The Effect of Tart Cherry Juice on Risk of Gout Attacks

• ClinicalTrials.gov Identifier: NCT03621215
• Recruitment Status: Unknown
• First Posted: August 8, 2018
• Last Update Posted: December 19, 2020
• Sponsor: Sheffield Hallam University
• Collaborator: Cherry Research Committee
• Information provided by (Responsible Party): Tony Lynn, Sheffield Hallam University

Tracking Information

• First Submitted Date: July 30, 2018
• First Posted Date: August 8, 2018
• Last Update Posted Date: December 19, 2020
• Actual Study Start Date: July 15, 2019
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 3, 2018)

Change in gout flare frequency [ Time Frame: Measured at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 months ]

Difference in gout flare frequency in tart cherry juice group versus placebo group from baseline to 12 months. Recorded as number per month.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 9, 2018)

• Change in gout flare intensity [ Time Frame: Measured at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 months ]
  Difference in gout flare intensity in tart cherry juice group versus placebo group from baseline to 12 months. Using a 0-10 Likert pain scale. The scale measures the pain of any gout flare. The possible score ranges from 0 for no pain through to 10 for worst pain imaginable. Change in pain scores between treatment and placebo groups will be compared throughout the duration of the intervention.
• Changes in serum urate (in millimoles per litre (mmol/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in serum urate in tart cherry juice group versus placebo group from baseline to 12 months.
• Change in fractional excretion of uric acid (as a percentage, %) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in fractional excretion of uric acid in tart cherry juice group versus placebo group from baseline to 12 months. Measured from 24 hour urine sample.
• Change in inflammatory markers (in milligrams per litre (mg/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in inflammatory markers (c reactive protein (CRP), inter leukin-6 (IL-6) and tumour necrosis factor- alpha (TNF-alpha)) in tart cherry juice group versus placebo group from baseline to 12 months. Measured using an enzyme-linked immunosorbent assay (ELISA).
• Change in oxidative damage (in percentage (%) of tail DNA) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in markers of oxidative stress in tart cherry juice group versus placebo group from baseline to 12 months. Measured using single-cell electrophoresis 'comet assay' as 8-oxo-dg levels in lymphocytes.
• Change in antioxidant status (in percentage (%) of tail DNA) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in antioxidant status in tart cherry juice group versus placebo group from baseline to 12 months. Measured using single-cell electrophoresis 'comet assay' as resistance of DNA lymphocyte to H202-induced DNA strand breaks.
• Change in blood pressure (in millimetres of mercury (mmHg)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in brachial and central blood pressure in tart cherry juice group versus placebo group from baseline to 12 months. Measured using a Vicorder.
• Change in arterial stiffness (in meters per second (m/s)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in arterial stiffness in tart cherry juice group versus placebo group from baseline to 12 months.
• Change in lipid profile (in millimoles per litre (mmol/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in total cholesterol, HDL cholesterol, LDL cholesterol and triacylglycerides) in tart cherry juice group versus placebo group from baseline to 12 months.
• Height (in meters (m)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Height and weight will be combined to report BMI in kg/m^2. Difference in BMI in tart cherry juice group versus placebo group from baseline to 12 months.
• Weight (in kilograms (kg)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Height and weight will be combined to report BMI in kg/m^2. Difference in BMI in tart cherry juice group versus placebo group from baseline to 12 months.

Original Secondary Outcome Measures (submitted: August 3, 2018)

