Effects of Dietary Supplement on Osteoarthritis

Knee Osteoarthritis Clinical Trial

Official title:

Effects of Arginine on Osteoarthritis: A Pilot Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03665116
• Other study ID #: 20190018
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 5, 2019
• Est. completion date: September 30, 2024

Study information

• Verified date: July 2023
• Source: Memorial University of Newfoundland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates the effects arginine on osteoarthritis (OA) in adults. Participants will be randomly divided into two groups, taking arginine and nothing, respectively. Outcomes will be evaluated by lab test results on OA joint cartilage and self-administered questionnaires. The hypothesis is that arginine can slow down or reverse OA.

Description:

1. Patients that meet the inclusion criteria will be approached by a member from their care team, details of this study will be explained. Verbal consent to screening will be obtained during this phone interview and recorded in the clinical trial database; patients will be screened for their eligibility, and a clinical visit will be arranged for eligible patients.

2. Consent form and questionnaires that are commonly used to collect general health information and assess OA patients' mental and physical functions (General Questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and 36-Item Short Form Health Survey (SF-36)) will be mailed to eligible patients. Patients will read consent form and fill up questionnaires.

3. Eligible patients will be reached by phone by the research assistant at a later date to obtain their verbal consent to further contact regarding participating in the study, and consent status will be recorded in the clinical trial database.

4. Initial clinical visit:

1. All questions and concerns will be answered by researchers, consent form will be signed by participants, research assistant, and one of the investigators, and participants will be given a copy as record.

2. Questionnaires (baseline) will be collected.

3. 6.5 ml of blood sample (baseline) will be collected by a qualified research nurse.

4. Participants will be randomly divided into 2 groups, each group will receive arginine and instruction or nothing, and will take arginine or nothing for 6 months:

• Group I (n=50): 1.5 g of L-arginine daily.

• Group II (n=50): No supplement.

5. Pre-admission clinical vist:

• WOMAC and SF-36 questionnaires (at 6 months of the trial) will be administered.

• 6.5 ml of blood sample (at 6 months of the trial) will be collected.

6. During total joint replacement surgery, small pieces of replaced joint cartilage tissue, which are normally thrown away, will be collected.

7. At 6 and 12 months after the surgery, participants will be reached via phone by the research assistant to complete WOMAC and SF-36 questionnaires. A blood requisition form will be mailed to participants after the last phone interview for their next scheduled routine fasting blood work; 4 ml of blood sample will be collected for the study and sent to the clinical trail lab by the blood collection centre.

8. Lab testing will be conducted; all outcome data will be obtained and analyzed.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 38
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• Undergoing total knee replacement surgery in 6 months due to primary knee OA

• Must be ambulatory

• Must live in 50 kilometers perimeter of St. John's, capital city of Newfoundland and Labrador, Canada

Exclusion Criteria:

• Clinical diagnosis of secondary OA or inflammatory arthritis

• Cod liver oil supplementation within 6 months

• Supplementation containing arginine within 6 months

• Osteoporotic fracture, previous knee surgery or arthroscopy within 6 months

• Use of bisphosphonates within 2 years

• Use of Intra-articular viscosupplementation or platelet rich plasma at any point

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Osteoarthritis

Intervention

Dietary Supplement:
• L-arginine
L-arginine capsule

Locations

Country	Name	City	State
Canada	Total Joint Assessment Clinic	St. John's	Newfoundland and Labrador

Sponsors (2)

Lead Sponsor	Collaborator
Memorial University of Newfoundland	Ocean Frontier Institute

Country where clinical trial is conducted

Canada, 

References & Publications (29)

Abu el Maaty MA, Hanafi RS, El Badawy S, Gad MZ. Association of suboptimal 25-hydroxyvitamin D levels with knee osteoarthritis incidence in post-menopausal Egyptian women. Rheumatol Int. 2013 Nov;33(11):2903-7. doi: 10.1007/s00296-012-2551-9. Epub 2012 Nov 4. — View Citation

