Purpose

Intra-articular (IA) placebo (PBO) comparators in knee osteoarthritis (OA) trials demonstrate durable improvements in patient-reported outcomes (PROs) over baseline. Controversy exists over whether responses to IA saline represent true PBO effects versus physiological benefit. IA vehicle PBO effects were compared to sham in a 24-week phase 2b study of lorecivivint (SM04690), a Wnt pathway inhibitor in development as a potential disease-modifying knee OA drug.

Methods and Materials

Subjects with knee OA, Kellgren-Lawrence grades 2-3, and Pain Numeric Rating Scale (NRS) ≥4 and ≤8 in the target knee and <4 in the contralateral knee were randomized to a single, 2 mL, IA injection of vehicle (PBO, 0.5% carboxymethylcellulose sodium and 0.05% polysorbate 80 in pH 7.4 saline), sham (dry needle), or lorecivivint at baseline. Patient-reported outcomes (PROs) included change from baseline in weekly average of daily target knee pain by NRS, WOMAC Pain, WOMAC Function, and Patient Global Assessment. Baseline-adjusted analysis of covariance was used to estimate change-over-time differences in PBO and sham outcomes compared to baseline.

Results

207 of 233 PBO and sham subjects completed the 24-week study. Both PBO and sham subjects showed clinically relevant improvements (>10%) in all PROs from baseline at first post-baseline measurement that persisted through Week 24. No clinically meaningful or statistically significant differences were evident between the two groups at any time point.

Conclusion

Subjects with knee OA receiving an IA PBO injection reported no differences in change from baseline in PROs compared to subjects who received an IA sham injection. These data suggested that the observed effects were “contextual,” meaning that they resulted from the injection procedure rather than from direct therapeutic PBO or saline effects in the joint.

Observations over time depicting mean change from baseline of PBO and sham injections.

A. Pain NRS, B. WOMAC Pain, C. WOMAC Function, and D. Patient Global Assessment; all subjects

Purpose

A pilot study using a single injection of amniotic suspension allograft (ASA) for the treatment of OA demonstrated safety and trends for improved pain and function. To further investigate these effects, a multi-center randomized controlled trial was designed to evaluate the efficacy of ASA injection for the treatment of knee OA symptoms.

Methods and Materials

200 blinded patients were randomized (across 12 sites) 1:1:1 to: saline, HA, or ASA. Patient reported outcomes (PROs) were completed at baseline and up to 1-year following injection. Changes in Visual Analog Scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) PROs from baseline were used to assess efficacy of the injections. Efficacy analysis consisted of ANCOVA in the PROC GLM of the change from baseline between treatment group means where the baseline was included as the covariate at 6 and 12 months.

Results

Patients receiving ASA had significantly lower VAS joint pain scores compared to both HA and saline (p<0.01) at 6 and 12 months. For the KOOS pain subscale, patients receiving ASA had significantly better scores compared to both HA and saline (p<0.05) at 6 and 12 months. ASA treatment resulted in significantly better KOOS symptom scores compared to both HA and saline at 6 and 12 months (p<0.01). For KOOS activities of daily living, ASA treatment resulted in significant increases compared to both HA and saline (p<0.01, p<0.05) at 6 and 12 months. Sports and recreation (S&R) and quality of life (QOL) KOOS subscales resulted in significantly higher scores at 6 months compared to HA (S&R p<0.05; QOL p<0.01) and significantly greater higher scores than HA and saline at 12 months (S&R p<0.05; QOL <0.001).

Conclusion

In this 200-patient clinical trial, subjects receiving ASA treatment showed greater improvement compared to HA and saline, providing evidence for the use of ASA to treat OA symptoms.

Purpose

This study reports the 5-year follow-up of clinical efficacy and longevity, after treatment of symptomatic cartilage defects in the knee with mesenchymal stromal cells (MSCs) mixed with recycled chondrons in the first-in-man one-stage cartilage repair (IMPACT).

