Study of Tamsulosin for Urolithiasis in the Emergency Department
Phase: PHASE4
Conditions: Ureterolithiases
Sponsor: Andrew Meltzer

A Multi Center Randomized Trial to Study
Tamsulosin for Urolithiasis
in the Emergency Department
STONE
Protocol
Sponsored by:
National Institute of Diabetes and Digestive and Kidney Diseases
Prepared by the:
Division of Research
Department of Emergency Medicine
The George Washington School of Medicine
2150 Pennsylvania Ave NW, Suite 2B-409
Washington DC 20037
and
Data Coordinating Center
The Biostatistics Center
The George Washington University
6110 Executive Boulevard, Suite 750
Rockville, MD 20852
(301) 881-9260
September 4, 2015

Table of Contents
1
Introduction...........................................................................................................................................1
1.1
Introduction and Objectives .................................................................................................1
1.2
Primary Hypothesis ..............................................................................................................1
1.3
Purpose of the Study Protocol..............................................................................................1
2
Background...........................................................................................................................................2
2.1
Background and Significance...............................................................................................2
2.1.1
The Pharmacology of Tamsulosin........................................................................................2
2.1.2
46BGIADG?C 6C9 DH>;F R-1 blockers in the Medical Management of Urolithiasis.................4
2.1.3
Dosing ..................................................................................................................................8
2.2
Rationale for the Proposed Study.........................................................................................8
3
Study Design.......................................................................................................................................10
3.1
Primary Research Question................................................................................................10
3.2
Secondary Research Questions...........................................................................................10
3.3
Design Summary ................................................................................................................10
3.4
Eligibility Criteria...............................................................................................................10
3.4.1
Inclusion Criteria................................................................................................................10
3.4.2
Exclusion Criteria...............................................................................................................11
3.5
Randomization Method and Masking.................................................................................11
4
Study Procedures ................................................................................................................................13
4.1
Screening and Randomization............................................................................................13
4.2
Medical Treatment Protocol...............................................................................................13
4.3
Study Outcomes and Ascertainment ..................................................................................13
4.3.1
Primary Outcome................................................................................................................13
4.3.2
Secondary Outcomes..........................................................................................................13
4.4
Baseline Procedures............................................................................................................14
4.5
Patient Management and Follow-up...................................................................................14
4.5.1
CT scan at 29 days..............................................................................................................14
4.6
Adverse Event Reporting ...................................................................................................15
5
Statistical Considerations....................................................................................................................16
5.1
Data Relevant to the Primary Outcome..............................................................................16
5.2
Interim Analysis .................................................................................................................16
5.3
Analysis Plan......................................................................................................................17
5.3.1
Preliminary Analyses..........................................................................................................17
5.3.2
Testing of efficacy and safety outcomes ............................................................................17
5.3.3
Exploratory Analyses .........................................................................................................18
5.3.4
Statistical Complications....................................................................................................18
5.4
Sample Size and Power ......................................................................................................18
5.4.1
Sample size.........................................................................................................................18
5.5
Statistical Analyses.............................................................................................................19
6
Data Collection and Management.......................................................................................................21
6.1
Data Collection Forms........................................................................................................21
6.2
Web Data Entry System .....................................................................................................21
6.3
Centralized Data Management System...............................................................................21
6.4
Performance Monitoring ....................................................................................................21
7
Study Administration..........................................................................................................................23
7.1
Organization and Funding..................................................................................................23
7.2
Committees.........................................................................................................................23
7.2.1
Steering Committee............................................................................................................23
7.2.2
Data Safety Monitoring Board ...........................................................................................23

8
Study Timetable..................................................................................................................................24
8.1
Training and Certification ..................................................................................................24
8.2
Data Collection Period .......................................................................................................24
8.3
Final Analysis.....................................................................................................................24
APPENDIX A. DESIGN SUMMARY…………………………………………………………………...25
APPENDIX B. INFORMED CONSENT FORM…………………………………………………………26
REFERENCES…………………………………………………………………………………………….32

