Table 3 Protocol amendments

Inclusion criteria

1. Males and females aged 40 to 64 years old.

2. Significant knee pain on most days (defined as a visual analogue scale (VAS) greater than or equal to 40mm).

3. Meet American College of Rheumatology (ACR) clinical criteria for knee osteoarthritis confirmed by a rheumatologist.

4. Any knee effusion-synovitis present on MRI.

5. Are willing to participate in the study for 6 months.

One inclusion criterion added:

Participants who are screened via Telehealth must have radiographic knee osteoarthritis defined as joint space narrowing or an osteophyte present (score ≥1 on the OARSI atlas).

The protocol has been updated to accommodate Telehealth visits. This is to minimise the impact of COVID-19 on recruitment and retention. Our preference will continue to be face-to-face clinic visits; however, if this is not possible, a Telehealth option will be available. All participants screened via Telehealth will have to have osteoarthritis confirmed on an x-ray, to minimise the risk of enrolling a patient without the condition of interest.

Dose of intervention

Participants will start the trial taking one capsule daily with food, containing 50 mg of diacerein, for the first 2 weeks. This will then be increased to two capsules daily with food, equating to 100 mg of diacerein, to be taken for the remainder of the 24-week trial.

Participants will be allowed to reduce their dose from 100 mg/day to 50 mg/day anytime during the trial after consulting with the medical doctor at each site.

Some participants have experienced side effects that prohibit them from increasing their dosage at week 2. Moreover, the effect of diacerein on pain improvement does not appear to be dose-responsive. For example, the literature suggests that 50 mg/day has a similar efficacy compared to 100mg per day (− 15.6 vs − 18.3) [37].

Statistical analysis

1. If there are baseline imbalances between treatment groups, we will consider adjusting for them based on whether we regard the imbalance as clinically significant.

2. Per protocol analyses will be performed as the secondary analyses, for study participants consuming ≥80% of capsules.

1. We will adjust for the baseline values of the corresponding outcome measure (e.g. change in pain scores will be adjusted for baseline pain scores). We will also run a model that additionally adjusts the primary outcome for sex, analgesic medication, and depression.

2. Per protocol analyses will be performed as the secondary analyses, for study participants consuming ≥80% of study medication between baseline and week 24 (allowing for 1 capsule (50 mg) per day).

For item 1, the trial statistician, along with the data safety monitoring board and steering committee recommended some minor changes to the statistical analysis plan, to adhere to best practice in RCT analysis.

For item 2, this is an update to reflect the change in dose of intervention (see above).