Study populations: Aggregate and Single Site
The aggregate study initially enrolled 224 subjects; however, 6 subjects withdrew prior to receiving treatment, leaving 218 subjects. Thirty-six patients voluntarily withdrew or were lost to follow-up before their 12-month assessment. One hundred eighty-two subjects completed the 12-month visit across all sites. As previously reported, there were clinically meaningful improvements from baseline in the 2 co-primary endpoints (ODI and VAS at 12 months) in the overall study population, but differences between treatment groups did not reach significance [16].
At the single study site subgroup chosen for this analysis, 34 subjects were considered for the trial; however, 10 subjects were excluded prior to randomization due to voluntary withdrawal or lack of clinical imaging factors deemed necessary by the physician. Twenty-four subjects were successfully randomized into the active allograft, saline, or nonsurgical management (NSM) group, 1 subject withdrew from the trial before receiving the injection, and 1 subject from the NSM group was lost to follow-up after the 6-month mark. Twenty-three subjects (due to the crossover from the NSM group) were treated: 22 subjects completed all safety and imaging evaluations at baseline, and at 3 (NSM group only), 6, and 12 months.
Following randomization, 17 subjects received the active allograft, 2 received the saline, and 4 began in the nonsurgical management group. All 4 subjects in the NSM group met eligibility criteria for crossover and opted into the active treatment arm at the 3-month mark (Table 1).
Table 1
Demographics and baseline characteristics
| Active allograft N = 17 | Saline N = 2 | NSM N = 4 |
Age (years) | | | |
Mean ± SD (N) | 42.65 ± 6.67 | 46.50 ± 16.26 | 41.50 ± 3.70 |
Sex n (%) | | | |
Female | 7 (41.2) | 0 (0.0) | 1 (25.0) |
Male | 10 (58.8) | 2 (100.0) | 3 (75.0) |
Race n (%)a | |
American Indian or Alaska Native | 1 (5.9) | 0 (0.0) | 0 (0.0) |
Asian | 0 (0.0) | 0 (0.0) | 1 (25.0) |
Black or African American | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Native Hawaiian or Pacific Islander | 0 (0.0) | 0 (0.0) | 0 (0.0) |
White or Caucasian | 17 (100.0) | 1 (50.0) | 3 (75.0) |
Other | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Not reported | 0 (0.0) | 1 (50.0) | 0 (0.0) |
Ethnicity n (%) |
Hispanic | 0 (.0.0) | 1 (50.0) | 0 (0.0) |
Non-Hispanic | 17 (100.0) | 1 (50.0) | 4 (100.0) |
Body Mass Index (kg/m2) |
Mean ± SD (N) | 24.31 ± 3.18 (17) | 29.35 ± 3.61 (2) | 23.88 ± 2.72 (4) |
Smoking History n (%) |
Never | 11 (64.7) | 1 (50.0) | 3 (75.0) |
Past smoker | 3 (17.6) | 1 (50.0) | 1 (25.0) |
Current smoker | 3 (17.6) | 0 (0.0) | 0 (0.0) |
Not reported | 0 (0.0) | 0 (0.0) | 0 (0.0) |
History of Endocrine or Metabolic Disorders n (%) |
Yes | 1 (5.9) | 0 (0.0) | 0 (0.0) |
No | 16 (94.1) | 2 (100.0) | 4 (100.0) |
Not reported | 0 (0/0) | 0(0/0) | 0 (0.0) |
Levels of Treatment n (%) |
One level | 7 (41.2) | 0 (0.0) | 2 (50.0) |
Two levels | 10 (58.87) | 2 (100.0) | 2 (50.0) |
aSubjects could report more than one race, so numbers may be greater than the total. |
Following IRB approval of the extension for the 24- and 36-month follow-up visits, all subjects with 12 months of follow-up were re-contacted for further collection of patient-reported outcomes and evaluation for a second injection. The study was coincident with the COVID-19 pandemic, and although 13 subjects consented, with the necessity of in-person visits, only 10 successfully completed all required questionnaires, clinical imaging, and laboratory assessments. Of the 10 subjects who completed their in-person 24-month visit, 9 had received the active allograft and 1 had received the saline. One subject from the active allograft arm met all inclusion criteria and opted to receive a second allograft treatment for levels L2-L3 and L3-L4.
Clinical Outcomes Sf-36
The Short Form 36 (SF-36) Health Survey was used to assess general health status of all study patients. The SF-36 measures specific health concepts related to physical functioning and limitations, social functioning, and health perceptions and can be summarized into 2 measures pertaining to mental health (MCS) and physical health (PCS).