September 4, 2015
1 Introduction
1.1
Introduction and Objectives
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes
of Health (NIH) has sponsored a collaborative agreement to conduct a multi-center randomized Study
TamsulOsiN for urolithiasis in the Emergency Department (STONE study). This protocol describes the
background, design, and organization of the multi-center phase of the trial which follows the vanguard
phase performed at George Washington University Medical Center only.
1.2
Primary Hypothesis
The primary objective of this study is to determine the effect of tamsulosin on the proportion of patients
passing a kidney stone as determined by patient report.
1.3
Purpose of the Study Protocol
This protocol describes the background, design and organization of the multi-center phase of the
randomized clinical trial and may be viewed as a written agreement among the study investigators.
Before recruitment begins, the protocol is approved by the Steering Committee and the Institutional
Review Board (IRB) of each clinical center. Any changes to the protocol during the study period require
the approval of the Steering Committee and the IRBs.
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September 4, 2015
2 Background
2.1
Background and Significance
Kidney stones affect up to 15% of men and 7% of women in the United States.1 The incidence is variable
according to geographical location and season, and the concept of the “stone belt” -geographical locations
with unusually high incidences of urinary calculi- is well accepted. The highest incidence of stone disease
occurs in the south-eastern United States in the summer months. The incidence of stone disease is twice
as common in whites as in African-Americans and Asians, and is twice as common in males as in
females. The highest incidence seems to be the fourth decade of life.1 The economic impact of
urolithiasis is enormous; in 1986, more than $2 billion was spent on the treatment of kidney stones,
mostly for removal and fragmentation, even before widespread use of shock-wave lithotripsy.2 Until the
1980s, urinary stones were a major health problem, with a significant proportion of patients requiring
extensive surgical procedures and a sizable minority losing a kidney. One study showed that about 20%
of patients with recurrent stone disease who underwent surgery for obstruction and infection went on to
develop mild renal insufficiency.3 The advent of extracorporeal techniques for stone destruction and the
refinements in endoscopic surgery have greatly decreased the morbidity associated with stone surgery.
One unfortunate result of this technologic success is that advances in the medical management of stone
disease and research in prevention have languished.3 The current standard of care for acute
ureterolithiasis includes only pain medication. When this fails, the patient moves on to procedural
therapy with its inherent risks and expense. There is no currently accepted or practiced medical treatment
for these patients.
The goals of medical conservative therapy are to prevent modifiable factors and control painful symptoms
until stone expulsion. The stone size and the site, as well as the internal anatomical structure of the ureter
and a history of spontaneous stone expulsion all affect the likelihood of stone expulsion and are
unmodifiable factors.4-6 Factors which encourage stone retention are spasm, edema and ureteral infection,
which are modifiable.7 Therefore the administration of spasmolytic drugs, anti-edemics and antibiotics
are recommended by several groups, even in the absence of current specific guidelines.7-10
Nifedipine, steroids, and tamsulosin have been studied as potential medical treatments for nephrolithiasis.
Each of the three has shown promise and safety in small studies. We propose to study tamsulosin alone
rather than nifedipine and steroids. We believe that tamsulosin has a more favorable safety profile and is
therefore a better choice than nifedipine for an extensive study.
2.1.1
The Pharmacology of Tamsulosin
Tamsulosin is an antagonist of alpha-1 adrenoceptors. The empirical formula of tamsulosin
hydrochloride is C20H28N2O5S • HCl. It is readily absorbed from the gastrointestinal tract and exhibits
linear kinetics following single and multiple dosing. Steady state concentrations are achieved by the fifth
day of once-a-day dosing. The effects of food on the pharmacokinetics of tamsulosin are consistent.
Tamsulosin HCL is metabolized in the liver by cytochrome P450 enzymes and less than 10% is excreted
unchanged in the urine. The half-life of tamsulosin HCL in healthy volunteers is 9-13 hours.
Mechanism of Action
In 1970 Malin, et al noted adrenergic receptors in the human ureter11, and several studies have focused on
the role of the adrenergic system in ureteral physiology. In general, the induction of ureteral contraction
by alpha-adrenergic agonists is dose dependent.12 The main alpha-adrenergic agonist noradrenaline
induces a positive ionotropic effect, increasing muscle tone until causing complete ureteral obstruction
from spasm at high doses. Hence alpha-adrenergic stimulation decreases the volume of urine flow
2

