Incidence of total knee replacement subsequent to intra-articular injection of the anti-inflammatory compound LMWF-5A versus saline: a long-term follow-up study to a randomized controlled trial

Incidence of total knee replacement subsequent to intra-articular injection of the... Background: The disease modifying potential of osteoarthritis therapies are of increasing interest, including their effects on delaying total knee replacement (TKR). To date, there have been no studies to determine the effect of LMWF-5A, a novel anti-inflammatory compound derived from human serum albumin, on delaying TKR. Methods: We evaluated time to TKR three years after patients participated in a randomized trial of three intra- articular injections of LMWF-5A or saline. Patients were contacted via last known phone number and were asked to participate in a short nine item telephone questionnaire; verbal consent was obtained. The primary endpoint was incidence of TKR (%). Results: In total, 39 of 45 patients responded (87% response rate). The overall incidence of TKR was 38.5% (15/39). TKR rates were higher in patients with more severe osteoarthritis defined by Kellgren-Lawrence grade 4, compared to patients with moderate osteoarthritis defined by Kellgren-Lawrence grade 3 (56% vs. 26%, p = 0.06). Overall, there were no differences in TKR rates by treatment arm (39% LMWF-5A vs. 38% saline, p = 0.92). In the severe osteoarthritis subset (n = 16), treatment with LMWF-5A resulted in a lower incidence of TKR compared to saline vehicle arm (40% vs. 83%, p = 0.15). TKR rates were significantly lower with LMWF-5A in patients who responded to treatment (14% with LMWF-5A, vs. 100% with saline, p =0.03). Conclusion: This study demonstrates significant delays in TKR for patients with severe osteoarthritis treated with LMWF-5A, suggesting that LMWF-5A has the potential to provide structure modifying/preserving therapy in this population. Keywords: Osteoarthritis, Kellgren-Lawrence grade, Total knee replacement Background cartilage loss and increasingly severe clinical manifesta- Osteoarthritis is a painful, chronic, degenerative, and tions over time [2, 3]. Progression to the most severe incurable inflammatory disease. Nearly half of all adults form of OAK, defined by Kellgren-Lawrence grade 4 will develop symptomatic osteoarthritis of the knee severity (0–4scale) [4], leaves patients with few treatment (OAK) during their lifetime [1]. The course of OAK is options other than surgical interventions including total progressive to more severe disease, characterized by knee replacement (TKR) surgery. The rate of TKR is anticipated to increase rapidly to over 3.5 million procedures * Correspondence: dbaror@ampiopharma.com in the U.S. by 2030 [5]. Trauma Research Department, Swedish Medical Center, 501 E. Hampden Current osteoarthritis treatments target symptomatic Ave Rm 4-454, Englewood, CO 80113, USA Ampio Pharmaceuticals, Inc, 373 Inverness Parkway, Englewood, CO 80112, short-term outcomes including pain and function. How- USA ever, OAK therapies have potential to be disease modifying, Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 2 of 5 including the reduction of cartilage loss and the delay Following completion of the study, a copy of the consent of TKR. Whether OAK therapies can delay TKR is of form and a $25 gift card was mailed to all consenting increasing interest to clinicians, patients, and researchers patients. alike. Very few studies have examined time to TKR or All analyses were performed using SAS 9.3 or later rates of TKR as an outcome parameter, including only (SAS Institute; Cary, NC). There was no imputation of three randomized controlled trials (RCTs) [6–8]. missing data. Results are presented for all subjects and LMWF-5A is a novel, non-steroidal, anti-inflammatory the subset with severe OAK (KL grade 4). Patients that compound consisting of the < 5 kilodalton (kDa) ultrafil- responded to treatment were also examined, where trate of 5% human serum albumin (HSA). LMWF-5A is response to treatment was defined as a 20% (0.5-point) currently in development to provide relief for severe reduction in pain between baseline and week 20 for the OAK. LMWF-5A has been shown to effectively reduce primary endpoint of Western Ontario and McMaster pain in patients with OAK when administered as an Universities Arthritis Index (WOMAC) pain on the intra-articular injection [9–11]. There have been no 5-point Likert scale. Descriptive statistics were used for in vivo studies determining the effects of LMWF-5A on all survey questions. The primary endpoint of incidence delaying TKR. In vitro studies suggest aspects of the of TKR (%) was examined with Fisher’s exact tests. The