Effects of Veverimer on Serum Bicarbonate and Physical Function in Diabetic Patients With Chronic Kidney Disease and Metabolic Acidosis

Subgroup Analysis From a Randomized, Controlled Trial

Vandana S. Mathur; Elizabeth Li; Donald E. Wesson

Disclosures

Nephrol Dial Transplant. 2022;37(7):1302-1309. 

In This Article

Materials and Methods

Methods for this study have been previously reported[13] and are briefly summarized below.

Study Design

This was a multicenter, randomized, blinded, placebo-controlled 40-week extension study of our 12-week parent study[14] conducted at 29 sites in 7 countries (TRCA-301E NCT03390842). The study protocol was approved by each site's institutional review board or ethic committee and appropriate regulatory authorities. Each patient gave his or her written informed consent prior to participation in the trial. Patients who continued from the parent study into the extension study did so with no gap in their study treatment and they continued the same blinded treatment they had received in the parent study. Following enrollment, scheduled visits were conducted at Weeks 14, 16, 20, 24, 28, 34, 40, 46 and 52 (Supplementary data, Figure S1).

Patients

Patients with CKD [estimated glomerular filtration rate (eGFR) 20–40 mL/min/1.73 m2] and metabolic acidosis (serum bicarbonate 12–20 mmol/L) were enrolled into the parent study and randomized 4:3 to veverimer (TRC101) or placebo by an interactive web-based response system. Eligibility was based on three qualifying bicarbonate values and two qualifying screening eGFR values not different by >20% and in the range of 20–40 mL/min/1.73 m2. Hemoglobin A1c at screening was required to be ≤9.0%. Eligibility for the extension study required completion of the 12-week parent study. Patients were excluded from participation if they: had a serum bicarbonate concentration low enough to need emergency intervention or had an assessment for an acute acidotic process; required dialysis for acute kidney injury or worsening CKD during the parent study; planned kidney replacement therapy within 6 months; had clinically significant diabetic gastroparesis, bariatric surgery, bowel obstruction, swallowing disorders, severe gastrointestinal disorders, inflammatory bowel disease, major gastrointestinal surgery or active gastric or duodenal ulcers or both.

Procedures

The starting study drug dose in the parent study was 6 g of veverimer once daily (two packets per day) or placebo once daily (two packets per day). Both were administered orally as a suspension in 60 mL of water. The study drug dose was algorithmically titrated by the interactive response technology system in the range of 0–9 g/day (or equivalent number of placebo packets) to a target serum bicarbonate concentration of 22–29 mmol/L based on bicarbonate measurement at each visit. Venous blood gases were also assessed at each visit. Background use of oral alkali supplements was permitted at a stable dose in the parent study and continued into the extension study. To avoid the long-term sodium or potassium load with oral alkali treatment in the extension study, the alkali dose was discontinued once the serum bicarbonate increased to ≥22 mmol/L. There were no protocol-specified dietary restrictions. Dietary counseling was provided to patients in accordance with dietary recommendations for patients with CKD [e.g. Kidney Disease Improving Global Outcome (KDIGO) 2012].[15] Bicarbonate measurements were made using a calibrated iSTAT Handheld Blood Analyzer (Abbott Point of Care, Princeton, NJ, USA). All other clinical laboratory measurements were done by a central laboratory. Management of glycemic control was at the discretion of the investigator.

The Kidney Disease and Quality of Life Short Form-36, question 3-Physical Function Domain (KDQoL-PFD) and standardized repeated chair stand test were administered at baseline and Weeks 12, 40 and 52. The KDQoL-PFD (Supplementary data, Figure S2) was forward and backward translated, linguistically validated (including clinician's review) and culturally adapted. The paper questionnaires, consisting of 10 questions, were completed by patients by themselves, while at the study site. Patients responded to the question: 'The following items are about activities you might do during a typical day. Does your health now limit you in the activities? If so, how much?' Answer choices were 'yes, limited a lot', 'yes, limited a little' and 'no, not limited at all'.

The five-repetition chair stand test, a component of the Short Physical Performance Battery, was administered by study site personnel using a verbatim written script (in the patient's spoken language) to instruct patients during the test. The time for a patient to complete five repeated sit–stands with arms folded across the chest from an armless chair was measured with a stopwatch.

The primary endpoint for the extension study was the long-term safety based on the incidence of adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Secondary endpoints (analyzed in pre-specified rank order) compared veverimer versus placebo at Week 52: achieving a ≥ 4 mmol/L increase from baseline in serum bicarbonate or a serum bicarbonate in the normal range (22–29 mmol/L); the change from baseline in serum bicarbonate to Week 52; the change from baseline to the Week 52 visit in total KDQoL-PFD score; and the change from baseline to the Week 52 visit in the time to complete the repeated chair stand test. Baseline serum bicarbonate was determined in the parent study as the mean of the serum bicarbonate values from Screening 1, Screening 2 and Day 1 (pre-dose) visits. Baseline values of total KDQoL-PFD score and repeated chair stand test were the measurements taken at the Day 1 (pre-dose) visit in the parent study.

AEs were identified by several methods. Patients were questioned at every study visit about any adverse effects they had experienced. Additionally, investigators were required to report any AEs revealed from physical examination, laboratory tests, electrocardiogram findings and other assessments.

The study patients were required to return all used and unused packets of the study drug at each visit. The compliance was calculated based on the returned empty packets and expected usage.

Statistical Methods

The safety analysis set was defined as all patients who received any amount of study drug (veverimer or placebo) in the extension study and was used for assessments of safety. A modified intention-to-treat analysis set, defined as all randomly assigned patients who had both baseline and at least one post-baseline serum bicarbonate value in the parent study and at least one serum bicarbonate value after the Week 12 visit in the extension study, was used for evaluation of efficacy (secondary endpoints), based on planned treatment assignment. To control family-wise error rate, hypothesis testing for the four durability-of-effect (secondary) endpoints was pre-specified to be done sequentially, with subsequent tests only being done when all previous tests were statistically significant at the two-sided 0.05 level: responder analysis at Week 52 using the Fisher's exact test; change from baseline to Week 52 in serum bicarbonate using a mixed model for repeated measurements; change from baseline to Week 52 in the total KDQoL-PFD score using a rank-based analysis of covariance (ANCOVA) model; and change from baseline to Week 52 in the duration of the repeated chair stand test using a rank-based ANCOVA model.

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