September 4, 2015
through the ureter. The blockade of alpha-adrenergic receptors by a specific antagonist results in
decreased ureteral peristaltic amplitude and frequency with a consequent loss of intra-ureteral pressure
and, therefore, an increase in fluid transport ability.13 Further study revealed a prevalence of the alpha-
1d-adrenoceptor subtype in the human ureter.14 Tamsulosin is a combined alpha-1a and alpha-1d
selective antagonist, and it is most likely that its effect on the obstructed ureter is to induce an increase in
the intra-ureteral pressure gradient around the stone, by increasing the urine bolus (and consequently
increasing intra-ureteral pressure) above the stone, as well as decreasing peristalsis below the ureter (and
consequently decreasing intra-ureteral pressure below the stone), in association with a decrease in basal
and micturition pressures at the bladder neck.15, 16
Safety Profile
The first empirical use of R1-adrenoceptor antagonists in urology occurred about 25 years ago in patients
with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hypertrophy (BPH), or
LUTS/BPH.17 The subselectivity and pharmacodynamic properties of tamsulosin may provide
advantages in safety, tolerability, and administration compared with other alpha blockers, such as
terazosin and doxazosin. Unlike other alpha blockers, tamsulosin does not require titration to be
efficacious. Studies have shown that it has a minimal and usually clinically insignificant effect on blood
pressure in normotensive and hypertensive patients.18, 19 Dizziness and abnormal ejaculation are stated to
be the most common adverse events, with asthenia, postural hypotension and palpitations being seen less
frequently (1 to 2% incidence).20 Studies vary in the frequency of symptomatic postural hypotension,
with reports ranging from 0-2.5%.19, 21
A recent study reported safety experience with 1784 patients receiving 0.4 mg tamsulosin for six months
(with a total drug exposure time of 811 patient years).22 The most frequent adverse events are shown
below in Table 1. Intraoperative floppy iris syndrome has been reported frequently in patients on
tamsulosin undergoing cataract surgery. Complications from this syndrome can be minimized as long as
the ophthalmologist is aware that the patient is taking tamsulosin.23 In logistic regression analysis alpha-
blockers, converting enzyme inhibitors, diabetic medications and diuretics did not significantly affect the
odds ratio for having an adverse event. However, concomitant alpha-antagonists (a protocol violation)
and treatment with verapamil (which also has alpha-antagonist activity) significantly enhanced the odds
ratio for having an adverse event to 3.87 (CI 1.52-9.85) and 3.17 (CI 1.52-6.58), respectively. Minor
increases in the odds ratio, which did not reach statistical significance, were also observed for Ca2+
antagonists other than verapamil and for nitrates. In a study of 756 patients with benign prostatic
hypertrophy randomized to tamsulosin (0.4 and 0.8mg/day) or placebo, the incidence of positive
orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group.24
While there are differences in the incidence of various side effects among alfuzosin, doxazosin,
tamsulosin and terazosin, the overall side-effect profiles of these agents have been characterized as “very
similar” by the Alpha-Blocker Committee at the 4th International Consultation on BPH.25 The results of
seventeen trials examining the safety and efficacy of various alpha- blockers were reviewed by Lowe,
who concluded that therapy with these agents is “…well tolerated, and the majority of side effects with
alpha-blockers are mild to moderate, seldom causing patients to prematurely discontinue therapy”.26 The
blood pressure effects of tamsulosin are comparable to those of either terazosin27 or doxazosin,28 although
tamsulosin was associated with a lower level of nocturnal orthostatic hypotension.27
3

September 4, 2015
Table 1 Most frequent adverse events during a 6 months treatment
with 0.4 mg tamsulosin o.d.22
Adverse Event
N
%
(95% CI)
Dizziness
45
2.5
(1.85, 3.36)
Abnormal ejaculation
29
1.6
(1.09, 2.33)
Headache
29
1.6
(1.09, 2.33)
Hypotension
26
1.5
(0.95, 2.13)
Gastrointestinal disorder
18
1.0
(0.60, 1.59)
Nausea
17
1.0
(0.56, 1.52)
Cardiovascular disorder
11
0.6
(0.31, 1.10)
Impotence
10
0.6
(0.27, 1.03)
Dry mouth
9
0.5
(0.23, 0.96)
Sweating
9
0.5
(0.23, 0.96)
Arrhythmia
8
0.4
(0.19, 0.88)
Postural hypotension
7
0.4
(0.16, 0.81)
Pruritus
7
0.4
(0.16, 0.81)
Tamsulosin in women
The current approved indication for tamsulosin is in the treatment of benign prostatic hypertrophy.
Because of this, the drug has not been as widely studied in women. Acute renal colic is approximately
twice as common in men as it is in women. However, it is a disease of both sexes, and any medication
that is to find a wide application for the treatment of renal colic must be safe in both men and women. In
recent years there have been studies on the effects of tamsulosin in females, and it has been shown to be
safe and effective. Animal studies have demonstrated that the female canine and pig urethra has alpha-1a
adrenoreceptors and binds tamsulosin.29, 30 In a study of eleven healthy women volunteers, tamsulosin
significantly reduced the mean and maximal uretheral pressure over the entire urethra.31 There was no
effect on systemic blood pressure. A small trial of the effect of tamsulosin on urodynamic voiding
parameters in patients with neurogenic bladder recently published has shown the medication is safe and
effective in both men and women.32 The preliminary studies looking at tamsulosin as a treatment for
urolithiasis included both men and women, and reported no complications specific to women.16, 33 We
believe that the evidence from animal and human studies supports the hypothesis that tamsulosin should
be equally as safe and effective in women as it is in men.
2.1.2
Tamsulosin a%" &($#' )-1 blockers in the Medical Management of Urolithiasis
Since 2002 there have been a number of trials evaluating the medical management of nephrolithiasis.
Among the first was a study of tamsulosin with floroglucine-trimetossibenzene, (an antispasmodic
agent),16 In addition, all patients received 30mg deflezacort daily for ten days, in addition to cotrimazole
twice daily for eight days. The study was limited to those with a unilateral juxtavesical stone and patients
were followed for a maximum of one month. The tamsulosin group had a significantly quicker time for
stone expulsion (a mean of 66 hours versus 111 hours, p=.020, see below Figure 1) and a significant
reduction in analgesia requirements as measured by the need for intramuscular diclofenac (a mean of 2.83
4