mechanism of action of LMWF-5A support disease secondary endpoint of time to TKR was examined with modification [12–15]. Kaplan-Meier survival curves. The objective of this study was to determine the effect of LMWF-5A on delaying TKR during long-term (three year) follow up of patients participating in a clinical trial Results evaluating LMWF-5A for the treatment of OAK In total, 39 of 45 patients responded (87% response rate); (AP-007-A) [11]. the remaining patients were unreachable. The response rate was similar with LMWF-5A (23/25, 92%) and saline Methods (16/20, 80%). The average time to follow-up was 3.2 years Patients were recruited from the population who partici- (min: 3.1, max: 3.3 years). pated in the prior clinical trial (AP-007-A). Detailed methods and results of that trial have previously been published [11]. In brief, patients with symptomatic OAK Survey responses were enrolled between August 1, 2014 and October 19, The overall rate of TKR was 38.5% (15/39). The primary 2014, with follow-up through October 12, 2015. Patients reasons for having TKR were (open-ended): severe were randomized 1:1 to three 4 mL intra-articular injec- osteoarthritis “bone-on-bone” with severe pain (n =6, tions (baseline, week 2, week 4) of either LMWF-5A or 40%), severe pain (n = 4, 27%), unable to perform saline vehicle control and followed to 20 weeks (primary activities of daily living (n = 3, 20%), no relief from endpoint), with an exploratory endpoint at 52 weeks to intra-articular injections (n = 2, 13%). Reasons patients quantitatively measure cartilage thickness change by did not have TKR included: absence of significant pain/ magnetic resonance imaging (MRI). As reported, mobility limitations (n = 13, 54%), currently receiving LMWF-5A resulted in a significant reduction in pain at effective treatment (n = 6, 25%), it is contraindicated/not 20 weeks compared to saline (64% vs. 40% reduction). recommended (n = 1), fear of operation or its effectiveness In this IRB-approved follow-up study, patients were (n = 1), fear of losing disability insurance (n =1), I do not followed three years (minimum: 3.1, maximum: 3.3) after need it yet/TKR is a “last resort” (n =1), and currently treatment with LWMF-5A or saline. Two patients were scheduled for TKR (n =1). excluded for mild severity OAK (KL grade 2); the In patients who had TKR, 40% (n = 6) were receiving remaining 45 patients were contacted via last known knee injections at least a few times each year to treat phone number and were asked to participate in a osteoarthritis, prior to surgery. Among patients who had telephone questionnaire. A maximum of three follow-up not had TKR, a similar proportion of patients (37.5%, phone calls were attempted. n = 9) reported receiving knee injections, a few times During the telephone call, research staff first obtained per year (n = 5) or less than yearly (n =4). verbal informed consent and then asked patients a total The majority of responses to the PGA, an overall of a nine questions. The survey included questions patient global assessment of disease severity, were very asking the patient whether they have received a TKR well or well (77%). PGA responses were more favorable (q1), time to TKR (q2), reasons for having/not having in patients who did not have TKR vs. patients with TKR TKR (q3), past history of analgesic therapies for treating (83% vs. 67% responded very well or well). Still, the OAK (q4–7), satisfaction with TKR (q8), and overall pa- majority of patients were satisfied with TKR (87% very tient global assessment of disease severity (PGA; q9). satisfied or satisfied). Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 3 of 5 Incidence of TKR previous findings that the treatment effect of LMWF-5A is Fifteen (39%) patients received TKR on average of greatest in patients with more severe disease [9, 10]. 21 months (SD: 13) after the trial commenced. TKR Federal Drug Administration (FDA) guidelines rates were higher in more severe osteoarthritis (KL4: propose that trials designed to evaluate delays in 9/16, 56% vs. KL3: 6/23, 26%, p = 0.06). Patients with structural progression measure joint space narrowing more severe osteoarthritis also appeared to have TKR [16]. Time to TKR may also be an acceptable outcome. more expeditiously (Fig. 1a). TKR rates were similar for Most studies examining time to TKR have been responders (10/29, 34%) compared to non-responders retrospective case series. There have only been three (5/10, 50%), p = 0.463. There were no differences in RCTs to examine time to TKR in patients with OAK. the timing of TKR by responder status (Fig. 1b). Raynauld et al. performed a post hoc follow-up four years Overall, there were no differences