Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical Trials: A Critical Appraisal

Fig. 1.1

Flow-chart summary of literature search and study selection

We found 22 RCTs to date (11 June 2014) on ADPKD management (Table 1.1). Most (16 of 22) of the studies were published over the current decade (2010 and onwards), six were published in the last decade (2000–2009), and only one study was conducted prior to the year 2000, and this was a subgroup analysis from the modification of diet in renal disease (MDRD) study that comprised ADPKD patients in almost a quarter of its study population.

The trials fell within six therapeutic categories:

Blood pressure lowering medications – 7 trials

Low-protein diet – 1 trial

Statins – 3 trials

mTOR inhibitors – 6 trials

Vasopressin receptor antagonists – 1 trial

Somatostatin analogues – 4 trials

Five major studies out of the total 22 published clinical trials were selected for a full appraisal based on their quality and rigorous methodological framework (Table 1.1). The remaining studies, which scored relatively poorly due to their small sample sizes, inadequate follow-up, suboptimal study designs, and/or lack of rigor in conduct, were not appraised in further details (Table 1.1).

Table 1.1

Summary of clinical appraisal scores for all the randomized controlled trials conducted in ADPKD

Trial No.	Intervention	Study with reference	Design	N	Intervention	Comparator	Follow-up	End points	Score %	Conclusions and comment
1	mTOR inhibitors	Stallone et al. [26]	Open label	55	Rapamycin + Ramipril	Ramipril alone	24 months	Total kidney volume, cyst volume, eGFR		Rapamycin reduced cyst volume Limited by:
										Open label – unblinded
										Short duration of follow-up
										Small sample size
										Use of surrogate end points
2	mTOR inhibitors	Soliman et al. [27]	Single blind, placebo controlled	16	Sirolimus + telmisartan	Telmisartan + placebo	24 months	Total kidney volume		Sirolimus slowed increase in total kidney volume in the first 6 months only
										Limited by:
										Lack of randomization
										Small sample size and inadequate power
										Surrogate end point
3	mTOR inhibitors	Walz et al. [7]	Double blind, placebo controlled	433	Everolimus	Placebo	24 months	Total kidney volume, cyst volume, parenchymal volume, eGFR	+13 %	See Appraisal
4	mTOR inhibitors	Serra et al. [11]	Open label	100	Sirolimus	No treatment	18 months	Total kidney volume, eGFR	+0 %	See Appraisal
5	mTOR inhibitors	Perico et al. [28]	Open label, crossover	21	Sirolimus	Conventional antihypertensives	6 months	Total kidney volume, cyst volume, eGFR		Sirolimus halted cyst growth and increased parenchymal volume Limited by:
										Open label and not blinded
										Small sample size and inadequate power
										Short follow-up period
										High dropout rates
										Use of surrogate end points
6	mTOR inhibitors	Braun et al. [29]	Open label	30	Rapamycin (low dose, standard dose)	Conventional anti-hypertensives	12 months	Total kidney volume, mGFR (iothalamate clearance)		Low-dose rapamycin increased mGFR
										Limited by:
										Open label and unblinded
										Small sample size and inadequate power
										Short duration of follow-up
7	Vasopression receptor antagonists	Torres et al. [13]	Double blind, placebo controlled	1,445	Tolvaptan	Placebo	36 months	Total kidney volume, eGFR	+62 %	See Appraisal
8	Somatostatin	Hogan et al. [30]	Double blind, placebo controlled	34	Octreotide	Placebo	12 months	Liver volume changes		Octreotide slowed increase in total kidney volume
								Total kidney volume, eGFR, quality of life		Limited by:
								Total kidney volume, eGFR, quality of life		Study not powered to detect renal changes
9	Somatostatin	Hogan et al. [31]	Open label	34	Octreotide	Placebo	12 months	Liver volume changes		The previous benefit on total kidney volume was not sustained with an additional 1 year of treatment
								Total kidney volume, eGFR, quality of life		Limited by:
								Total kidney volume, eGFR, quality of life		As above, not primarily a kidney study
10	Somatostatin	Ruggenenti et al. [22]	Double blind, placebo controlled, crossover	14	Long-acting octreotide	Placebo	6 months	Total kidney volume, cyst volume, parenchymal volume, mGFR (iohexol clearance)		Octreotide slowed increase in total kidney volume and cyst volume
										No difference in mGFR
										Limited by:
										Very small sample size and inadequate power
										Follow-up period of 6 months may have been sufficient to measure health-related quality of life changes but not to detect changes in GFR
11	Somatostatin	van Keimpema et al. [32]	Double blind, placebo controlled	32	Long-acting lanreotide	Placebo	6 months	Primary end-point liver volume		Lanreotide slowed increase in total kidney volume