September 4, 2015
versus 0.13 injections, p<0.0001). The tamsulosin group had no hospitalizations, compared with ten in
the antispasmodic arm, nine of whom underwent ureteroscopy (p<0.001).
Figure 1
These results strongly suggest a benefit from tamsulosin, but there are a number of methodological
problems with this study. Non-concealed allocation assignment rather than blinded randomization was
used. Furthermore, neither the patients, their treating clinicians, nor the individuals assessing outcomes
were blinded to treatment group assignment. A brief anonymous review of this study in the British
Medical Journal concluded that “even though this study is fraught with methodological shortcomings, it
seems highly likely that tamsulosin (Flomax) is effective in hastening the passage of juxtavesical ureteral
stones and decreasing both the severity and duration of renal colic”.34
A study 0 5*.'2$(. , %  *(& ," %(.$ )-%# /+ )-%#+" #' 

 " -,"(*+ *)(*,
improved outcomes in 51 patients treated with tamsulosin (0.4mg/day), when compared to a control
group.35 After one week of therapy, stone elimination was 80% in the tamsulosin group and 63% in the
control group. There are however, a number of methodological concerns and differences in treatment
approaches which make data from this trial difficult to generalize to the population in the United States.
For example, although the authors report this as a double blind study, it was not placebo controlled. All
the patients were hospitalized, and the treatment regimen included intravenous diazepam, although the
frequency is not specified. The authors fail to give a single confidence interval or p-value for their
results. All of this leads to the conclusion that while the study lends support to our hypothesis, it would
be inappropriate to treat patients in this country based on the Slovak approach. To our knowledge
however, this is only one of two small studies that has used tamsulosin without steroids for the treatment
of nephrolithiasis.
In 2005 Yilmaz published a study from Turkey which evaluated the effects of three different alpha-1
adrenergic blockers on the passage rate of distal ureteral stones.36 All three agents (tamsulosin, terazosin,
and doxazosin) were equally efficacious at increasing the frequency of spontaneous passage of distal
ureteral calculi. Moreover, the authors noted that there were no side-effects that led to a study subject
dropping from the study, and equally important, not one of the 114 patients in elected to have a surgical
intervention during the one month study period. Another interesting aspect of this study is that the
average stone size was 6.0 mm. In a study of American patients, Miller reported that 67% of patients
have a stone size less than 4 mm (see above section B3).5 While this difference in the two populations
cannot be easily explained, the results do add still further support to the hypothesis that tamsulosin will be
effective for stones even larger than 4 mm in diameter. Unfortunately the authors failed to provide a
power analysis, so the results cannot be easily generalized, and there was no study of the effect on those
5

September 4, 2015
patients with more proximal stones, which make up a sizeable minority of all patients with
ureterolithiasis.
In 2006, Hollingsworth reviewed nine randomized controlled trials (693 patients) which assessed the
efficacy of calcium-channel blockers or alpha blockers to treat urinary stone disease. 37 Patients given
calcium-channel or alpha blockers had a 65% greater likelihood of stone passage than those not given
such treatment. The pooled risk ratio in favor of the treatment group was 1.65 (95% CI: 1.45, 1.88,
p<0.0001); the absolute risk reduction was 0.31 (95% CI: 0.25, 0.38) and the number needed to treat
(NNT) was 4. In all trials the primary outcome of interest (the proportion of patients who passed stones)
occurred more often in the treatment group than in the control group. In 5 out of 6 trials the treatment
groups had shorter mean times to stone expulsion than the control groups. Of importance for our work
are the authors’ conclusions that despite these promising results, a definitive high-quality randomized
controlled trial is necessary to confirm the efficacy of alpha-blockers in patients with urolithiasis.
Hollingsworth suggested that such a study would involve 113 patients in each treatment arm to show a
significant effect (using the lower CI limit of the pooled relative risk 1.45, a background occurrence of
stone passage of 0.47, a two-sided alpha error of 0.05 and a power of 0.90); if the occurrence of stone
passage in the controls was lower (30%), the required sample would be 532 patients in total. This
suggested sample size is very similar to that initially calculated for our own study (see sample size section
5.4.1).
Singh performed a similar review in 2007, using a pooled analysis of 16 studies using an alpha blocker
and 9 using a calcium channel antagonist.38 He concluded that compared to standard therapy these agents
significantly improved spontaneous stone expulsion (alpha-antagonist RR 1.59; 95% CI 1.44 to 1.75;
NNT of 3.3 [95% CI 2.1 to 4.5]). Singh’s review concluded that because of the limitations of
methodological quality within the studies reviewed, a large, well-done, randomized, clinical trial is
needed to confirm these results before uniform adoption can be recommended. A similar call for a
randomized controlled trial was made in a Best Available Evidence review in the same issue of Annals of
Emergency Medicine as Singh’s paper.39 In a review of the cost effectiveness of medical expulsive
therapy (MET) using alpha-antagonists in a decision tree analysis, Bensalah calculated that using
tamsulosin would result in a cost advantage of $1,100 over observation alone.40 As such it was
recommended as a cost-effective strategy.
Parsons, who reviewed 11 trials, reported a meta-analysis of alpha blockers for ureteral stones in 2007.41
This analysis showed that compared to patients receiving conservative therapy only, patients receiving
conservative therapy plus alpha-blockers were 44% more likely to spontaneously expel the stones (RR
1.44, 95% CI 1.31 to 1.59, p<0.001), and stone expulsion incidence increased significantly (RD 0.28,
95% CI 0.22 to 0.34, p<0.001).
In 2009 Seitz performed a systematic review of 47 randomized control trials.42 Pooling of studies of
alpha-blockers and calcium channel blockers studies demonstrated a higher and faster expulsion rate
compared to a control group (risk ratio [RR]: 1.45 vs. 1.49; 95% confidence interval [CI]: 1.34–1.57 vs.
1.33–1.66). Additionally, lower analgesic requirements, fewer colic episodes, and fewer hospitalizations
were observed within treatment groups. Their forest plot for tamsulosin 0.4 mg. is shown below.
6