Methods and Materials

This study is an academically funded phase I/II prospective mono-center study, investigating the feasibility and safety of cartilage repair procedure. Between 2013 and 2014, a total of 35 patients (mean age 30±8 years) with an average follow up of 60 months (39-70) were treated with the Instant MSC Product accompanying Autologous Chondron Transplantation (IMPACT) one-stage cartilage repair procedure for a symptomatic cartilage defect on the femoral condyle or trochlea. Subsequent follow-up was performed yearly through online questionnaires. PROMs included the Knee injury and Osteoarthritis Outcome score (KOOS), Visual Analogue Scale for pain (VAS) and the EuroQol-5D (EQ5D) at 3, 6, 12, 18, 24, 36, 48 and 60 months. All clinical data, including additional treatment received after the index surgery, were recorded and will be complete in August 2019.

Results

After five years, no signs of a foreign body response were recorded and no serious adverse reactions were found. The vast majority of patients showed statistically significant clinical improvement in the KOOS (mean improvement from baseline 57.9±16.1 to 85.4±13.3 at 18 months and 79.1±17.9 at 60 months [p <.01]. The VAS pain score improved from baseline (45.3 ±23.6) to 18 months (9.7±14.7 [p < .0001]) and 60 months (15.5±13.1). 5 incidents of IMPACT failure were found after 5 years. 4 of these required additional treatment (2 autologous conditioned plasma injections, 1 MaioRegen, 1 unknown surgery elsewhere).

Conclusion

This is the first study showing long-term safety and efficacy of the proof of concept that allogeneic MSCs augment one‐stage articular cartilage repair. The absence of serious adverse events and the clinical outcome support the longevity of this unique concept. These data support IMPACT as a safe, and reliable solution for articular chondral defects in the knee.

Purpose

Augmentation techniques have been suggested to remedy the imperfection of microfracture to repair cartilage defects, but the efficacy of the proposed methods is unclear. Collagen-augmented chondrogenesis techniques (C-ACTs) intended to repair cartilage defects is thought to as safe and efficacious than microfracture. The purpose of this study was to examine the quality of articular cartilage repair by C-ACT and its clinical outcomes compared to those achieved by microfracture.

Methods and Materials

Altogether, 100 participants with knee cartilage defects were randomly assigned to the control group (n = 48, microfracture alone) or the investigational group (n = 52, modified microfracture using C-ACT). Clinical and magnetic resonance imaging (MRI) outcomes were assessed 12 and 24 months postoperatively for efficacy and adverse events. Clinical outcomes were assessed using the visual analogue scale (VAS)–pain, VAS–20% improvement based on minimal clinically important improvement (MCII), Knee Injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) score. The Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) assessment analyzed cartilage tissue repair. MRI outcomes for 50% filling of the defect and the Repair Tissue/Reference Cartilage (RT/RC) ratio were quantified by T2 mapping.

Results

At 24 months postoperatively, the odds ratio (OR) for the VAS–20% improvement rate was significantly higher in the investigational group (OR=2.808, P=0.047). The MOCART score in the investigational group showed improved defect repair and filling (P=0.0201), integration with the border zone (P=0.0062), and effusion (P=0.0079). MRI outcomes showed that the OR for ≥50% defect filling at 12 months was statistically higher in the investigational group (OR=3.984, P=0.0377). The likelihood of the RT/RC OR becoming ≥1 was significantly higher (OR=11.37, P=0.0126) in the investigational group.

Conclusion

This multicenter, randomized trial, both clinically and by imaging, indicated that C-ACT is as effective and safe as microfracture for treating cartilage defects.

Purpose

Early osteoarthritis of knee amounts to significant disability among middle aged patients. Various studies shows significant outcomes with injection of platelet rich plasma (PRP) and Mesenchymal stem cells (MSC’s) in treating this common indication. This study aims to assess any difference in outcome obtained in patients treated with adipose derived MSC injection and patients treated using PRP combined with Hyaluronic Acid (HA) injection.

