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Randomized Controlled Trial
. 2018 Mar 1;33(3):477-489.
doi: 10.1093/ndt/gfx043.

Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial

Vicente E Torres  1 , Arlene B Chapman  2 , Olivier Devuyst  3   4 , Ron T Gansevoort  5 , Ronald D Perrone  6 , Ann Dandurand  7 , John Ouyang  7 , Frank S Czerwiec  7 , Jaime D Blais  7 ; TEMPO 4:4 Trial Investigators
Affiliations
Randomized Controlled Trial

Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial

Vicente E Torres et al. Nephrol Dial Transplant. .

Abstract

Background: In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.

Methods: TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.

Results: Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). Adjusting for baseline covariates improved the TKV treatment difference at Month 24 in TEMPO 4:4 from -1.70% to - 4.15% between the groups (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4.

Conclusions: The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.

Trial registration: ClinicalTrials.gov NCT00428948.

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Figures

FIGURE 1
FIGURE 1
Subject disposition in TEMPO 4:4.
FIGURE 2
FIGURE 2
Percentage change in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 visit. Open circles and triangles represent off-treatment time points. Break in treatment from TEMPO 3:4 to TEMPO 4:4 ranged from 13 to 829 days from the Month 36 visit in TEMPO 3:4.
FIGURE 3
FIGURE 3
Change in eGFR from the TEMPO 3:4 baseline to the Month 24 visit of TEMPO 4:4. The inter-trial period is plotted as a 5-month interval, which approximates the 80th percentile of the treatment holiday (range 13–829 days). Open circles and triangles represent off-treatment time points.
FIGURE 4
FIGURE 4
Change from baseline in TKV and eGFR by gender. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for males (left panel) and females (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for males (left panel) and females (right panel). Open circles and triangles represent off-treatment time points.
FIGURE 5
FIGURE 5
Percentage change from baseline in TKV when adjusted for covariates. Open circles and triangles represent off-treatment time points. Blue and gray symbols are slightly offset for ease of interpretation. The following variables were included in an unstructured variance covariance matrix with fixed factors as in the primary analysis with the addition of copeptin and baseline covariates of age, gender, gender visit interaction, eGFR, eGFR visit interaction and urine ACR.
FIGURE 6
FIGURE 6
Change from baseline in TKV and eGFR by imaging classification. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in class 2A–B and 1B (left panel) and class 1C, D, E (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in class 2A–B and 1B (left panel) and class 1C, D, E (right panel). Open circles and triangles represent off-treatment time points.
FIGURE 7
FIGURE 7
Change from baseline in TKV and eGFR by genotype. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects with PKD2 (left panel), PKD1 non-truncating (NT, middle panel) and PKD1 truncating (T, right panel) genotypes. (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects PKD2 (left panel), PKD1 non-truncating (NT, middle panel) and PKD1 truncating (T, right panel) genotypes. Open circles and triangles represent off-treatment time points.
FIGURE 8
FIGURE 8
Change from baseline in TKV and eGFR by CKD stage. (A) Percent change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in CKD 1 (left panel) and CKD 2/3 (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in CKD 1 (left panel) and CKD 2/3 (right panel). Open circles and triangles represent off-treatment time points.
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References

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