• Change in gout flare intensity [ Time Frame: Measured at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 months ]
  Difference in gout flare intensity in tart cherry juice group versus placebo group from baseline to 12 months. Using a 0-10 Likert pain scale.
• Changes in serum urate (in millimoles per litre (mmol/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in serum urate in tart cherry juice group versus placebo group from baseline to 12 months.
• Change in fractional excretion of uric acid (as a percentage, %) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in fractional excretion of uric acid in tart cherry juice group versus placebo group from baseline to 12 months. Measured from 24 hour urine sample.
• Change in inflammatory markers (in milligrams per litre (mg/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in inflammatory markers (c reactive protein (CRP), inter leukin-6 (IL-6) and tumour necrosis factor- alpha (TNF-alpha)) in tart cherry juice group versus placebo group from baseline to 12 months. Measured using an enzyme-linked immunosorbent assay (ELISA).
• Change in oxidative damage (in percentage (%) of tail DNA) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in markers of oxidative stress in tart cherry juice group versus placebo group from baseline to 12 months. Measured using single-cell electrophoresis 'comet assay' as 8-oxo-dg levels in lymphocytes.
• Change in antioxidant status (in percentage (%) of tail DNA) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in antioxidant status in tart cherry juice group versus placebo group from baseline to 12 months. Measured using single-cell electrophoresis 'comet assay' as resistance of DNA lymphocyte to H202-induced DNA strand breaks.
• Change in blood pressure (in millimetres of mercury (mmHg)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in brachial and central blood pressure in tart cherry juice group versus placebo group from baseline to 12 months. Measured using a Vicorder.
• Change in arterial stiffness (in meters per second (m/s)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in arterial stiffness in tart cherry juice group versus placebo group from baseline to 12 months.
• Change in lipid profile (in millimoles per litre (mmol/l)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Difference in total cholesterol, HDL cholesterol, LDL cholesterol and triacylglycerides) in tart cherry juice group versus placebo group from baseline to 12 months.
• Height (in meters (m)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Height and weight will be combined to report BMI in kg/m^2. Difference in BMI in tart cherry juice group versus placebo group from baseline to 12 months.
• Weight (in kilograms (kg)) [ Time Frame: Measured at 0, 6 and 12 months ]
  Height and weight will be combined to report BMI in kg/m^2. Difference in BMI in tart cherry juice group versus placebo group from baseline to 12 months.

Current Other Pre-specified Outcome Measures (submitted: August 3, 2018)

• Changes in habitual diet [ Time Frame: Measured at 0, 6 and 12 months ]
  4 day diet diaries will be used to assess any changes in habitual diet as a result of, or over the course of, the study.
• Changes in habitual physical activity levels [ Time Frame: Measured at 0, 6 and 12 months ]
  4 day physical activity logs will be used to assess any changes in habitual activity levels as a result of, or over the course of, the study.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: The Effect of Tart Cherry Juice on Risk of Gout Attacks
• Official Title: The Effect of Tart Cherry Juice on Risk of Gout Attacks: a Randomised Controlled Trial
• Brief Summary: The purpose of this study is to determine whether consuming tart cherry juice daily for 12 months reduces the risk of gout attacks during this period. Individuals with an existing gout diagnosis and who have experienced at least one gout flare in the past year will be recruited to participate in this study.

Detailed Description

Gout is a painful and often debilitating condition affecting around 3% of adults in the UK. It is a type of inflammatory arthritis caused by high levels of uric acid which is deposited as crystals in joints, resulting in painful gout flares. Cherries and cherry products have received attention for their possible role in gout management owing to their anti-inflammatory and anti-oxidant properties. Their consumption has been associated with a lower risk of gout attacks in one observational study. The consumption of cherries is also endorsed by several gout information websites and in the British Society of Rheumatology's 2017 guidelines for the management of gout. However, there is limited evidence underpinning these claims and existing studies tend to be short in duration and have small participant numbers. Gout attacks are sporadic in nature and so a long-term trial is required to clarify the therapeutic effect of cherries on gout attack risk.

The investigators are aiming to recruit 120 participants who have had at least one gout flare in the previous 12 months. Using the work of Rothenbacher et al., 2011, the chance of these individuals experiencing at least one attack in the next 12 months has been calculated at 11%. It is predicted that treatment with daily cherry juice consumption will reduce gout flare recurrence (primary outcome measure) to 1/4 of the rate of the actual recurrence i.e. to 2.7%. Using these figures, a sample size of 93 participants would provide power of 0.95 at a significance level of 0.05. A sample size of 120 participants allows for an approximate 20% attrition rate.

Participants will consume either 30 mL tart cherry juice (CherryActive) diluted to 250 mL with water or a fruit-flavoured placebo drink daily with breakfast for 12 months. Participants will be followed up at 6 and 12 months at the investigators' laboratory to study changes in gout flare frequency and intensity, uric acid levels and levels of inflammation. This will help determine if tart cherry juice could help reduce or even prevent gout attacks. Additionally, as gout is associated with increased cardiovascular disease (CVD) risk, changes in CVD risk markers, including blood pressure, arterial stiffness and cholesterol levels, will also be assessed.