in TKR rates by after a twelve month RCT, with an 81% response rate treatment arm (LMWF-5A: 9/23, 39% vs. saline: 6/16, among 57 patients; the rate of TKR was non-significantly 38%, p = 0.92). In the severe KL4 subset (n = 16), lower in patients randomized to chondroitin sulfate vs. treatment with LMWF-5A resulted in a lower rate of TKR saline control (31% vs. 69%) [8]. Bruyere et al. evaluated compared to saline (40% (4/10) vs. 83% (5/6), p =0.15). patients participating in two previous RCTs who received Patients treated with LMWF-5A also had a longer delay at least one year of glucosamine sulphate (response rate toTKRthansaline(Fig. 1c). In patients who responded to 81%); the rate of TKR was significantly lower with treatment during the AP-007-A trial (≥20% reduction in glucosamine sulphate compared to placebo (6.3% vs. 14.5%) pain), TKR rates were significantly lower in the [6]. Blanco et al. examined time to TKR among 52 patients LMWF-5A arm compared to the saline (14% (1/7) vs. with severe OAK randomized 1:1 to hyaluronic acid or 100% (3/3), p = 0.03), with longer delays to TKR (Fig. 1d). saline; the rate of TKR was non-significantly lower with hyaluronic acid compared to saline (64% vs. 87%) [7]. Discussion Only the Blanco study excluded lower severity OAK; Theresults ofthis studyarethefirst to determinethe effect compared to that study, our rate of TKR was similar for of LMWF-5A on delaying TKR. The primary findings sug- saline arms (87% and 83%, respectively), with a lower gest treatment with LMWF-5A results in significant delay in rate of TKR with LMWF-5A than hyaluronic acid (40% TKR for patients with severe OAK. This result agrees with and 64%, respectively). ab cd Fig. 1 Kaplan-Meier survival curves for total knee replacement. a Osteoarthritis severity (Kellgren-Lawrence grade 3 vs. 4); (b). Responders to treatment (≥20% improvement in pain by week 20); (c). LMWF-5A vs. saline in patients with severe osteoarthritis (Kellgren-Lawrence grade 4); (d). LMWF-5A vs. saline in responders to treatment with severe osteoarthritis Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 4 of 5 The findings from this study support the MRI analysis Authors’ contributions Dr. JS is responsible for data interpretation and critical revisions. Mr. JS is of study AP-007-A that demonstrated potential cartilage responsible for collection of data, literature review, and revisions to the preservation with LMWF-5A compared to saline, manuscript. Ms. KS is responsible for study design, analysis and interpretation representing potential for disease modification. There of data, and drafting the manuscript. Dr. DBO is responsible for interpretation of the data and critical revisions. All authors approved the submitted were 37 patients with MRI data at baseline and at week manuscript. 52, including 20 patients with medial (n = 10) or lateral disease (n =10) and the remaining (n = 17) with either no Ethics approval and consent to participate The study was approved from the Integreview Institutional Review Board denudement or symmetrical disease. Patients treated with with waiver of documentation of informed consent (AP-007-B). LMWF-5A had less cartilage thickness loss than patients treated with saline in all 6 pre-specified anatomically Competing interests defined medial sub regions (medial disease), and in 5 of 6 Dr. Schwappach reports consulting fees paid to his institution. Mrs. Salottolo reports personal fees from Ampio Pharmaceuticals, Inc., and own stocks and stock lateral sub regions (lateral disease). LMWF-5A also showed options in the company. Dr. Bar-Or is an employee of Ampion Pharmaceuticals, increased cartilage thickness in 2 lateral sub regions. Inc. and serves as the chief Scientific officer of Ampio Pharmaceuticals and own There are limitations. First, this was a post hoc analysis stocks and stock options in the company. In addition, Dr. Bar-Or has more than 120 issued patents and 80 pending. Mr. Schultz has no competing interests. that was not powered to detect differences in TKR rates between treatment groups. A prospective RCT with incidence of TKR as the primary outcome would need to Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in be conducted to confirm these findings. Second, not all published maps and institutional affiliations. patients were reachable; 6 patients had disconnected phone numbers. Third, respondents were asked “Have Author details 1 2 Denver Metro Orthopedics, P.C, Englewood, CO 80113, USA. Trauma you had a total knee replacement in your study knee?”