German Clinical Trials Register

Acronym/abbreviation of the study

No Entry

URL of the study

No Entry

Brief summary in lay language

It is a non-interventional, single-center, clinical trial to determine drug adherence to tolvaptan therapy for autosomal dominant polycystic kidney disease (ADPKD). The study will enroll ADPKD patients who have entered Tolvaptan's approval trials and are currently receiving treatment with Jinarc® (tolvaptan). The determination of therapy adherence to tolvaptan is carried out with questionnaires. Further examination parameters is renal function.

Brief summary in scientific language

The autosomal dominant polycystic kidney disease (ADPKD) is a highly life-threatening, chronic and progressive genetic disease of the kidneys, which leads to kidney failure. The quality of life of those affected is limited with the progression of the disease more and more. Characteristic of ADPKD is the formation and steady expansion of fluid-filled cysts in the kidneys, resulting in a significant increase in kidney volume. Cyst growth causes progressive kidney damage, which in most patients ultimately leads to terminal kidney failure between the ages of 50 and 60 years. ADPKD patients usually suffer from hypertension, hematuria and proteinuria. Abdominal and flank pain may occur, occasionally also cyst infections with sometimes severe course. In addition, extrarenal cyst formation (especially in the liver), intracranial aneurysms, heart valve changes and colonic diverticulosis are possible. In approximately 85% of patients with ADPKD, there is a mutation of the PKD1 gene and in the majority of other cases of the PKD2 gene [1]. The mutation leads to an upregulation of cyclic adenosine monophosphate (cAMP), which is further enhanced by vasopressin [1, 2]. The increased cAMP promotes the formation and enlargement of renal cysts. Vasopressin is thus a decisive factor for the progression of ADPKD [3, 4]. The steady cyst growth leads to the progressive loss of functional nephrons. If the compensation capacity of the remaining nephrons is no longer sufficient, the kidney function is impaired. Jinarc® (tolvaptan) is the first European-approved drug for adult ADPKD patients with renal insufficiency stage 1-4 at baseline with signs of rapid disease progression (JINARC Specialist Information, as of September 2018). Tolvaptan is a selective vasopressin 2 receptor antagonist that reduces renal dysfunction and reduces renal cyst growth. Tolvaptan specifically blocks the binding of vasopressin to the vasopressin2 receptor in the tubular epithelial cells of the distal sections of the nephron. The binding affinity of tolvaptan to this receptor is 1.8 times higher than that of the body's own vasopressin. Vasopressin (also known as antidiuretic hormone, ADH) regulates water retention in the body (and therefore urine concentration) by activating water reabsorption in kidney tubes (antidiuresis). ADPKD is caused by mutation of PKD1 or PKD2 genes and others. to an upregulation of the vasopressin2 receptor and thus to an overactive vasopressin signaling. The resulting increase in cAMP promotes the formation and growth of cysts in the kidneys via the protein kinase A signaling pathway [1, 2, 3, 4, 5]. By displacing vasopressin at the vasopressin2 receptor, tolvaptan reduces cAMP production, resulting in a decrease in cell proliferation, cyst formation, and cyst growth, as well as increased water excretion. The efficacy and safety of tolvaptan in the treatment of autosomal dominant polycystic kidney disease was examined in particular in the TEMPO clinical program (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes). The multi-center, randomized, double-blind, placebo-controlled parallel-arm Phase 3 study (TEMPO 3: 4) enrolled 1445 ADPKD patients aged 18-50 years [6]. The primary endpoint was the annual change in the Total Kidney Volume (TKV). A secondary endpoint was the change in renal function. In the tolvaptan group, there was a significantly lower annual increase in total kidney volume of 2.8% compared to 5.5% (p <0.001) in the control group. In the tolvaptan-treated group, the loss of renal function (measured as the reciprocal of the serum creatinine level) was 1.2 mg / ml lower per year compared to placebo (p <0.001). Between March 2007 and January 2009, the inclusion of patients with autosomal dominant polycystic kidney disease in the TEMPO 3: 4 study, which was completed in January 2012, and the efficacy and safety of the vasopressin2 receptor antagonist tolvaptan took place at the University Hospital Carl Gustav Carus at the TU Dresden in the treatment of ADPKD. At the Dresden University Hospital, most of the participants in the TEMPO 3: 4 study also participated directly in the TEMPO 4: 4 study, which started in May 2010 and was completed in March 2016 [7]. In this open-label study, all study participants were treated with tolvaptan. The results of the TEMPO 4: 