								Total kidney volume, cyst volume, parenchymal volume, eGFR		Limited by:
										Primary end-point liver volume
										Study not powered to detect renal changes
12	Low-protein diet	Klahr et al. [33]	Unblinded	200	Low-protein diet	Normal protein diet	26 months	eGFR and mGFR (iothalamate)		In patients with GFR 13–24, low-protein diet slowed renal disease progression
										This is a subgroup analysis of the MDRD study, therefore not powered to detect changes in subgroups such as ADPKD
										At best hypothesis generating
13	Statin	Fassett et al. [19]	Open label	60	Pravastatin	No treatment	24 months	eGFR, urinary protein excretion		No changes with treatment
										Limited by:
										An open label trial which lends it to potential treatment bias during follow-up
										Small sample size and it is not clear whether the study sample had statistical power to answer the study question
										GFR not measured but estimated
14	Statin	van Dijk et al. [20]	Double blind, placebo controlled, crossover	10	Simvastatin	Placebo	4 weeks	iGFR (inulin clearance), effective renal plasma flow (PAH clearance)		Simvastatin increased renal plasma flow
										Limited by:
										The sample size was very small and power most likely to be inadequate
										This is a study primarily aimed at studying the functional and hemodynamic effects of statins in ADPKD
15	Statin	Cadnapaphornchai et al. [16]	Double blind, placebo controlled	110	Pravastatin + lisinopril	Placebo + lisinopril	36 months	HtTKV, UAE, LVMI	+73 %	See Appraisal
16	Anti-HTN	Nakamura et al. [34]	Unblinded	20	Telmisartan	Enalapril	12 months	BP, serum Cr, UAE		Telmisartan resulted in improved UAE
										Limited by:
										Open label trial which lends it to potential observer bias during follow-up
										Small sample size and it is not clear whether the sample had statistical power to answer the study question The use of surrogate end points further limits the clinical utility of the study findings; GFR not measured
										BP measured casually and not over 24 h; thus raising questions over accuracy of recordings
17	Anti-HTN	Ulusoy et al. [35]	Unblinded	32	Losartan	Ramipril	12 months	BP, GFR, LVMI		Both agents reduced BP and LVMI
										Limited by:
										Open label and unblended lending to observer bias
										Inadequate sample size to estimate impact on ADPKD progression
										Quality of BP measurements; BP measured casually and not over 24 h; thus raising questions over accuracy of recordings
										Method of CKD progression assessment; FGR not measured
18	Anti-HTN	Nutahara et al. [36]	Unblinded	49	Amlodipine	Candesartan	36 months	BP, creatinine clearance, UAE		Candesartan decreased UAE vs. amplodipine
										Limited by:
										Open label and unblinded lending to observer bias
										Inadequate sample size to detect changes in kidney function
										Quality of BP measurements; BP measured casually and not over 24 h; thus raising questions over accuracy of recordings
										GFR not measured
19	Anti-HTN	Ecder et al. [37]	Unblinded	24	Enalapril	Amlodipine	60 months	Mean arterial pressure, creatinine clearance, ACR		Enalapril decreased UAE
										Limited by:
										Open label and unblinded lending to observer bias
										Inadequate sample size to detect changes in kidney function
										Quality of BP measurements; BP measured casually and not over 24 h; thus raising questions over accuracy of recordings
										GFR not measured
20	Anti-HTN	Zeltner et al. [38]	Double blind	46	Ramipril	Metoprolol	36 months	BP, eGFR, ACR, LVMI		No difference in outcomes between ramipril and metoprolol in ADPKD
										Good BP control and monitoring (24 h ABPM) in both groups
										Limited by:
										Small sample size and inadequate power to show functional differences
										GFR was not measured
21	Anti-HTN	Schrier et al. [25]	Unblinded	75	BP target <120/80	BP target <135–140/85–90	84 months	LVMI, eGFR		Rigorous BP control decreased LVMI Limited by:
										Unblinded study
										Small sample size and inadequate power to detect renal functional changes
										High dropout rates
										GFR not measured
										24 h ABPM not recorded
22	Anti-HTN	van Dijk et al. [39]	Double blind, placebo controlled	104	Enalapril	Atenolol or placebo	36 months	mGFR (inulin)		Enalapril did not slow decline in mGFR vs. placebo or atenolol
										GFR measured by inulin clearance
										RPF measured by PAH clearance
										Limited by:
										Small sample size and inadequate power to detect renal functional changes, especially in ADPKD with normal renal function at onset
										24 h ABPM not recorded

