Table 2.

Protocol amendments for the IMPROVE-CKD study

Issue and version of protocol	Albuminuria/proteinuria; changes between protocol versions 1.0 and 2.0	Serum phosphate level; changes between protocol versions 1.0 to 2.0 and 3.0	Pulse wave velocity; changes between protocol versions 2.0 and 3.0
Protocol amendment	Initial inclusion criteria were urine albumin/creatinine ratio (ACR)>10 mg/mmol or protein/creatinine ratio (PCR)>15 mg/mmol. These criteria were subsequently removed.	Inclusion criterion was initially for serum phosphate level>1.2 mmol/L (3.72 mg/dL) at screening, but was changed to>1.2 mmol/L on at least one occasion over the previous 6 months. The serum phosphate level was then subsequently reduced from>1.2 to>1.0 mmol/L (3.10 mg/dL) on at least one occasion over the previous 6 months.	Exclusion criterion was added as inability to obtain a PWV measure.
Rationale for change	The initial introduction of these criteria was to increase the proportion of CKD 3b/4 subjects who were at greater risk of cardiovascular disease as well as increased risk of progression of renal impairment. Review of screening logs showed that albuminuria/proteinuria were the the most common exclusion criteria; therefore, these were removed as they were not considered essential, posed a significant impediment to recruitment and the population for recruitment was already deemed at increased cardiovascular risk regardless of albuminuria/proteinuria. Also, for this study, pulse wave velocity (PWV) is the primary surrogate end-point and there is only one publication which links albuminuria/proteinuria to PWV, so this association is not considered significant.46	The window for serum phosphate results to screen eligible patients was initially changed to be within the previous 6 months due to fluctuations above and below levels of 1.2 mmol/L. This change was made to improve study recruitment by broadening the population of suitable participants. Trial screening log review continued to show that this inclusion criterion was a major barrier to patient eligibility for the study and therefore the level was reduced to 1.0 mmol/L. This change was not thought to adversely affect the study outcomes because although the study is using a phosphate binder as an intervention, the primary purpose of the study is the attenuation of cardiovascular outcomes. A lower phosphate level was added as an exclusion criterion to ensure that patients with very low phosphate levels are not included into the study where further phosphate reduction may adversely affect their health.	As the trial progressed, a small percentage of the population was noted on whom a PWV reading could not be obtained. This was therefore added as an exclusion criterion in order to ensure the power of the study is not compromised by including individuals whose PWV is unattainable at screening. It is increasingly recognised that even for experienced operators, there is a small percentage of the population on whom PWV cannot be obtained. This has been documented on other studies.47–49

IMPROVE-CKD, Impact of Phosphate Reduction On Vascular End- points in CKD.