Clinical trial NCT02298023: Treatment of Tendon Injury Using Allogenic Adipose-derived Mesenchymal Stem Cells (Rotator Cuff Tear)
Official title: Treatment of Tendon Injury Using Allogenic Adipose-derived Mesenchymal Stem Cells: Phase II Double-Blind Placebo-Controlled Randomized Clinical Trials.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rotator Cuff Tear
Keywords: adipose derived mesenchymal stem cell
allogeneic stem cell
Rotator cuff tear
Lead sponsor: Seoul National University Hospital
Sponsor class: OTHER
First posted: 2014-11-21
Enrollment: 24
Sex: ALL
Minimum age (years): 19
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Main purpose of this study is to evaluate efficacy of allogenic adipose-derived mesenchymal stem cells in treatment of tendon injury. ALLO-ASC will be administrated to the patients with supraspinatus partial thickness tear by ultrasonographic guided injection.

Detailed description: Injection volume depends on the size of lesion on ultrasound examination. And all injection will be done under ultrasound guidance. Double blind Randomized placebo controlled study will be done with following 3 groups. Each group will have 8 people, so, the total patients will be 24 people.

1. Stem cell treatment group : stem cell 0.5cc (Total: 10 million cells) + Fibrin glue 0.5cc + range of motion exercise
2. Active control (fibrin glue) group : Normal saline 0.5cc + Fibrin glue 0.5cc + range of motion exercise
3. Control (normal saline) group : Normal saline 0.5cc + Normal saline 0.5cc + range of motion exercise

The investigators will compare the efficacy difference with VAS(visual analog scale, primary outcome), ASES(American Shoulder and Elbow Surgeons) Score, UCLA(University of California, Los Angles) Shoulder Score, DASH(The Disabilities of the Arm, Shoulder and Hand) Score and change of tear size compared to the baseline image assessed by MRI. These measurement will be done at 6 and 12 weeks after injections and long-term follow-up will be also planned to 6 months, 12months and 24 months except for the evaluation of the tear size which will be done at baseline, 3 months and 24 months after the intervention.

Eligibility criteria: Inclusion Criteria:

* clinically diagnosed as rotator cuff tear (supraspinatus partial thickness tear)
* recurrent pain in spite of conservative treatment such as physical therapy, medication, steroid injection
* symptom duration is over 3 months
* supraspinatus partial thickness tear proven ultrasonography and magnetic resonance image(MRI)
* patient that can understand the clinical trials

Exclusion Criteria:

* patient that underwent other injection treatment within 6 weeks
* some associated diseases (adhesive capsulitis, full thickness supraspinatus tear,. arthritis of related joint to the target lesion, muscle weakness or atrophy, innervated by suprascapular nerve, paralysis of related joint to target lesion, proximal humeral fracture, infectious disease, bilateral rotator cuff tear, generalized pain syndrome, radiculopathy, rheumatoid arthritis, impaired sensibility, dementia, history of allergic or hypersensitive reaction to bovine-derived proteins or fibrin glue and contraindication to MRI
* patient that enrolled other clinical trials within 30 days
* history of drug/alcohol addiction, habitual smoker, operation, allergic reaction to fibrin glue, local anesthetics and bovine-derived proteins and severe medical disease.

