to calculate radiographic fusion rates in the imputed dataset but were not separately analysed. Namely, the planned longitudinal modelling was omitted due to low rates of bilateral bridging in the non-imputed mITT dataset which are shown below. No bilateral bridging was observed in the LD Osteogrow arm at any time point.

End point type

Other pre-specified

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	47 ^[44]	50 ^[45]
Units: Percentage of subjects
number (not applicable)
Month 6	3.7	5.7
Month 12	4.3	6.0
Month 20	6.4	4.0

Notes
[44] - Subjects from the mITT dataset with actual observations at months 12 or 20 (54 at month 6)
[45] - Subjects from the mITT dataset with actual observations at months 12 or 20 (53 at month 6)

No statistical analyses for this end point

Other pre-specified: Incidence of new permanent neurological deficits

Top of page

End point title

Incidence of new permanent neurological deficits

End point description

Neurological status was assessed at screening, before surgery (only for subjects screened >7 days before surgery), on the day of hospital discharge, and 3 weeks, 6 weeks and 3, 6, 12 and 20 months after surgery. A new permanent neurological deficit was defined as any neurological deficit observed at the last subject’s visit, unless it was already present before surgery or was obviously unrelated to the treated spinal level in the investigator’s opinion.

End point type

Other pre-specified

End point timeframe

End of observation (up to 20 months after surgery)

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61	61	20
Units: Percentage of subjects
number (not applicable)	11.5	4.9	10.0

No statistical analyses for this end point

Other pre-specified: Incidence of surgical site swelling/edema

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End point title

Incidence of surgical site swelling/edema

End point description

Surgical site swelling/edema was assessed by a blinded evaluator and categorized as absent, mild, moderate, or severe. The endpoint values shown below and analysed are the percentages of subjects with swelling/edema of any severity, calculated based on the number of actual observations (severe swelling/edema was reported in only one subject in the SoC arm and one in the LD Osteogrow arm). Given that this variable, dichotomised into “Absent/Present”, was one of the predictors for imputation of missing ODI Pain scores, missing data on surgical site swelling/edema in the mITT dataset for the main arms (SoC and HD Osteogrow) were imputed as follows: (a) from month 6 onwards, “Absent” was imputed, unless the preceding or subsequent observed value was “Present” (the latter was imputed in this case); (b) from week 3 to month 3 inclusive, the last observation was carried forward and then the next observation was carried backward for the remaining missing values.

End point type

Other pre-specified

End point timeframe

Hospital discharge, weeks 3 and 6, and months 3, 6, 12 and 20

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	61 ^[46]	61 ^[47]	19 ^[48]
Units: Percentage of subjects
number (not applicable)
Discharge	68.9	75.4	57.9
Week 3	43.1	41.4	35.3
Week 6	17.2	6.8	11.1
Month 3	1.8	1.8	5.6
Month 6	0.0	0.0	0.0
Month 12	0.0	0.0	0.0
Month 20	0.0	0.0	0.0

Attachments

Percentage of patients with surgical site swelling

Notes
[46] - 61, 58, 58, 57, 56, 50 and 51 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively
[47] - 61, 58, 59, 56, 54, 50 and 51 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively
[48] - 19, 17, 18, 18, 17, 18 and 18 at discharge, week 3, week 6 and months 3, 6, 12 and 20, respectively

Adjusted probability of swelling/edema: Discharge

Statistical analysis description

The comparison was limited to the main arms. For each time point, the age-adjusted probability of surgical site swelling/edema was estimated by logistic regression and compared between arms on a probability scale (marginal means estimated on a response scale) using Wald’s z statistic (asymptotic normal approximation of the distribution of the relevant test statistic under infinite degrees of freedom); 2-sided tests at α=0.05.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.4938 ^[50]

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

0.0559

Confidence interval

level

95%

sides

2-sided

lower limit

-0.104

upper limit

0.2016

Variability estimate

Standard error of the mean

Dispersion value

0.0817

Notes
[49] - P-values were both unadjusted and adjusted for multiplicity using the Holm method. Results for other time points are shown in the attachment.
[50] - Wald’s z statistic unadjusted for multiplicity.