September 4, 2015
Table 2 Seitz’s Forest Plot
In an attempt to better understand why some studies did not show a significant benefit with respect to
chance of stone expulsion, they broke the trials down by mean stone size. Only 4 of 9 studies where this
was <5mm showed a significant benefit for alpha-blocker use whereas 19 of 20 where the mean stone size
K6G O 'BB G>DK;9 6C 69J6CH6=;# /H K6G >LEDH>;G?M;9 H>6H G?C8; GB6AA;F GHDC;G 6F; BDF; A?@;AL HD E6GG ?C
general, there was less chance of seeing a treatment effect. Interestingly, the studies that failed to show
an increased chance of stone expulsion still found more rapid and less painful stone passage.
Further analysis of the pooled data showed consistent decreases in time to stone passage, analgesic
requirement, need for hospitalization and days of work lost in patients treated with and alpha-blocker.
Safety of the various medications was noted to be excellent across all trials with minimal drop-out rates
due to adverse drug events.
The authors commented on the significant limitations of their meta-analysis primarily due to the fact that
most studies were small, single-institution trials typically lacking prior power calculation and proper
allocation concealment. In addition, the adjunctive usage of varying other medications (steroids,
NSAIDs), different durations of treatment and variability in radiographic study all led to moderate
heterogeneity of the data. A mild publication bias toward positive studies was noted. In conclusion, Seitz
too called for multicenter, randomized, placebo-controlled trials.
Negative studies
In 2009 Hermanns reported no difference in a study which compared tamsulosin to placebo for 21 days. 43
This study looked for a “clinically relevant difference in expulsion rate of 25%” and assumed that 65% of
patients would pass the stone without MET within 21 days. A total of 45 patients were allocated in each
of the two arms of the study. The primary end point (stone expulsion by day 21) was confirmed with
low-dose abdominal CT. The authors note that this study was the first randomized double blind placebo-
controlled study to evaluate MET, and it failed to find any difference in the rate of stone expulsion
between the two arms (placebo rate=88.9%, tamsulosin rate=86.7%). Although there was no difference
in the rate of expulsion, there was a trend to faster expulsion in the tamsulosin group, (median 7 days)
than in the placebo group (median 10 days), although this difference was not significant (p=0.36). There
was, however a significant difference in the number of analgesics required with patients in the tamsulosin
arm requiring less than those in the placebo arm (3 vs. 7, p=0.011). Of note was the large number of
patients (32%) in whom the time of stone passage was not known. It should also be noted that Hermanns
used a baseline passage rate at 21 days of 65%. In contrast to this passage rate, in Hollingsworth’s meta-
analysis the baseline expulsion rate across nine studies was 47%, with rates ranging from 20% to 73%.
Thus the baseline expulsion rate of 65% at 21 days seems high, and this may contribute to the negative
findings.
7

