Methods

Randomised, double blind, 3‐arm, parallel‐group, controlled trial

Duration: 3 months

Withdrawals: 18 (distribution of losses not known despite attempts to contact the study author)

Pre‐specified sample size calculation: reported

Intention‐to‐treat analysis: performed

Participants

N = 120

Inclusion criteria:

1. Adults aged ≥ 18 years

2. Gout diagnosed (according to the American College of Rheumatology diagnostic classification, recurrent gout flares (at least 2 flares in the preceding 4 months)

3. Participants experiencing frequent gout flares at the time of study enrolment (≥ 2 flares in the preceding 4 months)

Exclusion criteria:

1. Lactose intolerance
2. Severe renal impairment (defined as estimated glomerular filtration rate (eGFR) < 30 ml/min)

Lactose group (n = 40):

1. Males, n (%): 37 (93)

2. Mean age, years (SD): 57 (16)

3. Caucasian ethnicity, n (%): 28 (70)

4. Number of self reported flares in preceding 4 months, mean (SD): 3.9 (2.7)

5. Number of gout flares in baseline month, mean (SD): 1.3 (1.5)

6. Allopurinol use, n (%): 21 (53)

7. Colchicine use, n (%): 12 (30)

8. Prednisone use, n (%): 4 (10)

9. NSAID use, n (%): 11 (28)

10. Diuretic use, n (%): 2 (5)

11. Serum urate, mmol/l, mean (SD): 0.44 (0.11)
12. Tophaceous gout, n (%): 8 (20%)

13. Serum creatinine, μmol/l, mean (SD): 91 (18)

SMP group (n = 40):

1. Males, n (%): 36 (90)

2. Mean age, years (SD): 56 (12)

3. Caucasian ethnicity, n (%): 28 (70)

4. Number of self reported flares in preceding 4 months, mean (SD): 4.5 (2.3)

5. Number of gout flares in baseline month, mean (SD): 1.1 (1.4)

6. Allopurinol use, n (%): 22 (55)

7. Colchicine use, n (%): 7 (18)

8. Prednisone use, n (%): 8 (20)

9. NSAID use, n (%): 10 (25)

10. Diuretic use, n (%): 1 (2.5)

11. Serum urate, mmol/l, mean (SD): 0.41 (0.09)
12. Tophaceous gout, n (%): 17 (43)

13. Serum creatinine, μmol/l, mean (SD): 91 (19)

SMP/GMP/G600 (n = 40):

1. Males, n (%): 35 (88)

2. Mean age, years (SD): 56 (13)

3. Caucasian ethnicity, n (%): 22 (55)

4. Number of self reported flares in preceding 4 months, mean (SD): 5.1 (9.6)

5. Number of gout flares in baseline month, mean (SD): 1.8 (2.4)

6. Allopurinol use, n (%): 22 (55)

7. Colchicine use, n (%): 13 (33)
8. Prednisone use, n (%): 4 (10)
9. NSAID use, n (%): 11 (28)
10. Diuretic use, n (%): 8 (20)

11. Serum urate, mmol/l, mean (SD): 0.42 (0.11)
12. Tophaceous gout, n (%): 10 (25)

13. Serum creatinine, μmol/l, mean (SD): 93 (20)

Interventions

Intervention 1: lactose powder active control

Intervention 2: skim milk powder (SMP) active control

Intervention 3: SMP enriched with GMP and G600 (1.5 g GMP protein (10% total protein) and 0.525 g G600 (3.5% of total protein weight))

Outcomes

Outcome assessments at 1, 2 and 3 months:

Primary endpoint: change in frequency of gout flares

Secondary endpoints:

1. Change in swollen joint count (/66)

2. Change in tender joint count (/68)

3. Pain (10‐point Likert), (scored 0 to 10) where 0 (no pain) and 10 (severe pain)

4. Patient global assessment (0 to 100), where 0 (very well) and 100 (very poor)

5. C‐reactive protein (CRP) (mg/l)

6. Serum uric acid concentration (mmol/l)

7. Fractional excretion of UA (%)

8. Health Assessment Questionnaire (HAQ‐II), 10‐item questionnaire, each item scored from 0 (without any difficulty) to 3 (unable to perform). Sum of the scores of each questionnaire item is divided by the number of questions answered to obtain a value between 0 (minimal loss of function) and 3 (completely disabled)

9. Open‐ended enquiry to elicit adverse events

Notes

Unpublished data (HAQ results) sought and received from the study author

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized using a random block randomization algorithm"

Allocation concealment (selection bias)

Unclear risk

Quote: "Participants and study staff were blinded to treatment allocation throughout the study..." Comment: insufficient details provided of the actual method of allocation concealment to intervention. No further information obtained in spite of attempts to contact the study author.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The products were dry‐blended and packed into identical, custom‐made aluminium foil sachets...Each intervention was a cream‐coloured powder administered daily as a 250 ml vanilla flavoured shake"

Blinding of outcome assessment (detection bias)
Patient assessed outcomes

Low risk

1. Gout flare frequency

2. Patient global assessment

3. Health assessment questionnaire (HAQ‐II)

Blinding of outcome assessment (detection bias)
Examiner assessed outcomes

Unclear risk

1. Tender joint count

2. Swollen joint count

3. Adverse events

Quote: "Study staff were blinded to treatment allocation throughout the study..." Comment: although not explicitly stated, it was implied from the aforementioned statement that outcome assessors were blinded. No further clarification was available despite attempts to contact the study author.

Blinding of outcome assessment (detection bias)
Laboratory assessed outcomes

Unclear risk

1. Serum urate concentration

2. Fractional excretion of uric acid

3. C‐reactive protein

Quote: "Study staff were blinded to treatment allocation throughout the study..." Comment: although not explicitly stated, it was implied from the aforementioned statement that outcome assessors were blinded. No further clarification was available despite attempts to contact the study author.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "Of the 120 patients enrolled in the study, two patients discontinued due to adverse events, eight were lost to follow‐up, and eight continued in the study without taking the milk products after experiencing an adverse event (intention to treat). One hundred and two patients completed the study as per protocol." Comment: distribution of drop‐outs between groups not specified. No further clarification was available despite attempts to contact the study author.

Selective reporting (reporting bias)

Unclear risk

Comment: all prespecified outcomes reported. There was selective reporting of a post hoc comparison between SMP/GMP/G600 and lactose powder control on change in gout flare frequency and lowering of diastolic BP.

Other bias

Unclear risk

Quote: "The study was registered as a clinical trial with the Australian New Zealand Clinical Trials Registry (ACTRN12609000479202)". COI: "This work was funded by LactoPharma (a joint venture between Fonterra Ltd, Fonterra R&D Ltd and Auckland UniServices Ltd) and the New Zealand Government Foundation for Research Science and Technology. Barbara Kuhn‐Sherlock, Alastair MacGibbon and Kate Palmano are employees of Fonterra Co‐operative Group Ltd. Alastair MacGibbon, Nicola Dalbeth and Kate Palmano are named inventors on a patent application related to milk products and gout."