.It Research Department, Swedish Medical Center, 501 E. Hampden Ave Rm is possible that subjects with a partial knee replacement 3 4-454, Englewood, CO 80113, USA. Ampio Pharmaceuticals, Inc, 373 might have responded negatively. Lastly, there are Inverness Parkway, Englewood, CO 80112, USA. multiple factors that may have influenced the decision to Received: 30 April 2018 Accepted: 21 May 2018 have TKR, including current use of other pharmacologic interventions. We collected information on use of intra-articular injections and they were reported in a References 1. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. similar occurrence in the TKR group (prior to surgery) Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. and the non-TKR group (40% vs. 37.5%), but there 2008;59:1207–13. remains the risk of recall bias. 2. Davies-Tuck ML, Wluka AE, Wang Y, Teichtahl AJ, Jones G, Ding C, et al. The natural history of cartilage defects in people with knee osteoarthritis. Osteoarthr Cartil. 2008;16:337–42. 3. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. Conclusion American College of Rheumatology. Preliminary definition of improvement This study demonstrated delays to TKR among patients in rheumatoid arthritis. Arthritis Rheum. 1995;38:727–35. 4. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. with severe osteoarthritis treated with LMWF-5A Ann Rheum Dis. 1957;16:494–502. compared to saline, while showing no differences in 5. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and patients with moderate osteoarthritis. These results revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89:780–5. support the in vitro work suggesting the effect of 6. Bruyere O, Pavelka K, Rovati LC, Gatterova J, Giacovelli G, Olejarova M, et al. LMWF-5A is demonstrated with severe disease, and has Total joint replacement after glucosamine sulphate treatment in knee the potential to provide structure modifying/preserving osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthr Cartil. therapy in this population. 2008;16:254–60. 7. FJ Blanco JF-S, Pinto-Tasende JA, Fernandez-Lopez JC, Ramallal M, Freire A, Galdo F. Intra-articular Hyaluronan treatment of patients with knee Abbreviations osteoarthritis waiting for replacement surgery. Open Arthritis Journal. HSA: Human serum albumin; IRB: Institutional review board; KDa: Kilodalton; 2008;1:1–7. KL: Kellgren Lawrence; LMWF-5A: Low Molecular Weight Fraction of 5% 8. Raynauld JP, Martel-Pelletier J, Dorais M, Haraoui B, Choquette D, Abram F, human serum Albumin; MRI: Magnetic resonance imaging; et al. Total knee replacement as a knee osteoarthritis outcome: predictors OAK: Osteoarthritis of the knee; PGA: Patient global assessment; derived from a 4-year long-term observation following a randomized RCT: Randomized controlled trial; TKR: Total knee replacement; clinical trial using chondroitin sulfate. Cartilage. 2013;4:219–26. WOMAC: Western Ontario and McMaster Universities Arthritis Index 9. Bar-Or D, Salottolo KM, Loose H, Phillips MJ, McGrath B, Wei N, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS One. Funding 2014;9:e87910. The study was funded by Ampio Pharmaceuticals, Inc. 10. Cole B, McGrath B, Salottolo K. Bar-or D. LMWF-5A for the treatment of severe osteoarthritis of the knee: integrated analysis of safety and efficacy. Availability of data and materials Orthopedics. 2018;41(1):e77–e83. The datasets used and/or analyzed during the current study are available 11. Schwappach J, Dryden SM, Salottolo KM. Preliminary trial of intra-articular from the corresponding author on reasonable request. LMWF-5A for osteoarthritis of the knee. Orthopedics. 2017;40:e49-e53. Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 5 of 5 12. Bar-Or D, Thomas GW, Rael LT, Gersch ED, Rubinstein P, Brody E. Low molecular weight fraction of commercial human serum albumin induces morphologic and transcriptional changes of bone marrow-derived mesenchymal stem cells. Stem Cells Transl Med. 2015;4:945–55. 13. Frederick EDHM, Thomas GW, Rael LT, Brody E. Bar-or D. The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synoviocytes. Biochem Biophys Rep. 2016;8:68–74. 14. Thomas GW, Rael LT, Hausburg M, Frederick ED, Mains CW, Slone D, et al. The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2016;473:1328–33. 15. Thomas GW, Rael LT, Mains CW, Slone D, Carrick MM, Bar-Or R, et al. Anti-inflammatory activity in the low molecular weight fraction of commercial human serum albumin (LMWF5A). J Immunoassay Immunochem. 2016;37(1):55–67. 16. Federal Drug Administration. Clinical Development Programs for Drugs, Devices, and Biological Products. Intended for the Treatment of Osteoarthritis (OA). Rockville: U.S. Department of Health and Human Services; 1999. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Patient Safety in Surgery Springer Journals