Methods and Materials

A group of 50 patients affected by Kellgren-Lawrence grade 2 or grade 3 knee osteoarthritis were randomly allocated into two equal groups of 25 patients each. Group 1 were treated with 3 intra-articular injections (1 month apart) using autologous P.R.P combined with HA (Cellular Matrix, RegenLab, Switzerland) and group 2 patients were injected with adipose derived MSC (Lipogems, Italy) by supra-patellar approach. Outcomes were measured by collecting Tegner, Marx, VAS, IKDC and KOOS scores at before treatment, 6 months and 12 months after treatment.

Results

Patients were prospectively evaluated in the 12 month study period between November2016-December2017. The mean age was 62.7 ± 10.7 in group 1 patients and 59.9 ± 8.7 in group 2 patients. At 12 months follow-up, patient in both groups showed improvements in all scores. Median pre-treatment values of group 1 patients were, IKDC=56.98, KOOS Scores:S=75/P=78/ADL=87/SP=40/QOL=38; VAS scale 3.7. Median pre-treatment values of group 2 patients were, IKDC=40.23, KOOS Scores:S=69.5/P=67/ADL=69/SP=35/QOL=41; VAS scale 5.1. At final follow-up median scores in group 1 are: IKDC=62, KOOS Scores:S=80/P=72/ADL=83.5/SP=40/QOL=60; VAS scale 2.1 and at final follow up median scores in group 2 are: IKDC=61.49, KOOS Scores:S=75/P=86.5/ADL=89/SP=52.5/QOL=56; VAS scale 3.6.

Conclusion

This report shows, both groups lead to clinical and functional improvement at 6 and 12 months. But, there is no statistical significance between the groups. However, there are subtle advantages over one another. This finding will aid clinicians in formulating an algorithm when treating patients with early osteoarthritis.

Purpose

No current intervention leads to durable cartilage restoration in osteoarthritic knees. Our objective was to determine whether implantation of allogeneic human umbilical cord blood-derived MSCs (hUCB-MSCs)-hyaluronate composite restores cartilage in patients with symptomatic arthritic knee cartilage defects, and whether any improvements of pain and function can be maintained up to 5-years post-implantation.

Methods and Materials

A 48-week, randomized, open-label, phase 3 trial was conducted February 2009-January 2011, followed by a non-interventional extension (up to 60 months) study (June 2012-May 2015). Patients with multiple, symptomatic, full-thickness, degenerative, knee cartilage defects (International Cartilage Repair Society [ICRS] grade IV) were enrolled. The most symptomatic lesion was treated with an allogeneic hUCB-MSCs-4% hyaluronate composite (n=57) or microfracture (n=57). Primary outcome was proportion of subjects improved by ≥1 ICRS grade at 48 weeks. Secondary outcomes included histology, visual analogue scale (VAS) pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), International Knee Documentation Committee (IKDC) scores, surgical re-intervention rate, and adverse events.

Results

Among 114 randomized participants (age: 55.9 years), 89 completed the primary study, and 73 enrolled in the follow-up study. Mean defect size was 4.9 and 4.0 cm² for hUCB-MSCs and microfracture, respectively. Improvement by ≥1 ICRS grade at 48 weeks was observed in 97.7% treated with hUCB-MSC versus 71.7% with microfracture (p = 0.001); and histological assessment was superior with hUCB-MSCs. VAS pain, WOMAC, and IKDC score improvements from baseline were similar between groups at 48 weeks, but were significantly better with hUCB-MSCs than microfracture by 60 months (p < 0.05). No between-group differences in surgical re-intervention rate or incidence/nature of adverse events were found.