Arden NK, Cro S, Sheard S, Dore CJ, Bara A, Tebbs SA, Hunter DJ, James S, Cooper C, O'Neill TW, Macgregor A, Birrell F, Keen R. The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial. Osteoarthritis Cartilage. 2016 Nov;24(11):1858-1866. doi: 10.1016/j.joca.2016.05.020. Epub 2016 Jun 2. — View Citation

Aref-Eshghi E, Liu M, Harper PE, Dore J, Martin G, Furey A, Green R, Rahman P, Zhai G. Overexpression of MMP13 in human osteoarthritic cartilage is associated with the SMAD-independent TGF-beta signalling pathway. Arthritis Res Ther. 2015 Sep 23;17(1):264. doi: 10.1186/s13075-015-0788-x. — View Citation

Aref-Eshghi E, Liu M, Razavi-Lopez SB, Hirasawa K, Harper PE, Martin G, Furey A, Green R, Sun G, Rahman P, Zhai G. SMAD3 Is Upregulated in Human Osteoarthritic Cartilage Independent of the Promoter DNA Methylation. J Rheumatol. 2016 Feb;43(2):388-94. doi: 10.3899/jrheum.150609. Epub 2015 Dec 15. — View Citation

Bergink AP, Uitterlinden AG, Van Leeuwen JP, Buurman CJ, Hofman A, Verhaar JA, Pols HA. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: The Rotterdam Study. J Clin Rheumatol. 2009 Aug;15(5):230-7. doi: 10.1097/RHU.0b013e3181b08f20. — View Citation

Brand C, Snaddon J, Bailey M, Cicuttini F. Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann Rheum Dis. 2001 Oct;60(10):946-9. doi: 10.1136/ard.60.10.946. — View Citation

Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, March L. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1323-30. doi: 10.1136/annrheumdis-2013-204763. Epub 2014 Feb 19. — View Citation

Ding C, Cicuttini F, Parameswaran V, Burgess J, Quinn S, Jones G. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum. 2009 May;60(5):1381-9. doi: 10.1002/art.24486. — View Citation

Grant WB, Schwalfenberg GK, Genuis SJ, Whiting SJ. An estimate of the economic burden and premature deaths due to vitamin D deficiency in Canada. Mol Nutr Food Res. 2010 Aug;54(8):1172-81. doi: 10.1002/mnfr.200900420. — View Citation

Guermazi A, Roemer FW, Felson DT, Brandt KD. Motion for debate: osteoarthritis clinical trials have not identified efficacious therapies because traditional imaging outcome measures are inadequate. Arthritis Rheum. 2013 Nov;65(11):2748-58. doi: 10.1002/art.38086. No abstract available. — View Citation

Heidari B, Heidari P, Hajian-Tilaki K. Association between serum vitamin D deficiency and knee osteoarthritis. Int Orthop. 2011 Nov;35(11):1627-31. doi: 10.1007/s00264-010-1186-2. Epub 2010 Dec 30. — View Citation

Jin X, Jones G, Cicuttini F, Wluka A, Zhu Z, Han W, Antony B, Wang X, Winzenberg T, Blizzard L, Ding C. Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2016 Mar 8;315(10):1005-13. doi: 10.1001/jama.2016.1961. — View Citation

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001 Dec;25(4):402-8. doi: 10.1006/meth.2001.1262. — View Citation

McAlindon T, LaValley M, Schneider E, Nuite M, Lee JY, Price LL, Lo G, Dawson-Hughes B. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. JAMA. 2013 Jan 9;309(2):155-62. doi: 10.1001/jama.2012.164487. — View Citation

McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Wilson PW, Jacques P. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996 Sep 1;125(5):353-9. doi: 10.7326/0003-4819-125-5-199609010-00001. — View Citation

McAlindon TE, Jacques P, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Levy D, Felson DT. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996 Apr;39(4):648-56. doi: 10.1002/art.1780390417. — View Citation

Morris SM Jr. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol. 2009 Jul;157(6):922-30. doi: 10.1111/j.1476-5381.2009.00278.x. Epub 2009 Jun 5. — View Citation