September 4, 2015
Another negative study was published in 2009 by Ferre, in which the primary outcome was stone
expulsion at 14 days.44 The study was randomized but not placebo-controlled, and was powered to detect
a 30% difference between the study groups. It found no difference between the two treatment arms to
which 40 patients each had been randomized. The authors note that this 30% difference was “rather
large”, it is therefore of little surprise that the study failed to detect this difference.
Vincendeau published the most recent negative study in 2010.45 This study was a multi center
randomized placebo controlled trial in which the primary outcome was a reduction in the mean length of
stone expulsion by 50% - from 16 to 8 days. The study randomized 129 patients, and failed to detect any
difference between the placebo and tamsulosin arms. We are not surprised at the negative finding, since
the study was looking for a very large clinical difference between the two groups – a difference even
larger than that in the study by Ferre. Furthermore and for an unexplained reason, the rate for stone
passage in the control group the study was substantially higher than the mean for the alpha-blocker
studies in the meta-analysis by Hollingsworth noted above. In addition all study patients were initially
hospitalized and all were given phloroglucinol, neither of which is standard practice in the US.
2.1.3
Dosing
The European pilot studies that have used tamsulosin for urolithiasis used a dose of 0.4 mg/day.16, 46 This
is also the recommended starting dose of tamsulosin when used for the treatment of benign prostatic
hypertrophy. Using this dose rather than 0.8 mg/day which is sometimes used in the treatment of BPH
will also minimize the risks of side effects from the medication.24
2.2
Rationale for the Proposed Study
The earlier work on the medical management of urolithiasis involved nifedipine and steroids, and was
performed in Europe on patients all of whom were admitted.8 Admission is not routine in the United
States unless there are complications (such as a solitary kidney, inability to manage pain, or superimposed
infection). Another European study performed on outpatients was not a placebo-controlled double blind
study, and involved weekly x-ray exposure and expensive ultrasound examination.7 Furthermore, the
studies have tended to be small, involving less than 50 patients in each arm. The most recently published
trial47 comparing an antispasmodic with tamsulosin or nifedipine was neither blinded or placebo
controlled, and did not examine any independent effect of steroids. The outpatient regimen involved
routine antibiotics, and intramuscular analgesia, which are not a routine part of patient management in the
USA.
A single US trial involving the use of steroids and nifedipine was published in 2000.9 However this trial
looked at these agents as part of an intensive medical management program, and other agents used
included routine antibiotics. This trial was not blinded and was performed in the private offices of
urologists. It involved on 35 patients in each arm of the trial, and there was no IRB oversight. It also had
no placebo arm. Although the addition of nifedipine and steroids resulted in a higher rate of stone passage
and fewer lost work days, the lack of appropriate blinding and the confounding addition of antibiotics
make it difficult to generalize from this study.
A European study involving tamsulosin and steroids was published in 2003.16 This was a very small pilot
study, with only thirty patients in each treatment arm, and non-concealed allocation assignment rather
than blinded randomization was used. Furthermore, neither the patients, their treating clinicians, nor the
individuals assessing outcomes were blinded to treatment group assignment. The authors concluded that
tamsulosin and steroids increased stone expulsion rate and reduced the need for surgical intervention.
A second small European study was recently published by Porpiglia.46 This compared nifedipine and
tamsulosin (each with steroids) to a control group. The three treatment arms were small (thirty patients or
8

September 4, 2015
less) and neither physician nor patients were blinded to treatment allocation. No placebo was used. The
authors concluded that both tamsulosin and nifedipine with steroids were safe and improved outcomes,
but that tamsulosin with steroids was a superior therapy. There has been no attempt in any of the previous
studies to evaluate the role of steroids separately from that of either tamsulosin or nifedipine.
To date there has been only one published study looking at the effects of tamsulosin alone.35 Although
this study showed improved outcomes in the treatment group, the methodological approach (hospitalizing
all the patients, and the use of IV diazepam in all) and lack of statistical rigor (including a lack of
confidence intervals and p-value) prevent it from being used as a basis for urologists in the USA to
change their treatment stratagems. A second and much more recent study from Turkey compare the
events of three different alpha-1 adrenergic blockers. The study found all three medications tested to be
equally efficacious.36 This study however, only looked at the effect of tamsulosin on distal ureteral stones
(defined by the researchers as those in the juxtavesical tract and ureterovesical junction), and did not
compare this treatment group to a steroid alone group. This study was not blinded or placebo controlled,
and there was no power analysis.
In contrast, we will investigate the role of tamsulosin in a randomized and placebo-controlled study, to
enable the efficacy and optimum treatment regimen to be determined. We believe that a federally-funded
study will provide both the objectivity and publicity to ensure that results are widely disseminated. This
will ensure that if a benefit from the study medications is demonstrated, both emergency physicians and
urologists will feel comfortable in prescribing the medications, a situation which is not the case for
nifedipine and steroids.
9