Incidence of total knee replacement subsequent to intra-articular injection of the anti-inflammatory compound LMWF-5A versus saline: a long-term follow-up study to a randomized controlled trial

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Abstract

Background: The disease modifying potential of osteoarthritis therapies are of increasing interest, including their effects on delaying total knee replacement (TKR). To date, there have been no studies to determine the effect of LMWF-5A, a novel anti-inflammatory compound derived from human serum albumin, on delaying TKR. Methods: We evaluated time to TKR three years after patients participated in a randomized trial of three intra- articular injections of LMWF-5A or saline. Patients were contacted via last known phone number and were asked to participate in a short nine item telephone questionnaire; verbal consent was obtained. The primary endpoint was incidence of TKR (%). Results: In total, 39 of 45 patients responded (87% response rate). The overall incidence of TKR was 38.5% (15/39). TKR rates were higher in patients with more severe osteoarthritis defined by Kellgren-Lawrence grade 4, compared to patients with moderate osteoarthritis defined by Kellgren-Lawrence grade 3 (56% vs. 26%, p = 0.06). Overall, there were no differences in TKR rates by treatment arm (39% LMWF-5A vs. 38% saline, p = 0.92). In the severe osteoarthritis subset (n = 16), treatment with LMWF-5A resulted in a lower incidence of TKR compared to saline vehicle arm (40% vs. 83%, p = 0.15). TKR rates were significantly lower with LMWF-5A in patients who responded to treatment (14% with LMWF-5A, vs. 100% with saline, p =0.03). Conclusion: This study demonstrates significant delays in TKR for patients with severe osteoarthritis treated with LMWF-5A, suggesting that LMWF-5A has the potential to provide structure modifying/preserving therapy in this population. Keywords: Osteoarthritis, Kellgren-Lawrence grade, Total knee replacement Background cartilage loss and increasingly severe clinical manifesta- Osteoarthritis is a painful, chronic, degenerative, and tions over time [2, 3]. Progression to the most severe incurable inflammatory disease. Nearly half of all adults form of OAK, defined by Kellgren-Lawrence grade 4 will develop symptomatic osteoarthritis of the knee severity (0–4scale) [4], leaves patients with few treatment (OAK) during their lifetime [1]. The course of OAK is options other than surgical interventions including total progressive to more severe disease, characterized by knee replacement (TKR) surgery. The rate of TKR is anticipated to increase rapidly to over 3.5 million procedures * Correspondence: dbaror@ampiopharma.com in the U.S. by 2030 [5]. Trauma Research Department, Swedish Medical Center, 501 E. Hampden Current osteoarthritis treatments target symptomatic Ave Rm 4-454, Englewood, CO 80113, USA Ampio Pharmaceuticals, Inc, 373 Inverness Parkway, Englewood, CO 80112, short-term outcomes including pain and function. How- USA ever, OAK therapies have potential to be disease modifying, Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 2 of 5 including the reduction of cartilage loss and the delay Following completion of the study, a copy of the consent of TKR. Whether OAK therapies can delay TKR is of form and a $25 gift card was mailed to all consenting increasing interest to clinicians, patients, and researchers patients. alike. Very few studies have examined time to TKR or All analyses were performed using SAS 9.3 or later rates of TKR as an outcome parameter, including only (SAS Institute; Cary, NC). There was no imputation of three randomized controlled trials (RCTs) [6–8]. missing data. Results are presented for all subjects and LMWF-5A is a novel, non-steroidal, anti-inflammatory the subset with severe OAK (KL grade 4). Patients that compound consisting of the < 5 kilodalton (kDa) ultrafil- responded to treatment were also examined, where trate of 5% human serum albumin (HSA). LMWF-5A is response to treatment was defined as a 20% (0.5-point) currently in development to provide relief for severe reduction in pain between baseline and week 20 for the OAK. LMWF-5A has been shown to effectively reduce primary endpoint of Western Ontario and McMaster pain in patients with OAK when administered as an Universities Arthritis Index (WOMAC) pain on the intra-articular injection [9–11]. There have been no 5-point Likert scale. Descriptive statistics were used for in vivo studies determining the effects of LMWF-5A on all survey questions. The primary endpoint of incidence delaying TKR. In vitro studies suggest aspects of the of TKR (%) was examined with Fisher’s exact tests. The mechanism of action of LMWF-5A support disease secondary