Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments

Abstract

Background: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme.

Methods: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety.

Results: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103.

Conclusions: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA.

Trial registration: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.

Keywords: Gastrointestinal tolerability; Palatability; Plasma bicarbonate; Plasma potassium; dRTA.

Graphical abstract

Fig. 1

Design of the study. D day, h hour, PC phone call, SP study period, SS steady state, t0 timepoint before first morning dose

Fig. 2

Steady state mean (± SD) plasma bicarbonate levels in the different age groups before administration of the first morning dose of SoC (multiple daily intakes) and ADV7103 (morning and evening), ITT set. Blue bars: SoC, orange bars: ADV7103

Fig. 3

Steady state mean (± SD) plasma potassium levels in the different age groups before administration of the first morning dose of SoC (multiple daily intakes) and ADV7103 (morning and evening), ITT set. Blue bars: SoC, orange bars: ADV7103

Fig. 4

Percentage of patients for each a palatability and b gastrointestinal discomfort response category. Patient/parent-rated VAS or FHS scores translated into five categories. Blue bars: SoC, orange bars: ADV7103