September 4, 2015
3 Study Design
The study is a multi-center randomized, placebo-controlled, double-blind clinical trial. Participants are
randomized to one of two treatment groups, placebo or active tamsulosin. The primary objectives of this
study are to test the hypothesis that tamsulosin is clinically useful in the treatment of acute urolithiasis. If
tamsulosin achieves similar results in a properly conducted placebo controlled trial to those noted in
previous smaller pilot studies, we expect to see a significant reduction in days lost from work and
decreased morbidity, as well as cost savings resulting from a decreased number of patients referred for the
surgical management of retained stones.
3.1
Primary Research Question
Does the administration of tamsulosin after the clinical and radiographic diagnosis of acute urolithiasis
produces an increase in the proportion of patients passing their stone at 28 days by patient report?
3.2
Secondary Research Questions
The secondary research questions are whether tamsulosin produces a reduction in each of the following:
#
Time to passage of stone
#
Length of time in pain
#
Number of days lost from work
#
Need for surgical intervention or lithotripsy
#
Overall costs
#
Stone passage confirmation on CT scan
#
Crossover to open label tamsulosin/Flomax
3.3
Design Summary
The multi-center trial will be conducted in the Departments of Emergency Medicine (ED) at The George
Washington University Hospital in Washington D.C, Mercy Hospital of Pittsburgh and Presbyterian-
University Hospital, both part of the University of Pittsburgh Medical Center, and Thomas Jefferson
University Hospital. It is a continuation of the vanguard phase of the study performed solely at The
George Washington University Hospital.
This research study is a blinded randomized controlled clinical trial of 400 patients in addition to the 109
enrolled in the vanguard phase. Patients diagnosed with kidney stones via radiographic imaging are
approached for screening. Patients who satisfy the eligibility criteria and consent to randomization will
be centrally randomized to one of the following two medical protocols, each to be taken once a day for 30
days:
o
The active group who receive 30 tablets of 0.4 mg tamsulosin.
o
The placebo group who receive 30 similar inactive tablets.
3.4
Eligibility Criteria
3.4.1
Inclusion Criteria
1.
+=; O %( L;6FG
10

September 4, 2015
2.
Evidence of ureterolithiasis (i.e. stone is located in ureter) as demonstrated on CT with confident
diagnosis. This does not include stones located in the bladder or solely in the kidney.
3.
Willingness to participate and able to proceed with standard outpatient management (no personal
or job-related issues, e.g. airline pilot).
4.
Has a telephone in order to be contacted for follow-up.
3.4.2
Exclusion Criteria
1.
Patient desiring or requiring immediate surgical intervention making them not a candidate for
outpatient kidney stone management. (This includes prior surgery for the same stone).
2.
Current urinary tract infection based on urine dipstick or micro urinanalysis as admission and
urgent procedural management are likely indicated.
3.
Known anatomical genitourinary abnormalities or prior GU surgeries. (Shockwave lithotripsy
and ureteroscopy for prior stone(s) are not exclusionary.)
4.
Positive pregnancy test making proper radiological imaging contraindicated.
5.
Breastfeeding mothers.
6.
History of hypersensitivity to tamsulosin.
7.
Current use of alpha blockers or calcium channel blockers.
8.
Current use of steroids which may have an independent effect on stone expulsion.
9.
Spontaneous stone expulsion prior to enrollment.
10. 16F=;GH GHDC; 9?B;CG?DC O )BB 6GG;GG;9 IG?C= F69?DAD=?8 ?B6=?C=" 7;?C= J;FL ICA?@;AL HD E6GG
spontaneously.
11. Previous treatment for the current ureteral stone not elsewhere classified (including shockwave
lithotripsy, ureteroscopy and medications not currently being taken).
12. Current use of vardenafil which is tamsulosin contraindicated.
13. Ipsilateral, transplanted or solitary kidney as hospitalization may be necessary.
14. Known renal insufficiency (by patient history).
15. Fever defined as >101.5°F which may indicate infection.
16. Floppy iris syndrome which is tamsulosin contraindicated.
17. Planned cataract surgery in the next 60 days which is tamsulosin contraindicated.
18. Prisoners /wards of state.
19. Prior enrollment in STONE (Candidates who are screened and found ineligible may be
rescreened at a later date.)
3.5
Randomization Method and Masking
Consenting patients will be assigned to one of the two treatment groups with a randomization sequence
prepared and maintained centrally by the Biostatistical Coordinating Center (BCC). The active and
placebo study medication will be packaged according to the randomization sequence, so that the patient is
randomized when he or she is assigned to the next available individual supply of study medication. The
study is double masked; neither the patient nor the clinical staff will be aware of the treatment
assignment.
11