endpoint of time to TKR was examined with modification [12–15]. Kaplan-Meier survival curves. The objective of this study was to determine the effect of LMWF-5A on delaying TKR during long-term (three year) follow up of patients participating in a clinical trial Results evaluating LMWF-5A for the treatment of OAK In total, 39 of 45 patients responded (87% response rate); (AP-007-A) [11]. the remaining patients were unreachable. The response rate was similar with LMWF-5A (23/25, 92%) and saline Methods (16/20, 80%). The average time to follow-up was 3.2 years Patients were recruited from the population who partici- (min: 3.1, max: 3.3 years). pated in the prior clinical trial (AP-007-A). Detailed methods and results of that trial have previously been published [11]. In brief, patients with symptomatic OAK Survey responses were enrolled between August 1, 2014 and October 19, The overall rate of TKR was 38.5% (15/39). The primary 2014, with follow-up through October 12, 2015. Patients reasons for having TKR were (open-ended): severe were randomized 1:1 to three 4 mL intra-articular injec- osteoarthritis “bone-on-bone” with severe pain (n =6, tions (baseline, week 2, week 4) of either LMWF-5A or 40%), severe pain (n = 4, 27%), unable to perform saline vehicle control and followed to 20 weeks (primary activities of daily living (n = 3, 20%), no relief from endpoint), with an exploratory endpoint at 52 weeks to intra-articular injections (n = 2, 13%). Reasons patients quantitatively measure cartilage thickness change by did not have TKR included: absence of significant pain/ magnetic resonance imaging (MRI). As reported, mobility limitations (n = 13, 54%), currently receiving LMWF-5A resulted in a significant reduction in pain at effective treatment (n = 6, 25%), it is contraindicated/not 20 weeks compared to saline (64% vs. 40% reduction). recommended (n = 1), fear of operation or its effectiveness In this IRB-approved follow-up study, patients were (n = 1), fear of losing disability insurance (n =1), I do not followed three years (minimum: 3.1, maximum: 3.3) after need it yet/TKR is a “last resort” (n =1), and currently treatment with LWMF-5A or saline. Two patients were scheduled for TKR (n =1). excluded for mild severity OAK (KL grade 2); the In patients who had TKR, 40% (n = 6) were receiving remaining 45 patients were contacted via last known knee injections at least a few times each year to treat phone number and were asked to participate in a osteoarthritis, prior to surgery. Among patients who had telephone questionnaire. A maximum of three follow-up not had TKR, a similar proportion of patients (37.5%, phone calls were attempted. n = 9) reported receiving knee injections, a few times During the telephone call, research staff first obtained per year (n = 5) or less than yearly (n =4). verbal informed consent and then asked patients a total The majority of responses to the PGA, an overall of a nine questions. The survey included questions patient global assessment of disease severity, were very asking the patient whether they have received a TKR well or well (77%). PGA responses were more favorable (q1), time to TKR (q2), reasons for having/not having in patients who did not have TKR vs. patients with TKR TKR (q3), past history of analgesic therapies for treating (83% vs. 67% responded very well or well). Still, the OAK (q4–7), satisfaction with TKR (q8), and overall pa- majority of patients were satisfied with TKR (87% very tient global assessment of disease severity (PGA; q9). satisfied or satisfied). Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 3 of 5 Incidence of TKR previous findings that the treatment effect of LMWF-5A is Fifteen (39%) patients received TKR on average of greatest in patients with more severe disease [9, 10]. 21 months (SD: 13) after the trial commenced. TKR Federal Drug Administration (FDA) guidelines rates were higher in more severe osteoarthritis (KL4: propose that trials designed to evaluate delays in 9/16, 56% vs. KL3: 6/23, 26%, p = 0.06). Patients with structural progression measure joint space narrowing more severe osteoarthritis also appeared to have TKR [16]. Time to TKR may also be an acceptable outcome. more expeditiously (Fig. 1a). TKR rates were similar for Most studies examining time to TKR have been responders (10/29, 34%) compared to non-responders retrospective case series. There have only been three (5/10, 50%), p = 0.463. There were no differences in RCTs to examine time to TKR in patients with OAK. the timing of TKR by responder status (Fig. 1b). Raynauld et al. performed a post hoc follow-up four years Overall, there were no differences in TKR rates by after a twelve month RCT, with an 