ACR urinary albumin to creatinine ratio, ADPKD adult polycystic kidney disease, BP blood pressure, CKD chronic kidney disease, Cr creatintine, GFR glomerular filtration rate, eGFR estimated GFR, mGFR measured GFR, HTN hypertension, HtTKV height-adjusted total kidney volume, LVMI left ventricular mass index, mTOR mammalian target of rapamycin

Keywords: ADPKD, Clinical trials, Management, BP, Cysts growth, Novel agents

mTOR Inhibitors Trials

The inhibition of mTOR has proved to have antiproliferative effects in a number of experimental models and clinical disease characterized by dysregulated cell growth. One of the hypotheses behind the pathogenesis of ADPKD is that a dysregulation renal tubules proliferation leads to cystic dilatations. With that notion in mind, successful attempts have been made in experimental models of PKD to slow the progression of cystic expansion as well as the associated decline in kidney function by mTOR inhibition. This has led to a number of RCTs testing this hypothesis in humans with ADPKD.

Everolimus in patients with autosomal dominant polycystic kidney disease

Walz G, Budde K, Mannaa M, et al. N Engl J Med. 2010;363(9):830–40 [7]

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth.

Methods: In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months.

Results: Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P = 0.02) and between baseline and 2 years by 230 and 301 ml, respectively (P = 0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P = 0.27) and by 181 and 215 ml, respectively, after 2 years (P = 0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P = 0.003) and by 56 and 93 ml, respectively, after 2 years (P = 0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m² of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P = 0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups.

Conclusions: Within the 2-year study period, as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment.

Critical Appraisal

Parameters	Yes	No	Comment
Validity
Is the randomization procedure well described?		−1	Randomization was only described as 1:1 with the eligible patients assigned to either receive everolimus or placebo
Double blinded?	+2		Described as double blinded
Is the sample size calculation described/adequate?	+3		N = 433; exceeded requirement of N = 260 to detect a 50 % relative reduction in annual increase in total kidney volume, 90 % power and two-sided significance of 4 %. The sampling allowed for dropout and was larger than estimated SD
Does it have a hard primary end point?		−1	The primary outcome was a change in kidney volume measured on MRI and secondary outcomes of changes in cyst sizes and parenchymal volume at months 12 and 24 and in renal function at month 24
Is the end-point surrogate?	−2		Surrogate end points only
Is the follow-up appropriate?		−1	24-month follow-up period was likely insufficient to show any impact on disease progression towards ESRD
Was there a Bias?	−1		Early CKD patients only, all Caucasians and of younger age extraction
Is the dropout >25 %?	−1		~35 %: largely due to side effects associated with everolimus, including leukopenia, thrombocytopenia, and hyperlipidemia
Is the analysis ITT?	+3		Analysis was based on the initial treatment intent
Utility/usefulness
Can the findings be generalized?	+1		Included patients with stage I–III CKD and ADPKD diagnosed clinically or by MRI single kidney volume >1,000 mL only
Score		13 %	Study with major limitations

ADPKD adult polycystic kidney disease, CKD chronic kidney disease, GFR glomerular filtration rate, ITT intention to treat, MRI magnetic resonance imaging, SD standard deviation

Comments and Discussion

This trial by Walz et al. was a multicenter (patients were recruited from 24 academic centers in three countries – Germany, Austria, and France), double-blinded, placebo-controlled study aimed to assess the effect of everolimus in ADPKD progression (cyst growth). It was a 2-year trial and randomized 433 patients with ADPKD. Patients were given either everolimus 2.5 mg twice a day or placebo (control). Everolimus slowed the increase in total kidney volume (TKV) but not the decline in kidney function (worsening of eGFR) compared to placebo.

Despite its robust design and large sample size, the study has important limitations on several key fronts:

Limited generalizability: The study was focused on patients with early CKD (Stages 1–3), a group of patients with ADPKD that hardly progress. This coupled with the use of surrogate end points and the high incidence of everolimus adverse effects, and consequent high dropout rate of 35 % limits the application of these study findings to clinical practice. Further, the study was limited to younger patients with CKD (mean age of 44 years) and all whites. The implications of the study findings in patients with a more advanced disease, the elderly, and other racial backgrounds could not be ascertained.

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Jul 4, 2016 | Posted by admin in NEPHROLOGY | Comments Off

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical Trials: A Critical Appraisal

mTOR Inhibitors Trials

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Critical Appraisal

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical Trials: A Critical Appraisal

mTOR Inhibitors Trials

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Critical Appraisal

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