In this study, both the mean MCS and PCS postoperative scores were higher than preoperative scores for both cohorts (Table 2). In the active allograft group, the mean PCS improvement from baseline was 13.62 points at 6 months and 9.82 points at 12 months. Thresholds of substantial clinical benefit that the patient recognizes as a major improvement for the PCS quality-of-life measure following lumbar spine arthrodesis have been established. Suggested substantial clinical benefit thresholds for PCS score are a 6.2-point net improvement or a final raw score of ≥ 35.1 points.
Table 2
Summary of SF-36 scores of single-site subjects
| Active allograft N = 17 | Saline N = 2 | NSM N = 4 | Crossover* N = 4 |
Mental component score (Mean ± SD) | |
Baseline | 42.87 ± 134.64 | 40.47 ± 0.98 | 46.20 ± 9.05 | - |
Month 3 | - | - | 39 ± 10.99 | - |
Month 6 | 50.28 ± 9.00 | 54.08 ± 1.47 | - | 55.12 ± 4.15 |
Month 12 | 53.67 ± 6.81 | 54.63 ± 4.45 | - | 49.01 ± 11.39 |
Physical component score (Mean ± SD) | |
Baseline | 29.03 ± 5.70 | 24.74 ± 7.52 | 31.63 ± 3.86 | - |
Month 3 | - | - | 27.30 ± 5,62 | - |
Month 6 | 42.65 ± 10.34 | 36.64 ± 23.84 | - | 49.04 ± 10.33 |
Month 12 | 38.85 ± 11.66 | 36.93 ± 31.50 | - | 43.88 ± 7.88 |
*Crossover includes any NSM subject who crossed over and received Active Allograft Treatment |
Clinical outcomes ODI and VAS
Pain and function responder analyses were conducted post hoc to discriminate between improved and nonimproved patients. VAS for pain and ODI for a condition-specific physical measure before and after intervention were used to assess treatment specific outcomes.
Comparisons were made between response outcomes for the active allograft group from the aggregate data and from the single study site at 12 months to determine likelihood of reproducibility of longer-term results. Importantly, in comparing the active allograft group from the single site (n = 17) against the aggregate (n = 103), data from subjects from the single study site were not included in the aggregate responses.
For the active allograft group from aggregate sites, the overall mean reduction in ODI from baseline to 12 months was 27.20 compared with an overall mean reduction of 28.69 in single-site graft recipients. Regarding VAS pain scores, the allograft group of aggregate sites had an overall mean reduction of 33.06 and the single study site had an overall mean reduction of 34.18. A comparison of ODI and VAS outcomes between these 2 groups did not reach statistical significance 12 months post-procedure (Table 3).
Table 3
Change in Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores in active allograft subjects from baseline to 12 months
Outcome Tool | Active allograft Single site N = 17 | Active allograft Other sites N = 103 | p value* |
VAS average back pain (Mean ± SD (N) | |
Baseline | 64.35 ± 18.11 (17) | 63.85 ± 18.85 (103) | - |
Change from baseline | -33.06 ± 29.59 (17) | 34.18 ± 27.60 (103) | 0.875 |
Oswestry Disability Index (Mean ± SD (N) | | | |
Baseline | 53.63 13.11 (16) | 51.60 ± 11.65 (103) | - |
Change from baseline | -28.69 ± 19.16 (16) | -27.20 ± 18.75 (103) | 0.813 |
*P value is derived from the Wilcoxon Rank Sum Test. NSM 12- month crossover visit was used. Month 3 value was used as baseline. |
MCID Outcomes
A significant MCID was demonstrated between the allograft and saline group in a planned analysis of ODI responders with ≥15-point reduction. Post hoc analyses included responders with ≥20-point ODI reduction and VAS responders with ≥ 20-point reduction in pain 12 months post-allograft treatment (Table 4).