81% response rate treatment arm (LMWF-5A: 9/23, 39% vs. saline: 6/16, among 57 patients; the rate of TKR was non-significantly 38%, p = 0.92). In the severe KL4 subset (n = 16), lower in patients randomized to chondroitin sulfate vs. treatment with LMWF-5A resulted in a lower rate of TKR saline control (31% vs. 69%) [8]. Bruyere et al. evaluated compared to saline (40% (4/10) vs. 83% (5/6), p =0.15). patients participating in two previous RCTs who received Patients treated with LMWF-5A also had a longer delay at least one year of glucosamine sulphate (response rate toTKRthansaline(Fig. 1c). In patients who responded to 81%); the rate of TKR was significantly lower with treatment during the AP-007-A trial (≥20% reduction in glucosamine sulphate compared to placebo (6.3% vs. 14.5%) pain), TKR rates were significantly lower in the [6]. Blanco et al. examined time to TKR among 52 patients LMWF-5A arm compared to the saline (14% (1/7) vs. with severe OAK randomized 1:1 to hyaluronic acid or 100% (3/3), p = 0.03), with longer delays to TKR (Fig. 1d). saline; the rate of TKR was non-significantly lower with hyaluronic acid compared to saline (64% vs. 87%) [7]. Discussion Only the Blanco study excluded lower severity OAK; Theresults ofthis studyarethefirst to determinethe effect compared to that study, our rate of TKR was similar for of LMWF-5A on delaying TKR. The primary findings sug- saline arms (87% and 83%, respectively), with a lower gest treatment with LMWF-5A results in significant delay in rate of TKR with LMWF-5A than hyaluronic acid (40% TKR for patients with severe OAK. This result agrees with and 64%, respectively). ab cd Fig. 1 Kaplan-Meier survival curves for total knee replacement. a Osteoarthritis severity (Kellgren-Lawrence grade 3 vs. 4); (b). Responders to treatment (≥20% improvement in pain by week 20); (c). LMWF-5A vs. saline in patients with severe osteoarthritis (Kellgren-Lawrence grade 4); (d). LMWF-5A vs. saline in responders to treatment with severe osteoarthritis Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 4 of 5 The findings from this study support the MRI analysis Authors’ contributions Dr. JS is responsible for data interpretation and critical revisions. Mr. JS is of study AP-007-A that demonstrated potential cartilage responsible for collection of data, literature review, and revisions to the preservation with LMWF-5A compared to saline, manuscript. Ms. KS is responsible for study design, analysis and interpretation representing potential for disease modification. There of data, and drafting the manuscript. Dr. DBO is responsible for interpretation of the data and critical revisions. All authors approved the submitted were 37 patients with MRI data at baseline and at week manuscript. 52, including 20 patients with medial (n = 10) or lateral disease (n =10) and the remaining (n = 17) with either no Ethics approval and consent to participate The study was approved from the Integreview Institutional Review Board denudement or symmetrical disease. Patients treated with with waiver of documentation of informed consent (AP-007-B). LMWF-5A had less cartilage thickness loss than patients treated with saline in all 6 pre-specified anatomically Competing interests defined medial sub regions (medial disease), and in 5 of 6 Dr. Schwappach reports consulting fees paid to his institution. Mrs. Salottolo reports personal fees from Ampio Pharmaceuticals, Inc., and own stocks and stock lateral sub regions (lateral disease). LMWF-5A also showed options in the company. Dr. Bar-Or is an employee of Ampion Pharmaceuticals, increased cartilage thickness in 2 lateral sub regions. Inc. and serves as the chief Scientific officer of Ampio Pharmaceuticals and own There are limitations. First, this was a post hoc analysis stocks and stock options in the company. In addition, Dr. Bar-Or has more than 120 issued patents and 80 pending. Mr. Schultz has no competing interests. that was not powered to detect differences in TKR rates between treatment groups. A prospective RCT with incidence of TKR as the primary outcome would need to Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in be conducted to confirm these findings. Second, not all published maps and institutional affiliations. patients were reachable; 6 patients had disconnected phone numbers. Third, respondents were asked “Have Author details 1 2 Denver Metro Orthopedics, P.C, Englewood, CO 80113, USA. Trauma you had a total knee replacement in your study knee?”