Other pre-specified: Incidence of unintended soft tissue ossification (USTO)

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End point title

Incidence of unintended soft tissue ossification (USTO)

End point description

USTO was assessed by 3 blinded assessors on CT scans or lumbar spine x-rays, if CT was not available, and was considered present if reported by at least 2 assessors. It was categorized as distant (if observed in the lateral gutter of adjacent spinal segments or beyond the line connecting the lateral edges of transverse processes at the treated or adjacent segments), medially spreading (if reaching neuroforamina or spinal canal), or “other” (if observed elsewhere). The endpoint values shown below were calculated based on the number of actual observations. Given that USTO (any type) was one of the predictors used for MICE, missing USTO data in the mITT dataset for the main arms (SoC and HD Osteogrow) were imputed as follows: a) from week 3 to month 3, “Absent” was imputed by default; b) from month 6 onwards, the last observation was carried forward and then the next observation was carried backward where applicable; if there were no data to carry in any direction, “Absent” was imputed.

End point type

Other pre-specified

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (SAF)	HD Osteogrow (SAF)	LD Osteogrow (SAF)
Number of subjects analysed	57 ^[51]	55 ^[52]	19 ^[53]
Units: Percent of patients
number (not applicable)
Distant ossification: Month 6	1.8	1.9	5.6
Distant ossification: Month 12	2.0	9.8	0.0
Distant ossification: Month 20	2.0	3.9	5.6
Distant ossification: Subject’s last visit	1.8	16.7	11.1
Medially spreading: Month 6	0.0	1.9	0.0
Medially spreading: Month 12	0.0	2.0	0.0
Medially spreading: Month 20	0.0	0.0	0.0
Medially spreading: Subject’s last visit	0.0	0.0	0.0
Other unintended: Month 6	1.8	3.7	0.0
Other unintended: Month 12	2.0	3.9	0.0
Other unintended: Month 20	4.0	17.6	5.6
Other unintended: Subject’s last visit	3.5	18.2	5.3
Any of the above: Month 6	3.5	7.4	5.6
Any of the above: Month 12	4.0	13.7	0.0
Any of the above: Month 20	6.0	21.6	11.1
Any of the above: Subject’s last visit	5.3	21.8	10.5

Notes
[51] - 57 for the subject’s last visit, and 57, 50 and 50 for months 6, 12 and 20, respectively
[52] - 55 for the subject’s last visit, and 54, 51 and 51 for months 6, 12 and 20, respectively
[53] - 19 for the subject’s last visit, and 18, 19 and 18 for months 6, 12 and 20, respectively

Distant ossification: Overall incidence

Statistical analysis description

The overall incidence of individual categories of USTO across months 6, 12, 20 was compared between the main arms using a logistic regression model (treatment arm interacted with USTO category allowing the effect to vary across categories) and Wald’s z statistic; 2-sided tests at α=0.05. CIs were calculated on the logit scale and back transformed. P-values and 95% CIs for SoC - HD Osteogrow differences were both unadjusted and adjusted for multiplicity using the mvt method.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

= 0.111 ^[55]

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.103

Confidence interval

level

95%

sides

2-sided

lower limit

-0.229

upper limit

0.024

Variability estimate

Standard error of the mean

Dispersion value

0.065

Notes
[54] - For each USTO category, the overall incidence across months 6, 12 and 20 was calculated by combining data for the three visits as follows: it was counted as “present” if detected at any of these visits, and “absent” only if absent at all three visits. Subjects who did not meet these criteria were excluded from the analysis, resulting in an overall incidence of distant ossification of 3/47 (6.4%) in the SoC arm vs. 8/48 (16.7%) and 2/18 (11.1%) in the HD and LD Osteogrow arms, respectively.
[55] - Wald’s z statistic unadjusted for multiplicity.

Medially spreading ossification: Overall incidence

Statistical analysis description

The same as for the analysis of distant ossification.

Comparison groups

Standard of Care (SAF) v HD Osteogrow (SAF)

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

= 0.149 ^[57]

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.042

Confidence interval

level

95%

sides

2-sided

lower limit

-0.098

upper limit

0.015

Variability estimate

Standard error of the mean

Dispersion value

0.029

Notes
[56] - For each USTO category, the overall incidence across months 6, 12 and 20 was calculated by combining data for the three visits as follows: it was counted as “present” if detected at any of these visits, and “absent” only if absent at all three visits. Subjects who did not meet these criteria were excluded from the analysis, resulting in an overall incidence of medially spreading USTO of 0/46 (0.0%) in the SoC arm vs. 2/48 (4.2%) and 0/18 (0.0%) in the HD and LD Osteogrow arms, respectively.
[57] - Wald’s z statistic unadjusted for multiplicity.

Other unintended ossification: Overall incidence

Statistical analysis description

The same as for the analysis of distant ossification.