Participants will be recruited through the use of posters, advertising on the UK Gout Society website, emails to large organisations and through letters sent from General Practitioners' (GP) surgeries to eligible patients. Potentially eligible patients will be identified by surgery staff using their patient database before contact information is passed to the research team at the surgery to prepare and send out invitation letters. As this method of recruitment involves accessing patient identifiable data (name and home address) prior to patient consent being given, an application to the Confidentiality Advisory Group (CAG) will be submitted for consideration.

A general linear mixed model analysis will be used to assess the effect of treatment allocation, time and their interaction on both primary and secondary outcome measures.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants will be randomly allocated to consume either tart cherry juice or a fruit-flavoured placebo drink (matched as closely as possible for energy and sensory characteristics) daily for 12 months.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

Condition

• Gout Flare
• Gout Attack

Intervention

• Dietary Supplement: Tart cherry juice
  30 mL tart cherry juice concentrate (CherryActive, UK), diluted with water to 250 mL. This is consumed daily by participants, with breakfast, for 12 months.
• Other: Fruit-flavoured placebo drink
  Consumed daily by participants, with breakfast, for 12 months.

Study Arms

• Experimental: Tart cherry juice
  30 mL tart cherry concentrate (CherryActive, UK) diluted with 220 mL of water once per day (250 mL total volume per day). According to available manufacturers data, this is equivalent to consuming 90-100 fresh cherries per day.
  Intervention: Dietary Supplement: Tart cherry juice
• Placebo Comparator: Fruit-flavoured placebo drink

  Matched for sensory characteristics and energy (with the addition of glucose).

  once per day (250 mL total volume per day)

  Intervention: Other: Fruit-flavoured placebo drink

Publications *

• Zhang Y, Neogi T, Chen C, Chaisson C, Hunter DJ, Choi HK. Cherry consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012 Dec;64(12):4004-11. doi: 10.1002/art.34677.
• Jacob RA, Spinozzi GM, Simon VA, Kelley DS, Prior RL, Hess-Pierce B, Kader AA. Consumption of cherries lowers plasma urate in healthy women. J Nutr. 2003 Jun;133(6):1826-9. doi: 10.1093/jn/133.6.1826.
• Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis. 2015 Apr;74(4):661-7. doi: 10.1136/annrheumdis-2013-204463. Epub 2014 Jan 15.
• Cea Soriano L, Rothenbacher D, Choi HK, Garcia Rodriguez LA. Contemporary epidemiology of gout in the UK general population. Arthritis Res Ther. 2011 Mar 3;13(2):R39. doi: 10.1186/ar3272.
• Rothenbacher D, Primatesta P, Ferreira A, Cea-Soriano L, Rodriguez LA. Frequency and risk factors of gout flares in a large population-based cohort of incident gout. Rheumatology (Oxford). 2011 May;50(5):973-81. doi: 10.1093/rheumatology/keq363. Epub 2011 Jan 12.
• Dalbeth N, Ames R, Gamble GD, Horne A, Wong S, Kuhn-Sherlock B, MacGibbon A, McQueen FM, Reid IR, Palmano K. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012 Jun;71(6):929-34. doi: 10.1136/annrheumdis-2011-200156. Epub 2012 Jan 23.
• Lamb KL, Lynn A, Russell J, Barker ME. Effect of tart cherry juice on risk of gout attacks: protocol for a randomised controlled trial. BMJ Open. 2020 Mar 15;10(3):e035108. doi: 10.1136/bmjopen-2019-035108.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: August 3, 2018): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• existing diagnosis of gout
• have experienced at least one gout flare in the previous 12 months
• able and willing to participate in the study and provide written informed consent

Exclusion Criteria:

• frequently consume cherries or cherry products e.g. cherry supplements and juice (more than once a week)
• severe renal impairment (estimated glomerular filtration rate of <30ml/min)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03621215
• Other Study ID Numbers: ER7166682; AA4736173 ( Other Grant/Funding Number: Cherry Research Committee/Cherry Marketing Institute )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Tony Lynn, Sheffield Hallam University
• Original Responsible Party: Same as current
• Current Study Sponsor: Sheffield Hallam University
• Original Study Sponsor: Same as current
• Collaborators: Cherry Research Committee

Investigators

• Principal Investigator: Margo Barker; Sheffield Hallam University

• PRS Account: Sheffield Hallam University
• Verification Date: December 2020