.It Research Department, Swedish Medical Center, 501 E. Hampden Ave Rm is possible that subjects with a partial knee replacement 3 4-454, Englewood, CO 80113, USA. Ampio Pharmaceuticals, Inc, 373 might have responded negatively. Lastly, there are Inverness Parkway, Englewood, CO 80112, USA. multiple factors that may have influenced the decision to Received: 30 April 2018 Accepted: 21 May 2018 have TKR, including current use of other pharmacologic interventions. We collected information on use of intra-articular injections and they were reported in a References 1. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. similar occurrence in the TKR group (prior to surgery) Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. and the non-TKR group (40% vs. 37.5%), but there 2008;59:1207–13. remains the risk of recall bias. 2. Davies-Tuck ML, Wluka AE, Wang Y, Teichtahl AJ, Jones G, Ding C, et al. The natural history of cartilage defects in people with knee osteoarthritis. Osteoarthr Cartil. 2008;16:337–42. 3. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. Conclusion American College of Rheumatology. Preliminary definition of improvement This study demonstrated delays to TKR among patients in rheumatoid arthritis. Arthritis Rheum. 1995;38:727–35. 4. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. with severe osteoarthritis treated with LMWF-5A Ann Rheum Dis. 1957;16:494–502. compared to saline, while showing no differences in 5. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and patients with moderate osteoarthritis. These results revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89:780–5. support the in vitro work suggesting the effect of 6. Bruyere O, Pavelka K, Rovati LC, Gatterova J, Giacovelli G, Olejarova M, et al. LMWF-5A is demonstrated with severe disease, and has Total joint replacement after glucosamine sulphate treatment in knee the potential to provide structure modifying/preserving osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthr Cartil. therapy in this population. 2008;16:254–60. 7. FJ Blanco JF-S, Pinto-Tasende JA, Fernandez-Lopez JC, Ramallal M, Freire A, Galdo F. Intra-articular Hyaluronan treatment of patients with knee Abbreviations osteoarthritis waiting for replacement surgery. Open Arthritis Journal. HSA: Human serum albumin; IRB: Institutional review board; KDa: Kilodalton; 2008;1:1–7. KL: Kellgren Lawrence; LMWF-5A: Low Molecular Weight Fraction of 5% 8. Raynauld JP, Martel-Pelletier J, Dorais M, Haraoui B, Choquette D, Abram F, human serum Albumin; MRI: Magnetic resonance imaging; et al. Total knee replacement as a knee osteoarthritis outcome: predictors OAK: Osteoarthritis of the knee; PGA: Patient global assessment; derived from a 4-year long-term observation following a randomized RCT: Randomized controlled trial; TKR: Total knee replacement; clinical trial using chondroitin sulfate. Cartilage. 2013;4:219–26. WOMAC: Western Ontario and McMaster Universities Arthritis Index 9. Bar-Or D, Salottolo KM, Loose H, Phillips MJ, McGrath B, Wei N, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS One. Funding 2014;9:e87910. The study was funded by Ampio Pharmaceuticals, Inc. 10. Cole B, McGrath B, Salottolo K. Bar-or D. LMWF-5A for the treatment of severe osteoarthritis of the knee: integrated analysis of safety and efficacy. Availability of data and materials Orthopedics. 2018;41(1):e77–e83. The datasets used and/or analyzed during the current study are available 11. Schwappach J, Dryden SM, Salottolo KM. Preliminary trial of intra-articular from the corresponding author on reasonable request. LMWF-5A for osteoarthritis of the knee. Orthopedics. 2017;40:e49-e53. Schwappach et al. Patient Safety in Surgery (2018) 12:14 Page 5 of 5 12. Bar-Or D, Thomas GW, Rael LT, Gersch ED, Rubinstein P, Brody E. Low molecular weight fraction of commercial human serum albumin induces morphologic and transcriptional changes of bone marrow-derived mesenchymal stem cells. Stem Cells Transl Med. 2015;4:945–55. 13. Frederick EDHM, Thomas GW, Rael LT, Brody E. Bar-or D. The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synoviocytes. Biochem Biophys Rep. 2016;8:68–74. 14. Thomas GW, Rael LT, Hausburg M, Frederick ED, Mains CW, Slone D, et al. The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2016;473:1328–33. 15. Thomas GW, Rael LT, Mains CW, Slone D, Carrick MM, Bar-Or R, et al. Anti-inflammatory activity in the low molecular weight fraction of commercial human serum albumin (LMWF5A). J Immunoassay Immunochem. 2016;37(1):55–67. 16. Federal Drug Administration. Clinical Development Programs for Drugs, Devices, and Biological Products. Intended for the Treatment of Osteoarthritis (OA). Rockville: U.S. Department of Health and Human Services; 1999.

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Patient Safety in SurgerySpringer Journals

Published: Jun 4, 2018

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