Comparison groups

HD Osteogrow (SAF) v Standard of Care (SAF)

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[58]

P-value

= 0.041 ^[59]

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.139

Confidence interval

level

95%

sides

2-sided

lower limit

-0.272

upper limit

-0.005

Variability estimate

Standard error of the mean

Dispersion value

0.068

Notes
[58] - For each USTO category, the overall incidence across months 6, 12 and 20 was calculated by combining data for the three visits as follows: it was counted as “present” if detected at any of these visits, and “absent” only if absent at all three visits. Subjects who did not meet these criteria were excluded from the analysis, resulting in an overall incidence of “other” USTO of 3/46 (6.5%) in the SoC arm vs. 10/49 (20.4%) and 1/18 (5.6%) in the HD and LD Osteogrow arms, respectively.
[59] - Wald’s z statistic unadjusted for multiplicity; p=0.119 after mvt correction for 3 tests.

Any unintended ossification: Overall incidence

Statistical analysis description

The overall incidence of any USTO across months 6, 12, 20 (distant, medially spreading and “other” USTO combined) was compared between the main arms using the 2-sample Wald’s chi-squared test for equality of proportions.

Comparison groups

HD Osteogrow (SAF) v Standard of Care (SAF)

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[60]

P-value

= 0.0163

Method

Wald’s chi-squared test

Confidence interval

Notes
[60] - For any USTO, the overall incidence across months 6, 12 and 20 was calculated by combining data for the three visits as follows: it was counted as “present” if detected at any of these visits, and “absent” only if absent at all three visits. Subjects who did not meet these criteria were excluded from the analysis, resulting in an overall incidence of any USTO of 6/47 (12.8%) in the SoC arm vs. 16/49 (32.7%) and 3/18 (16.7%) in the HD and LD Osteogrow arms, respectively.

Post-hoc: Alternative neurological success (ANS) over time

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End point title

Alternative neurological success (ANS) over time

End point description

Given that the obtained neurological success rates were largely driven by changes in reflexes and inconsistent with other outcomes, e.g., changes in other components of neurological status or overall ratings of neurological status made by the same evaluator, they were recalculated using an alternative definition of neurological success: absence of clinically relevant abnormalities in neurological status with no new permanent neurological deficits. For the main arms (SoC, HD Osteogrow), missing binary data (Yes/No) were imputed by MICE using the same predictors as for neurological success: treatment arm, “no evidence of motion”, any unintended ossification, ODI, SF36 PCS score, age, smoking, BMI, and sex. The endpoint values shown below were pooled from 20 imputed datasets. The observed ANS rates in all arms (based on the number of subjects who completed the visit; those with missing data counted as non-success), interpreted as observed probabilities, are shown in the attachment.

End point type

Post-hoc

End point timeframe

3 weeks, 6 weeks, and 3, 6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Week 3	81.7	85.3
Week 6	79.6	86.8
Month 3	85.3	85.4
Month 6	83.0	89.1
Month 12	74.5	91.2
Month 20	71.4	84.6

Attachments

Longitudinal analysis of alternative neurological

NI/S of HD Osteogrow vs SoC: ANS at 20 months

Statistical analysis description

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[61]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

13.2

Confidence interval

level

95%

sides

1-sided

lower limit

-1

upper limit

Notes
[61] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Age-adjusted ANS over time: Month 20

Statistical analysis description

Age-adjusted probabilities of ANS over time were modeled and compared between the main arms in the same manner as described for spinal function success. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

other

P-value

= 0.3757 ^[62]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.1162

Confidence interval

level

95%

sides

2-sided

lower limit

-0.082

upper limit

0.315

Variability estimate

Standard error of the mean

Dispersion value

0.1162

Notes
[62] - Wald’s z statistic with mvt correction for 3 tests (adjustments for multiplicity were limited to tests at months 6, 12 and 20, the most relevant time points from a clinical perspective); unadjusted p=0.1679.

Post-hoc: Alternative overall success (AOS) at 6, 12 and 20 months

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End point title

Alternative overall success (AOS) at 6, 12 and 20 months

End point description

Given that overall clinical success (OCS) rates were inconsistent with other findings, success rates were recalculated post-hoc using a less stringent definition of success, termed AOS. AOS had the same components as OCS, but radiographic fusion was defined as “no evidence of motion” at the treated spinal level, and neurological success as the absence of clinically relevant abnormalities in neurological status with no new permanent neurological deficits (alternative neurological success). The remaining three components were the same as for OCS. For the main arms (SoC and HD Osteogrow), missing data on individual AOS components were imputed using MICE or univariate methods, as described elsewhere. The endpoint values shown below were pooled from 20 imputed datasets. The observed success rates in all arms (based on the number of subjects who completed the visit; those with missing data counted as “failure”), interpreted as observed probabilities, are shown in the attachment.