Table 4
Primary efficacy endpoint in average visual analog scale (VAS) and Oswestry Disability Index (ODI) scores in single-site subgroup subjects at 12 months
| Active Allograft N = 17 | Saline | Nonsurgical Management | Overall p value* | Allograft vs. Saline p value* | Allograft vs. Nonsurgical Management p value* | Saline vs. Nonsurgical Management p value* |
VAS average back pain |
≥50% reduction | 47.1% (8/17) | 50.0% (1/2) | 66.7% (2/3) | >0.999 | >0.999 | >0.999 | >0.999 |
≥15 point reduction | 64.7% (11/17) | 50.0% (1/2) | 100.0% (3/3) | 0.565 | >0.999 | 0.521 | 0.400 |
≥20 point reduction | 52.9% (9/17) | 50.0% (1/2) | 100.0% (3/3) | 0.352 | >0.999 | 0.242 | 0.400 |
ODI |
≥10 point reduction | 81.3% (13/16) | 100.0% (2/2) | 100.0% (3/3) | >0.999 | >0.999 | >0.999 | NA |
≥15 point reduction | 75.0% (12/16) | 100.0% (2/2) | 100.0% (3/3) | >0.999 | >0.999 | >0.999 | NA |
≥20 point reduction | 68.8% (11/16) | 50.0% (1/2) | 100.0% (3/3) | 0.557 | >0.999 | 0.530 | 0.400 |
*P value is derived from Fisher’s exact test Note: Nonsurgical Management 12-month crossover visit is used. Month 3 value is used as baseline. |
Of the active allograft subjects in the aggregate sites (n = 103), 76.7% had ≥15-point reduction of ODI from baseline to 12 months. Similarly, 75% of active allograft subjects from the single study site (n = 17) achieved ≥15-point reduction of ODI, showing similarity in MCID. This similarity can also be seen for the responder group characterized by ≥20-point ODI reduction, in which 68.9% and 68.8% of active allograft subjects achieved significant pain reduction as seen in the aggregate group and single study site group, respectively. Of the aggregate randomized allograft group, 68.9% showed ≥ 20-point reduction in VAS from baseline to 12 months. Similarly, 52.9% of patients at the single site who received active allograft group showed ≥20-point reduction within the same timeframe.
ODI and VAS Clinical Outcomes from single study site at 24 and 36 months
Ten subjects from the single site completed their 24-month visit, 9 of whom were from the active allograft group and 1 was from the saline group. At baseline, these 9 active allograft subjects had an average VAS score of 62.11 and average ODI score of 52.44. At 24 months post-treatment, these 9 subjects had an average VAS and ODI score of 25.22 and 26.42, showing an average improvement from baseline of 36.89 and 26.02 points, respectively (Figs. 1 and 2). These results indicate sustained improvements in back pain scores and functional outcomes for the allograft treatment arm recipients that were available at follow up. At 24 months, 8 of the 9 active allograft subjects did not receive any secondary disc interventions such as surgery or repeat injections. One of the active allograft subjects did meet the eligibility criteria for a second injection at 24 months.
At the time of this review, 4 active allograft subjects (approximately 40% of the patients consenting to long-term follow up) from the single site reached and completed their 36-month visit. At 36 months, the 4 subjects had an average VAS score of 13 and average ODI score of 29.44, showing improvements by 51.35 and 25.21 points, respectively from baseline (n=17). This sustained trend from 24 to 36 months is promising, although data is incomplete.
Adverse Events
The aggregate study had a total of 80 adverse events (AE) across all sites in all treatments. There were 66 events in the active allograft group, 5 in the saline group, 1 in the NSM group, and 8 in the crossover group. Eleven of these 80 events occurred at the single-site subgroup reviewed in this report (Table 5). Of these 11 AEs, 9 events occurred in the active allograft group (52.9% of 17 subjects), 0 events in the saline group, and 2 events in the crossover group (25% of 4 subjects). Seven of the 9 adverse events in the active allograft group were related to musculoskeletal and connective tissue disorders. Five of these musculoskeletal AEs were back pain and are common following intradiscal injection [17, 18]. In the study population, these complaints were self-limited and transient in nature and resolved with the use of non-narcotic pain medications and antispasmodic medications.
Table 5
Adverse events in single-site subjects
| Active Allograft | Saline | NSM | Crossover |
Adverse event | Number of events | Number of subjects with events %(N) | Number of events | Number of subjects with events %(N) | Number of events | Number of subjects with events %(N) | Number of events | Number of subjects with events %(N) |
Musculoskeletal and connective tissue disorders | 7 | 41.2% (7/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 2 | 25.0% (1/4) |
Back pain | 5 | 29.4% (5/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 1 | 0.0% (0/4) |
Intervertebral disc protrusion | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 0.0% (0/4) |
Muscular weakness | 0 | 0.0% (0/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 25.0% (1/4) |
Pain in extremity | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 0.0% (0/4) |
Nervous system disorders | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 1 | 25.0% (1/4) |
Hypoaesthesia | 0 | 0.0% (0/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 1 | 25.0% (1/4) |
Lumbar radiculopathy | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 0.0% (0/4) |
Skin and subcutaneous tissue disorders | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 0.0% (0/4) |
Rash | 1 | 5.9% (1/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 0 | 0.0% (0/4) |
TOTAL | 9 | 52.9% (9/17) | 0 | 0.0% (0/2) | 0 | 0.0% (0/4) | 2 | 25.0% (1/4) |
Subjects were analyzed according to the treatment received as baseline regardless of initial randomization. Crossover group includes any NSM subject who crossed over to receive Active Allograft treatment. |
There were no serious adverse events reported at the single study site. Of the adverse events reported, 4 of the 11 noted at the single site were reported to be possibly related to the allograft or the procedure, or both; 2 were seen in the cross-over group and 2 in the active allograft group. All 4 of these events resolved.