Conclusion

hUCB-MSC implantation resulted in cartilage repair tissue in more patients and provided a robust improvement of knee pain and function than microfracture in patients with symptomatic knee osteoarthritis. hUCB-MSCscould be a therapeutic option for patients suffering from osteoarthritic cartilage defects.

Purpose

The aim of this study is to evaluate, through a single-blind randomized controlled trial (RCT), the benefit provided by micro-fragmented adipose-derived mesenchymal stem cells (ADSCs) to treat symptomatic knee osteoarthritis (OA) in comparison with a single injection of platelet-rich plasma (PRP), one of the most studied injective treatment currently adopted for this condition.

Methods and Materials

A total of 118 patients were treated with a single intra-articular injection (59 treated with ADSCs and 59 with PRP). Patients were enrolled according to the following inclusion criteria: male or female with age > 18 and < 75; symptomatic knee OA with Kellgren-Lawrence grade of 1-4; failure of at least one conservative treatment for OA knee pain. Up-to-date, 70 patients (35 ADSCs and 35 PRP) were prospectively evaluated up to 6 months after treatment using IKDC subjective, EQ-VAS, and KOOS scores.

Results

At 6 months’ follow-up, both groups presented a significant clinical improvement for all scores. The IKDC subjective score improved from 40.4 to 56.6 in ADSCs group, and from 41.4 to 55.7 in PRP group; the mean EQ-VAS in ADSCs group improved from 64.4 to 71.9, and from 66.0 and 74.3 in PRP group; the KOOS pain improved from 61.0 to 75.9 in the ADSCs group and from 61.5 to 74.1 in the PRP group, and a similar trend was observed also for the other KOOS subscales. No statistically significant difference was found between the two groups at 6 months follow-up.

Conclusion

The preliminary results of this RCT between ADSCs and PRP showed a significant improvement for both groups at 6 months’ follow-up, without any significant difference between the two groups. The analysis of all included patients at the planned 2 years follow-up is needed to confirm these results, in order to provide evidence-based suggestions about the use of ADSCs for the treatment of knee OA.

Purpose

In this clinical trial, we evaluated the safety and efficacy of rhBMP6 undergoing HTO. The systemic pharmacokinetics (PK), safety, acceleration of new bone formation, and tolerability were examined.

Methods and Materials

We assigned 20 HTO patients into this randomized, controlled, blinded Phase I-II clinical trial (EudraCT number 2015-001691-21). RhBMP6 or placebo were implanted into the tibial wedge-defects. Patients were followed for 24 months by clinical examination, x-rays and CT scans. Efficacy outcome was defined as percentage of defect filled with newly formed bone, based on x-ray analyses of day 1, week 6 and 24, month 12, 18 and 24. The bone mineral density (BMD), as well as bone formation in the defect area, was measured on CT scans by ITK-SNAP program transferring voxels into BMD (mgs/cm³) by using a bone 3 CT calibration phantom at weeks 9 and 14 post-surgery.

Results

CT scans from HTO defects of patients treated with rhBMP6/ABC (n=10) showed an accelerated bone healing when compared to placebo treated patients (n=10). BMD gain was higher in the treatment group after 9 and 14 weeks: 47.8 ± 24.1 vs. 22.2 ± 12.3 (P=0.008) and 89.7 ± 29.1 vs. 53.6 ± 21.9 (P=0.006). X-rays from day 1, weeks 6 and 24, and months 12, 18, 24 confirmed the enhanced bone formation in rhBMP6/ABC treated patients. The use of rhBMP6/ABC was not associated with serious adverse events during the entire 24 months follow-up. The availability of rhBMP6 was detected in the plasma of only one out of 10 patients (8.3 mg/ml) from locally administered rhBMP6/ABC implants within the first 15 minutes after implantation. As measured on CT scans, the BMD increased distally from the osteotomy wedge in rhBMP6/ABC treated patients.

Conclusion

rhBMP6/ABC at a dose of 100 µg/ml accelerated the bone formation rate without serious adverse events, with a good tolerability and no systemic distribution.