End point type

Post-hoc

End point timeframe

6, 12 and 20 months after surgery

End point values	Standard of Care (mITT)	HD Osteogrow (mITT)
Number of subjects analysed	55	56
Units: Pooled percentage of subjects
number (not applicable)
Month 6	38.5	44.8
Month 12	45.5	46.3
Month 20	39.5	48.2

Attachments

Longitudinal analysis alternative overall success

NI/S of HD Osteogrow vs SoC: AOS at 20 months

Statistical analysis description

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[63]

Method

Parameter type

Mean (pooled) difference in percentages

Point estimate

8.7

Confidence interval

level

95%

sides

1-sided

lower limit

-7.7

upper limit

Notes
[63] - The lower limit of the 1-sided 95% CI for the HD Osteogrow - SoC difference greater than -10 percentage points (pp) indicated non-inferiority and the lower limit >0 pp indicated superiority.

Covariate-adjusted AOS over time: Month 20

Statistical analysis description

Probabilities of AOS over time were modeled and compared between the main arms as described for spinal function success, but adjustments were made for both age and body mass index. Results for all time points are shown in the attachment.

Comparison groups

Standard of Care (mITT) v HD Osteogrow (mITT)

Number of subjects included in analysis

111

Analysis specification

Post-hoc

Analysis type

other

P-value

= 0.6 ^[64]

Method

Regression, Logistic

Parameter type

Mean difference in probabilities

Point estimate

0.1026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.135

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.1015

Notes
[64] - Wald’s z statistic with mvt correction for 3 tests.

Adverse events

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Timeframe for reporting adverse events

0-20 months

Adverse event reporting additional description

AEs were collected before and after surgery, at hospital discharge, and 3 weeks, 6 weeks, and 3, 6, 12, and 20 months after surgery. Treatment-emergent AEs (TEAEs), ie, AEs occurring after placement of study implant (Osteogrow or autologous bone graft) into the lateral gutter, were analyzed.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Standard of Care

Reporting group description

Reporting group title

HD OSTEOGROW

Reporting group description

Standard of Care plus Osteogrow (1 mg rhBMP6 in 5 mL ABC; 0.2 mg/mL), supplemented with allograft (1.3 ± 0.2 g of commercially available human cancellous bone granules, 2-8 mm), implanted into each lateral gutter instead of autologous bone graft, 2 mg rhBMP6 in total

Reporting group title

LD OSTEOGROW

Reporting group description

Standard of Care plus Osteogrow (0.5 mg rhBMP6 in 5 mL ABC; 0.1 mg/mL), supplemented with allograft (1.3 ± 0.2 g of commercially available human cancellous bone granules, 2-8 mm), implanted into each lateral gutter instead of autologous bone graft, 1 mg rhBMP6 in total