Primary outcomes:
measure: Change of Pain During Activity From Baseline to 3 Months After Intervention
timeFrame: Baseline and 3 months after intervention
Secondary outcomes:
measure: Pain During Rest
timeFrame: Baseline, 6 weeks, 12 weeks, 6, 12, 24 months after intervention
measure: Pain During Activity
timeFrame: Baseline, 6 weeks, 12 weeks, 6, 12, 24 months after intervention
measure: American Shoulder and Elbow Surgeons (ASES) Shoulder Score
timeFrame: Baseline, 6 weeks, 12 weeks, 6, 12, 24 months after intervention
measure: Disability of Arm, Shoulder and Hand (DASH) Score
timeFrame: Baseline, 6 weeks, 12 weeks, 6, 12, 24 months after intervention
measure: University of California, Los Angeles(UCLA) Shoulder Score
timeFrame: Baseline, 6 weeks, 12 weeks, 6, 12, 24 months after intervention
measure: Tear Size at 3 Months After Injection
timeFrame: baseline and 3 months after intervention
measure: Tear Size at 12 Months After Injection
timeFrame: baseline and12 months after intervention
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Seoul National University College of Medicine
Study officials:
affiliation: Seoul National University College of Medicine
name: Sun Gun Chung, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Isaac C, Gharaibeh B, Witt M, Wright VJ, Huard J. Biologic approaches to enhance rotator cuff healing after injury. J Shoulder Elbow Surg. 2012 Feb;21(2):181-90. doi: 10.1016/j.jse.2011.10.004.
citation: Muller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc. 2015 Jul;23(7):2097-105. doi: 10.1007/s00167-013-2680-z. Epub 2013 Sep 21.
citation: Tashjian RZ. Epidemiology, natural history, and indications for treatment of rotator cuff tears. Clin Sports Med. 2012 Oct;31(4):589-604. doi: 10.1016/j.csm.2012.07.001. Epub 2012 Aug 30.
citation: Coombes BK, Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials. Lancet. 2010 Nov 20;376(9754):1751-67. doi: 10.1016/S0140-6736(10)61160-9. Epub 2010 Oct 21.
citation: Sanchez M, Azofra J, Anitua E, Andia I, Padilla S, Santisteban J, Mujika I. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc. 2003 Oct;35(10):1648-52. doi: 10.1249/01.MSS.0000089344.44434.50.
citation: Price R, Sinclair H, Heinrich I, Gibson T. Local injection treatment of tennis elbow--hydrocortisone, triamcinolone and lignocaine compared. Br J Rheumatol. 1991 Feb;30(1):39-44. doi: 10.1093/rheumatology/30.1.39.
citation: Solveborn SA, Buch F, Mallmin H, Adalberth G. Cortisone injection with anesthetic additives for radial epicondylalgia (tennis elbow). Clin Orthop Relat Res. 1995 Jul;(316):99-105.
citation: Johnson GW, Cadwallader K, Scheffel SB, Epperly TD. Treatment of lateral epicondylitis. Am Fam Physician. 2007 Sep 15;76(6):843-8.
citation: Maffulli N, Longo UG, Denaro V. Novel approaches for the management of tendinopathy. J Bone Joint Surg Am. 2010 Nov 3;92(15):2604-13. doi: 10.2106/JBJS.I.01744.
citation: Arce G, Bak K, Bain G, Calvo E, Ejnisman B, Di Giacomo G, Gutierrez V, Guttmann D, Itoi E, Ben Kibler W, Ludvigsen T, Mazzocca A, de Castro Pochini A, Savoie F 3rd, Sugaya H, Uribe J, Vergara F, Willems J, Yoo YS, McNeil JW 2nd, Provencher MT. Management of disorders of the rotator cuff: proceedings of the ISAKOS upper extremity committee consensus meeting. Arthroscopy. 2013 Nov;29(11):1840-50. doi: 10.1016/j.arthro.2013.07.265. Epub 2013 Sep 13.
citation: Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006 Nov;34(11):1774-8. doi: 10.1177/0363546506288850. Epub 2006 May 30.
citation: Kon E, Filardo G, Delcogliano M, Presti ML, Russo A, Bondi A, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma: new clinical application: a pilot study for treatment of jumper's knee. Injury. 2009 Jun;40(6):598-603. doi: 10.1016/j.injury.2008.11.026. Epub 2009 Apr 19.
citation: Sanchez M, Anitua E, Azofra J, Andia I, Padilla S, Mujika I. Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am J Sports Med. 2007 Feb;35(2):245-51. doi: 10.1177/0363546506294078. Epub 2006 Nov 12.
citation: Slater M, Patava J, Kingham K, Mason RS. Involvement of platelets in stimulating osteogenic activity. J Orthop Res. 1995 Sep;13(5):655-63. doi: 10.1002/jor.1100130504.
citation: Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med. 2010 Feb;38(2):255-62. doi: 10.1177/0363546509355445.
citation: Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011 Jun;20(4):518-28. doi: 10.1016/j.jse.2011.02.008.
citation: Randelli PS, Arrigoni P, Cabitza P, Volpi P, Maffulli N. Autologous platelet rich plasma for arthroscopic rotator cuff repair. A pilot study. Disabil Rehabil. 2008;30(20-22):1584-9. doi: 10.1080/09638280801906081.
citation: Mizuno H. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch. 2009 Apr;76(2):56-66. doi: 10.1272/jnms.76.56.
citation: Casteilla L, Planat-Benard V, Laharrague P, Cousin B. Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J Stem Cells. 2011 Apr 26;3(4):25-33. doi: 10.4252/wjsc.v3.i4.25.