4 study were able to confirm the influence of tolvaptan on the eGFR. Since August 2016, Jinarc® (tolvaptan) is now available as an approved drug for the treatment of ADPKD patients with signs of a rapid disease progression in Germany. Tolvaptan therapy requires a high level of therapeutic adherence due to its strong aquaretic effect. According to a drug-induced diabetes insipidus renalis daily drinking amounts of up to 8 liters are necessary to compensate for the renal fluid loss. So far, no study is available to investigate the adherence of ADPKD patients to tolvaptan therapy. We want to know if there are correlations in our cohort of long-term tolvaptan-treated ADPKD patients between: 1. Therapy adherence and frequency of urological complications (gross hematuria, flank pain, cyst infections). 2. Therapy adherence and development of renal function (Δ eGFR). 3. Therapy adherence and development of normalized total kidney volume (Δ htTKV). The primary outcome is the therapy predisposition. Secondary outcomes are the frequency of urological complications (gross hematuria, flank pain, cyst infections), the development of renal function (Δ eGFR), and the development of normalized total kidney volume (Δ htTKV) in the subgroup of patients at the individual decision of the physician New onset symptoms (renal pain, gross hematuria) during the study have been followed by computed tomography (CT) or magnetic resonance imaging (MRI) of the kidneys. The experimental design is planned as follows: A patient with ADPKD, who has participated in both the TEMPO 3: 4 (Verum Group) and TEMPO 4: 4 trials and is currently receiving treatment with Jinarc® (tolvaptan), will be included as part of his routine visit to the Nephrological Outpatient Clinic in Dresden after detailed information and written consent included in the study. On the day of study enrollment, questionnaires will be provided to the patient to determine the therapy adherence to tolvaptan. The questionnaires are the German versions of the "Satisfaction with Information on Medicines Scale" (SIMS) [8] and the "Medication Adherence Report Scale" (MARS) [9]. To determine the urological complications (gross hematuria, flank pain, cyst infections), a questionnaire is also provided. As part of the routine presentation in the nephrological outpatient department, the determination of the eGFR according to CKD-EPI is regularly carried out by blood sampling. This routine clinical parameter (no blood-related studies!) will be used to assess current renal function in the study. The questionnaires will be returned to the next routine appointment in the nephrological outpatient department by the study participants. If unclear kidney complaints such as pain, gross hematuria or suspected complicated renal cyst infection occur during the study, the decision to carry out a CT or MRI of the kidneys is made after individual medical consideration. On the basis of the CT or MRI examination, the current htTKV is calculated in addition to the clarification of the underlying pathology. The study will include ADPKD patients who have participated in both the TEMPO 3: 4 (Verum Group) and TEMPO 4: 4 trials and are currently receiving treatment with Jinarc® (tolvaptan). literature [1] V. E. Torres, P.C. Harris, and Y. Pirson, "Autosomal dominant polycystic kidney disease," Lancet, vol. 369, no. 9569, pp. 1287-1301, Apr. 2007. [2] K.M. Dell, "The spectrum of polycystic kidney disease in children.," Adv. Chronic Kidney Dis., Vol. 18, no. 5, pp. 339-47, Sep. 2011th [3] J.J. Grantham, S. Mulamalla, and K.I. Swenson-Fields, "Why kidneys fail in autosomal dominant polycystic kidney disease.," Nat. Rev. Nephrol., Vol. 7, no. 10, pp. 556-66, Aug. 2011. [4] E. Meijer, W.E. Boertien, R. Zietse, and R.T. Gansevoort, "Potential deleterious effects of vasopressin in chronic kidney disease and especially autosomal dominant polycystic kidney disease.," Kidney Blood Press. Res., Vol. 34, no. 4, pp. 235-44, 2011. [5] V. Takiar and M.J. Caplan, "Polycystic Kidney Disease: Pathogenesis and Potential Therapies.," Biochim. Biophys. Acta, vol. 1812, no. 10, pp. 1337-43, Oct. 2011th [6] VE Torres, AB Chapman, O. Devuyst, RT Gansevoort, JJ Grantham, E. Higashihara, RD Perrone, HB Krasa, J. Ouyang, and FS Czerwiec, "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease," N Engl. J. Med., Vol. 367, no. 25, pp. 2407-2418, 2012. [7] V. E. Torres, A. B. Chapman, O. Devuyst [8] R. Horne, M. Hankins, and R. Jenkins, “The Satisfaction with Information about Medicines Scale (SIMS): A new measurement tool for audit and research,” Qual. Heal. Care, vol. 10, pp. 135–140, 2001. [9] C. Mahler, K. Hermann, R. Horne, S. Ludt, W. E. Haefeli, J. Szecsenyi, and S. Jank, “Assessing reported adherence to pharmacological treatment recommendations. Translation and evaluation of the Medication Adherence Report Scale (MARS) in Germany.,” J. Eval. Clin. Pract., vol. 16, no. 3, pp. 574–9, Jun. 2010.