Serious adverse events	Standard of Care	HD OSTEOGROW	LD OSTEOGROW
Total subjects affected by serious adverse events
subjects affected / exposed	33 / 61 (54.10%)	20 / 61 (32.79%)	5 / 20 (25.00%)
number of deaths (all causes)	3	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Cerebrovascular accident
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Cardiac pacemaker insertion
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carpal tunnel decompression
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb immobilisation
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral nerve decompression
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Medical device implantation
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Medical device repositioning
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Impaired healing
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device fastener issue
subjects affected / exposed	1 / 61 (1.64%)	3 / 61 (4.92%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Arthroscopy
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural pulmonary embolism
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 61 (1.64%)	2 / 61 (3.28%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Nervous system disorders
Carpal tunnel syndrome
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal incontinence
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 61 (0.00%)	2 / 61 (3.28%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	3 / 61 (4.92%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteochondritis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudarthrosis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Standard of Care	HD OSTEOGROW	LD OSTEOGROW
Total subjects affected by non serious adverse events
subjects affected / exposed	60 / 61 (98.36%)	55 / 61 (90.16%)	18 / 20 (90.00%)
Investigations
C-reactive protein increased
subjects affected / exposed	12 / 61 (19.67%)	10 / 61 (16.39%)	4 / 20 (20.00%)
occurrences all number	13	10	4
Gamma-GT increased
subjects affected / exposed	5 / 61 (8.20%)	3 / 61 (4.92%)	1 / 20 (5.00%)
occurrences all number	5	3	1
Prothrombin time shortened
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	1
Blood immunoglobulin G increased
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Glucose urine present
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Platelet count increased
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Post procedural hypotension
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	1
Postoperative wound complication
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences all number	0	1	1
Adjacent segment degeneration
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Post procedural swelling
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	6 / 61 (9.84%)	9 / 61 (14.75%)	1 / 20 (5.00%)
occurrences all number	9	12	1
Nervous system disorders
Hypoaesthesia
subjects affected / exposed	3 / 61 (4.92%)	6 / 61 (9.84%)	0 / 20 (0.00%)
occurrences all number	3	7	0
Sciatica
subjects affected / exposed	3 / 61 (4.92%)	3 / 61 (4.92%)	1 / 20 (5.00%)
occurrences all number	4	3	1
Headache
subjects affected / exposed	4 / 61 (6.56%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences all number	4	9	0
Dysaesthesia
subjects affected / exposed	2 / 61 (3.28%)	2 / 61 (3.28%)	1 / 20 (5.00%)
occurrences all number	2	2	1
Vertigo
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences all number	1	1	1
Monoparesis
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	2 / 61 (3.28%)	3 / 61 (4.92%)	2 / 20 (10.00%)
occurrences all number	2	3	2
Impaired healing
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	2
Gastrointestinal disorders
Haemorrhoids
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences all number	0	1	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Psychiatric disorders
Sleep disorder
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	11 / 61 (18.03%)	9 / 61 (14.75%)	1 / 20 (5.00%)
occurrences all number	12	9	1
Arthralgia
subjects affected / exposed	6 / 61 (9.84%)	5 / 61 (8.20%)	3 / 20 (15.00%)
occurrences all number	7	7	4
Pain in extremity
subjects affected / exposed	4 / 61 (6.56%)	6 / 61 (9.84%)	0 / 20 (0.00%)
occurrences all number	4	6	0
Osteoarthritis
subjects affected / exposed	6 / 61 (9.84%)	0 / 61 (0.00%)	0 / 20 (0.00%)
occurrences all number	6	0	0
Sacral pain
subjects affected / exposed	5 / 61 (8.20%)	1 / 61 (1.64%)	0 / 20 (0.00%)
occurrences all number	5	1	0
Osteonecrosis
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	2
Metatarsalgia
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Infections and infestations
COVID-19
subjects affected / exposed	4 / 61 (6.56%)	5 / 61 (8.20%)	0 / 20 (0.00%)
occurrences all number	4	5	0
Urinary tract infection
subjects affected / exposed	5 / 61 (8.20%)	1 / 61 (1.64%)	2 / 20 (10.00%)
occurrences all number	5	1	3
Nasopharyngitis
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences all number	2	1	1
Otitis media acute
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	4 / 61 (6.56%)	4 / 61 (6.56%)	0 / 20 (0.00%)
occurrences all number	4	4	0
Hypercholesterolaemia
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	1 / 20 (5.00%)
occurrences all number	0	1	1
Iron deficiency
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	2

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Were there any global substantial amendments to the protocol? Yes

23 Oct 2017

Protocol v5, EC approved on 2.11.2017, initial version

14 Mar 2018

Protocol v6: Procedures to accommodate adjusted implant application (lowering of implant blood volume), patient blood sampling (anti-rhBMP6 antibody collected from all patients at M24), modification of Box B ancillary items to collect smaller blood amount, adjusted ICF, IB

12 Nov 2019

Protocol v9, inclusion criterion #5 was relaxed (“healthy” replaced with “in good general condition”) as well as exclusion criteria #12 (diabetes mellitus was narrowed to certain clinical types) and #14 (numerical ECG findings were replaced with ECG abnormalities that represent a safety risk for surgery in the investigator’s opinion). Hemoglobin A1c was added to the screening tests for subjects with a history of diabetes.