citation: Uysal AC, Mizuno H. Tendon regeneration and repair with adipose derived stem cells. Curr Stem Cell Res Ther. 2010 Jun;5(2):161-7. doi: 10.2174/157488810791268609.
citation: Gimble J, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003;5(5):362-9. doi: 10.1080/14653240310003026.
citation: Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002 Dec;13(12):4279-95. doi: 10.1091/mbc.e02-02-0105.
citation: Mizuno H, Hyakusoku H. Mesengenic potential and future clinical perspective of human processed lipoaspirate cells. J Nippon Med Sch. 2003 Aug;70(4):300-6. doi: 10.1272/jnms.70.300.
citation: von Heimburg D, Hemmrich K, Haydarlioglu S, Staiger H, Pallua N. Comparison of viable cell yield from excised versus aspirated adipose tissue. Cells Tissues Organs. 2004;178(2):87-92. doi: 10.1159/000081719.
citation: Smith RK, Webbon PM. Harnessing the stem cell for the treatment of tendon injuries: heralding a new dawn? Br J Sports Med. 2005 Sep;39(9):582-4. doi: 10.1136/bjsm.2005.015834. No abstract available.
citation: Chong AK, Ang AD, Goh JC, Hui JH, Lim AY, Lee EH, Lim BH. Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit achilles tendon model. J Bone Joint Surg Am. 2007 Jan;89(1):74-81. doi: 10.2106/JBJS.E.01396.
citation: Ouyang HW, Goh JC, Thambyah A, Teoh SH, Lee EH. Knitted poly-lactide-co-glycolide scaffold loaded with bone marrow stromal cells in repair and regeneration of rabbit Achilles tendon. Tissue Eng. 2003 Jun;9(3):431-9. doi: 10.1089/107632703322066615.
citation: Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL. Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis. Am J Vet Res. 2008 Jul;69(7):928-37. doi: 10.2460/ajvr.69.7.928.
citation: Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA. Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med. 2009 Nov;37(11):2126-33. doi: 10.1177/0363546509339582. Epub 2009 Aug 14.
citation: Del Bue M, Ricco S, Ramoni R, Conti V, Gnudi G, Grolli S. Equine adipose-tissue derived mesenchymal stem cells and platelet concentrates: their association in vitro and in vivo. Vet Res Commun. 2008 Sep;32 Suppl 1:S51-5. doi: 10.1007/s11259-008-9093-3.
citation: Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012 Feb;20(2):373-7. doi: 10.1007/s00167-011-1607-9. Epub 2011 Jul 20.
citation: MacIsaac ZM, Shang H, Agrawal H, Yang N, Parker A, Katz AJ. Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells. Exp Cell Res. 2012 Feb 15;318(4):416-23. doi: 10.1016/j.yexcr.2011.12.002. Epub 2011 Dec 13.
citation: Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis. 2012 May;27(5):595-600. doi: 10.1007/s00384-011-1350-1. Epub 2011 Nov 9.
citation: Guest DJ, Smith MR, Allen WR. Monitoring the fate of autologous and allogeneic mesenchymal progenitor cells injected into the superficial digital flexor tendon of horses: preliminary study. Equine Vet J. 2008 Mar;40(2):178-81. doi: 10.2746/042516408X276942.
citation: Shiri R, Viikari-Juntura E, Varonen H, Heliovaara M. Prevalence and determinants of lateral and medial epicondylitis: a population study. Am J Epidemiol. 2006 Dec 1;164(11):1065-74. doi: 10.1093/aje/kwj325. Epub 2006 Sep 12.
citation: Hohendorff B, Siepen W, Spiering L, Staub L, Schmuck T, Boss A. Long-term results after operatively treated Achilles tendon rupture: fibrin glue versus suture. J Foot Ankle Surg. 2008 Sep-Oct;47(5):392-9. doi: 10.1053/j.jfas.2008.05.006. Epub 2008 Jul 14.
citation: Minagawa H, Yamamoto N, Abe H, Fukuda M, Seki N, Kikuchi K, Kijima H, Itoi E. Prevalence of symptomatic and asymptomatic rotator cuff tears in the general population: From mass-screening in one village. J Orthop. 2013 Feb 26;10(1):8-12. doi: 10.1016/j.jor.2013.01.008. eCollection 2013.
citation: Jo CH, Shin JS, Lee YG, Shin WH, Kim H, Lee SY, Yoon KS, Shin S. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blind, parallel-group trial. Am J Sports Med. 2013 Oct;41(10):2240-8. doi: 10.1177/0363546513497925. Epub 2013 Aug 6.
citation: Oh JH, Chung SW, Kim SH, Chung JY, Kim JY. 2013 Neer Award: Effect of the adipose-derived stem cell for the improvement of fatty degeneration and rotator cuff healing in rabbit model. J Shoulder Elbow Surg. 2014 Apr;23(4):445-55. doi: 10.1016/j.jse.2013.07.054. Epub 2013 Oct 12.
citation: Buchbinder R, Green SE, Struijs P. Tennis elbow. BMJ Clin Evid. 2008 May 28;2008:1117.
citation: Levin D, Nazarian LN, Miller TT, O'Kane PL, Feld RI, Parker L, McShane JM. Lateral epicondylitis of the elbow: US findings. Radiology. 2005 Oct;237(1):230-4. doi: 10.1148/radiol.2371040784. Epub 2005 Aug 18.
citation: Chun SW, Kim W, Lee SY, Lim CY, Kim K, Kim JG, Park CH, Hong SH, Yoo HJ, Chung SG. A randomized controlled trial of stem cell injection for tendon tear. Sci Rep. 2022 Jan 17;12(1):818. doi: 10.1038/s41598-021-04656-z.