Perez-Portela R, Riesgo A. Optimizing preservation protocols to extract high-quality RNA from different tissues of echinoderms for next-generation sequencing. Mol Ecol Resour. 2013 Sep;13(5):884-9. doi: 10.1111/1755-0998.12122. Epub 2013 May 20. — View Citation

Pritzker KP, Gay S, Jimenez SA, Ostergaard K, Pelletier JP, Revell PA, Salter D, van den Berg WB. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. 2006 Jan;14(1):13-29. doi: 10.1016/j.joca.2005.07.014. Epub 2005 Oct 19. — View Citation

Sanghi D, Mishra A, Sharma AC, Singh A, Natu SM, Agarwal S, Srivastava RN. Does vitamin D improve osteoarthritis of the knee: a randomized controlled pilot trial. Clin Orthop Relat Res. 2013 Nov;471(11):3556-62. doi: 10.1007/s11999-013-3201-6. Epub 2013 Aug 1. — View Citation

Schwalfenberg G. Not enough vitamin D: health consequences for Canadians. Can Fam Physician. 2007 May;53(5):841-54. — View Citation

Sharif B, Kopec J, Bansback N, Rahman MM, Flanagan WM, Wong H, Fines P, Anis A. Projecting the direct cost burden of osteoarthritis in Canada using a microsimulation model. Osteoarthritis Cartilage. 2015 Oct;23(10):1654-63. doi: 10.1016/j.joca.2015.05.029. Epub 2015 Jun 5. — View Citation

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. doi: 10.1093/ajcn/69.5.842. — View Citation

Vukic M, Neme A, Seuter S, Saksa N, de Mello VD, Nurmi T, Uusitupa M, Tuomainen TP, Virtanen JK, Carlberg C. Relevance of vitamin D receptor target genes for monitoring the vitamin D responsiveness of primary human cells. PLoS One. 2015 Apr 13;10(4):e0124339. doi: 10.1371/journal.pone.0124339. eCollection 2015. — View Citation

Wluka AE, Stuckey S, Brand C, Cicuttini FM. Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002 Dec;29(12):2585-91. — View Citation

Zhai G, Dore J, Rahman P. TGF-beta signal transduction pathways and osteoarthritis. Rheumatol Int. 2015 Aug;35(8):1283-92. doi: 10.1007/s00296-015-3251-z. Epub 2015 Mar 15. — View Citation

Zhang W, Likhodii S, Aref-Eshghi E, Zhang Y, Harper PE, Randell E, Green R, Martin G, Furey A, Sun G, Rahman P, Zhai G. Relationship between blood plasma and synovial fluid metabolite concentrations in patients with osteoarthritis. J Rheumatol. 2015 May;42(5):859-65. doi: 10.3899/jrheum.141252. Epub 2015 Mar 1. — View Citation

Zhang W, Sun G, Aitken D, Likhodii S, Liu M, Martin G, Furey A, Randell E, Rahman P, Jones G, Zhai G. Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology (Oxford). 2016 Sep;55(9):1566-74. doi: 10.1093/rheumatology/kew207. Epub 2016 May 9. — View Citation