20 Dec 2019

Protocol v10, reduced sample size from 192 to 134 patients in total (Stage 2 of the trial reduced from 75 to 45, and Stage 3 from 102 to 74), reduced number of treatment arms in Stage 3 from three to two (only one of the two experimental treatment arms will be progressed into Stage 3 based on the outcome of originally planned 2nd safety review by the Independent Drug Safety Monitoring Board; if there is no safety differentiation between the two dose levels, the higher dose will be progressed), reduced power of the trial from 95% to 90%, shortened follow-up period for all patients from 24 to 20 months

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
20 Mar 2020	Due to the COVID pandemic urgent safety measures were in effect from mid-March until mid-June 2020. During this period, enrolment was suspended, and follow-up visits were conducted by phone, except for Month 20 visits, which were postponed until the reopening of hospitals for non-emergency patients when these measures were retired.	18 Jun 2020

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

The low overall clinical success rates in all arms, including SoC, indicated an overly strict definition of “success”. More realistic estimates were obtained using a less stringent definition of overall success (see alternative overall success).

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall clinical success (OCS) 20 months after surgery

Primary: Overall clinical success (OCS) 20 months after surgery

Secondary: Overall clinical success (OCS) at 6 and 12 months after surgery

Secondary: Overall clinical success (OCS) at 6 and 12 months after surgery

Secondary: Radiographic fusion (RF) at 6, 12 and 20 months after surgery

Secondary: Radiographic fusion (RF) at 6, 12 and 20 months after surgery

Secondary: The size of the bone generated between the transverse processes (minimum axial diameter of the bridges)

Secondary: The size of the bone generated between the transverse processes (minimum axial diameter of the bridges)

Secondary: Oswestry Disability Index (ODI) over time

Secondary: Oswestry Disability Index (ODI) over time

Secondary: Spinal function (ODI) success at 6, 12 and 20 months after surgery

Secondary: Spinal function (ODI) success at 6, 12 and 20 months after surgery

Secondary: Back pain over time

Secondary: Back pain over time

Secondary: Back pain relief success (BPRS) over time

Secondary: Back pain relief success (BPRS) over time

Secondary: Leg pain over time

Secondary: Leg pain over time

Secondary: Leg pain relief success (LPRS) over time

Secondary: Leg pain relief success (LPRS) over time

Secondary: Quality of life (QoL): Physical component summary (PCS) scores over time

Secondary: Quality of life (QoL): Physical component summary (PCS) scores over time

Secondary: PCS success (PCSS; meaningful improvement in physical health) at 6, 12 and 20 months after surgery

Secondary: PCS success (PCSS; meaningful improvement in physical health) at 6, 12 and 20 months after surgery

Secondary: Quality of life (QoL): Mental component summary (MCS) scores over time

Secondary: Quality of life (QoL): Mental component summary (MCS) scores over time

Secondary: MCS success (MCSS; meaningful improvement in mental health) at 6, 12 and 20 months after surgery

Secondary: MCS success (MCSS; meaningful improvement in mental health) at 6, 12 and 20 months after surgery

Secondary: Neurological success (NS) over time

Secondary: Neurological success (NS) over time

Secondary: Incidence of adverse events (AEs) and treatment-emergent adverse events (TEAEs)

Secondary: Incidence of adverse events (AEs) and treatment-emergent adverse events (TEAEs)

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Incidence

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Incidence

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Number of additional procedures

Secondary: Additional surgical procedures related to the treated spinal level (ASP): Number of additional procedures

Secondary: Pelvic/hip pain over time

Secondary: Pelvic/hip pain over time

Secondary: Anti-rhBMP antibodies

Secondary: Anti-rhBMP antibodies

Secondary: Operative time

Secondary: Operative time

Secondary: Intraoperative blood loss

Secondary: Intraoperative blood loss

Secondary: Number of hospital days

Secondary: Number of hospital days

Other pre-specified: “No evidence of motion” at the treated spinal level

Other pre-specified: “No evidence of motion” at the treated spinal level

Other pre-specified: Bony bridging on at least one side

Other pre-specified: Bony bridging on at least one side

Other pre-specified: Bilateral bony bridging

Other pre-specified: Bilateral bony bridging

Other pre-specified: Incidence of new permanent neurological deficits

Other pre-specified: Incidence of new permanent neurological deficits

Other pre-specified: Incidence of surgical site swelling/edema

Other pre-specified: Incidence of surgical site swelling/edema

Other pre-specified: Incidence of unintended soft tissue ossification (USTO)

Other pre-specified: Incidence of unintended soft tissue ossification (USTO)

Post-hoc: Alternative neurological success (ANS) over time

Post-hoc: Alternative neurological success (ANS) over time

Post-hoc: Alternative overall success (AOS) at 6, 12 and 20 months

Post-hoc: Alternative overall success (AOS) at 6, 12 and 20 months

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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