Purpose

Primary care physicians (PCP) highlighted the lack of validated tools to objectively assess the knee joint function to guide conservative treatment decision-making, as recommended in guidelines. Assessing mechanical factors linked to disease progression with a knee kinesiography exam (Knee-KG) is a promising avenue to fill this clinical gap and help PCPs guide joint preservation strategies. This study assessed the impact on clinical outcomes of adding a Knee-KG exam to current medical management (CMM) of knee osteoarthritis patients.

Methods and Materials

In this 6-month cluster randomized controlled trial, eligible patients from a primary care clinic were defined as a cluster and randomized to one of the 3 groups: 1-CMM by PCPs, 2-CMM+Knee-KG, and 3-CMM+Knee-KG+Education (one-hour session on self-management and two follow-up supervised group meetings). Primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS).

Results

Eligibility was assessed for 894 patients from 87 clinics: 515 were randomized and 449 (87.2%) completed the study. At 6-month follow-up, patients in both Knee-KG groups reported a statistically significant reduction in symptoms and pain, and improvement in function during activities of daily living on KOOS compared to the control group (all p<0.05). They also demonstrated higher satisfaction levels regarding their treatment (both p<0.01). Patients in Group 3-CMM+Knee-KG+Education significantly improved in objective functional tests and showed a greater global impression of change in pain, function, quality of life, and global condition relative to the two other groups (all p<0.05).

Conclusion

Results support the added value of assessing mechanical biomarkers linked to osteoarthritis progression to assist PCPs in the management of their knee osteoarthritis patients. Providing them with objective information on mechanical markers through a Knee-KG exam yields improvements in patients’ pain, function, and satisfaction. A maximum of three sessions including education and follow-up reinforces adherence to PCPs recommendations and further improves patient outcomes.

Purpose

Prior to undergoing a cartilage restoration procedure of the knee, such as osteochondral allograft (OCA), osteochondral autograft (OAT), or autologous chondrocyte implantation (ACI), a diagnostic scope is often performed to evaluate the knee joint and characterize the cartilage damage. After diagnostic arthroscopy, a subset of patients experiences substantial relief and elects not to undergo a cartilage procedure. This study aims to identify factors which may be associated with successful outcomes after diagnostic arthroscopy.

Methods and Materials

99 patients scheduled to undergo diagnostic arthroscopy for cartilage evaluation, OCA, or ACI between May 2017 and March 2019 and were prospectively enrolled and age, BMI, procedure, size and location of lesion were collected. KOOS, IKDC and Marx were also collected pre-operatively as well as at 6-weeks, 6-months, and 1-year post-operatively. Patient demographics and lesion characteristics were compared between those who underwent only a diagnostic arthroscopy and those who underwent a cartilage restoration procedure.

Results

52 patients underwent only diagnostic arthroscopy (average age 32.48±9.55 years, BMI 28.21±5.72, 53.4% male). Average total lesion area was 4.29±3.22cm². Average number of lesions was 1.4±0.71. 47 patients underwent cartilage restoration procedure (average age 34.04±8.17 years, BMI 28.08±4.95, 49.0% male). Average total lesion area was 4.98±2.37cm². Average number of lesions was 1.40±0.64. No significant difference in total lesion area (p=0.22), number of lesions (p=0.97), sex (p=0.88), age (p=0.39) or BMI (0.92) was found between the two groups. In the diagnostic arthroscopy group, 28 (53.8%) had isolated patellofemoral cartilage damage, significantly more than the 15 (31.9%) in the cartilage procedure group that had isolated patellofemoral cartilage damage (p=0.02) .

Conclusion

While basic patient demographics and lesion size are not significantly different between those undergoing diagnostic arthroscopy alone and those electing to undergo cartilage restoration procedure, those with isolated patellofemoral cartilage damage are less likely to continue to a cartilage restoration procedure.