Zhang W, Sun G, Likhodii S, Liu M, Aref-Eshghi E, Harper PE, Martin G, Furey A, Green R, Randell E, Rahman P, Zhai G. Metabolomic analysis of human plasma reveals that arginine is depleted in knee osteoarthritis patients. Osteoarthritis Cartilage. 2016 May;24(5):827-34. doi: 10.1016/j.joca.2015.12.004. Epub 2015 Dec 18. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Target Gene Expressions in Osteoarthritic Knee Cartilage after 6 Months of Supplementation	After participants have been taking arginine or nothing for 6 months, and cartilage tissue has been obtained during participants' total knee replacement surgery, target gene expressions in cartilage are measured with quantitative polymerase chain reaction (qPCR). Genes include cartilage degradation enzymes - matrix metallopeptidase 13 (MMP13), cathepsin K (CTSK), cathepsin B (CTSB), and cartilage syntheses genes - aggrecan (ACAN) and type II collagen (CTXII).	up to 20 months
Secondary	OA Severity Grade of Osteoarthritic Knee Cartilage after 6 Months of Supplementation	After participants have been taking arginine or nothing for 6 months, and cartilage tissue has been obtained during participants' total knee replacement surgery, the Osteoarthritis Research Society International (OARSI) cartilage histopathology assessment protocol is used to grade OA severity of cartilage on a 7-point scale, with grade 0 as normal cartilage, 1 to 4 with articular cartilage changes only, and 5 to 6 involving subchondral bone.	up to 6 months
Secondary	WOMAC to Measure Changes in Joint Pain and Function between baseline and at 6 Months	WOMAC is used to collect data on participants' self reported joint pain intensity (5 items) and functional deficit (17 items) on a scale of 0-4, which correspond to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with a possible score range of 0-20 for pain, and 0-68 for functional deficit, and total scores for joint pain and functional deficit at 6 months are compared to baseline, respectively.	at baseline and in 6 months
Secondary	WOMAC to Measure Changes in Joint Pain and Function between baseline and at 6 Months Post-surgery	WOMAC is used to collect data on participants' self reported joint pain intensity (5 items) and functional deficit (17 items) on a scale of 0-4, which correspond to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with a possible score range of 0-20 for pain, and 0-68 for functional deficit, and total scores for joint pain and functional deficit at 6 months post surgery are compared to baseline, respectively.	at baseline and 6 months post-surgery
Secondary	WOMAC to Measure Changes in Joint Pain and Function between baseline and at 12 Months Post-surgery	WOMAC is used to collect data on participants' self reported joint pain intensity (5 items) and functional deficit (17 items) on a scale of 0-4, which correspond to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with a possible score range of 0-20 for pain, and 0-68 for functional deficit, and total scores for joint pain and functional deficit at 12 months post surgery are compared to baseline, respectively.	at baseline and 12 months post-surgery
Secondary	SF-36 to Measure Changes in Physical and Mental Function between baseline and at 6 Months	SF-36 is used to collect data on self reported mental and physical health state on 8 scales: physical functioning (10 items); role limitations due to physical health (4 items); role limitations due to emotional problems (3 items); energy/fatigue (4 items); emotional well-being (5 items); social functioning (2 items); pain (2 items); general health (5 items); and self reported health change within one year. All 36 scores are recoded according to "Scoring Rules for the RAND 36-Item Health Survey (Version 1.0)", and items in the same scale are averaged together to generate 8 scale scores, each ranging between 0-100, with higher scores representing a more favorable health state. Scores at 6 months are compared to baseline.	at baseline and in 6 months
Secondary	SF-36 to Measure Changes in Physical and Mental Function between baseline and at 6 Months Post-surgery	SF-36 is used to collect data on self reported mental and physical health state on 8 scales: physical functioning (10 items); role limitations due to physical health (4 items); role limitations due to emotional problems (3 items); energy/fatigue (4 items); emotional well-being (5 items); social functioning (2 items); pain (2 items); general health (5 items); and self reported health change within one year. All 36 scores are recoded according to "Scoring Rules for the RAND 36-Item Health Survey (Version 1.0)", and items in the same scale are averaged together to generate 8 scale scores, each ranging between 0-100, with higher scores representing a more favorable health state. Scores at 6 months post-surgery are compared to baseline.	at baseline and 6 months post-surgery
Secondary	SF-36 to Measure Changes in Physical and Mental Function between baseline and at 12 Months Post-surgery	SF-36 is used to collect data on self reported mental and physical health state on 8 scales: physical functioning (10 items); role limitations due to physical health (4 items); role limitations due to emotional problems (3 items); energy/fatigue (4 items); emotional well-being (5 items); social functioning (2 items); pain (2 items); general health (5 items); and self reported health change within one year. All 36 scores are recoded according to "Scoring Rules for the RAND 36-Item Health Survey (Version 1.0)", and items in the same scale are averaged together to generate 8 scale scores, each ranging between 0-100, with higher scores representing a more favorable health state. Scores at 12 months post-surgery are compared to baseline.	at baseline and 12 months post-surgery