September 4, 2015
The simple urn method will be used to generate the randomization sequences because it provides a high
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit
randomization analysis,48, 49 to be conducted with relative ease. Randomization will be stratified by
clinical site to assure balance between the two treatment groups with respect to anticipated differences
within the clinic populations and possible differences in patient management.
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September 4, 2015
4 Study Procedures
4.1
Screening and Randomization
Potential study subjects will be identified while present in the Emergency Department. While the patient
is in the ED, a member of the research team will be notified. This researcher will determine if the patient
meets the inclusion and exclusion criteria. If the patient meets enrollment criteria, the study protocol will
be explained to the patient. If they express interest in participation, informed consent will be obtained,
randomization will take place, study medications will be dispensed, and urological follow-up will be
arranged before the patient is discharged from the ED.
4.2
Medical Treatment Protocol
The placebo group will receive placebo plus active analgesia, and the active treatment groups will receive
analgesia together with a thirty day course of tamsulosin. Standard follow-up care will be offered. Other
than administration of tamsulosin or placebo, there will be no differences in the approach to treatment.
Any treating physicians will be blinded to treatment group. A one-page guideline for enrolled patients to
bring to their physician to help further standardize treatment has been designed.
4.3
Study Outcomes and Ascertainment
4.3.1
Primary Outcome
The administration of tamsulosin after the clinical and radiographic diagnosis of acute urolithiasis
produces an increase in the proportion of patients passing their stone within 28 days.
Determination of the symptomatic stone
In cases in which there is more than one stone noted on the CT scan, the physician treating the patient will
determine the likely location and dimensions of the stone causing symptoms by reviewing the patient’s
ED record.
Multiple stones
If the physician believes that the symptomatic stone has not yet reached the bladder the patient may be
offered enrollment. If there are multiple stones and the physician believes that the stone causing
symptoms has reached the bladder, the patient will not be eligible for enrollment.
Definition of stone expulsion
Stone expulsion will be defined as a report by the patient that the stone was noted to have passed by
visualization or capture after urination and that the pain has been relieved.
4.3.2
Secondary Outcomes
The secondary outcomes are:
#
Length of time in pain
#
Surgical intervention or lithotripsy
#
Cost savings based on days of work lost, surgical interventions, hospitalizations, etc.
#
Time until stone expulsion
#
Total amounts of analgesia taken
#
Days of work lost
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September 4, 2015
#
Complications including repeat ED visits or other hospitalizations
#
Stone passage confirmation on CT scan
#
Crossover to open-label tamsulosin/Flomax
Together with these secondary hypotheses, a secondary objective is to identify the most appropriate
clinical subgroup(s) for treatment.
4.4
Baseline Procedures
In this randomized clinical trial, the following data and procedures will be performed at screening:
#
Informed consent
#
Eligibility
#
Medical history
#
Physical exam
#
Labs: dipstick urinalysis
#
Labs: pregnancy test for females
#
Labs: hematology and/or serum chemistry, if clinically indicated
#
Result of CT scan
4.5
Patient Management and Follow-up
After randomization, patients are contacted on days 2 and 7, and then on days 15, 20, 29 (to capture status
through Day 28), and finally on day 90, as outlined below along with the procedures to be completed in
this study and frequency that they will be performed. All the interventions and clinical follow-up in this
study are those normally performed in the treatment of patients diagnosed with nephrolithiasis. The only
treatment that is not routine is taking tamsulosin or placebo. Follow–up data will be collected in one of
three ways: telephone follow-up is the most preferred method, but email communication or texting to the
patient’s cell-phone can also be used in the case that a telephone call is not feasible.
Table 3: Phone call follow-up Days 2-90
Day 2
Day 7
Day 15
Day 20
Day 29
Day 90
Study drug taken
X
X
X
X
X
Total NSAIDs taken
X
X
X
X
X
-
Total Percocet taken
X
X
X
X
X
-
Other analgesics taken?
X
X
X
X
X
-
Stone captured?
X
X
X
X
X
X
Returned to work?
X
X
X
X
X
X
Side effects: Dizzy/nausea/other
X
X
X
X
X
-
Seen PCP for follow-up?
X
X
X
X
X
X
Seen urologist for follow-up?**
X
X
X
X
X
X
Any return ED visits?
X
X
X
X
X
X
Hospitalizations?
X
X
X
X
X
X
Surgical interventions for the stone?
X
X
X
X
X
X
Stone seen on any repeat CT/KUB?
-
-
X
X
X
-
CT scan
-
-
-
-
X
-
**if the patient was seen for urology follow-up, data regarding repeat urinalysis and blood pressure will be collected.
4.5.1
CT scan at 29 days
A follow-up low dose CT scan of the abdomen and pelvis will be performed at day 29 (with a window to
day 36). If a documented CT was done outside the study before 29 days that shows passage, it will be
14

September 4, 2015
reviewed by the PI who will determine if the information is comparable and sufficient. If so, the study
CT will not be performed. This scan will be used in conjunction with the follow-up data to confirm stone
passage.
4.6
Adverse Event Reporting
Detailed information concerning adverse events will be collected and evaluated throughout the conduct of
the protocol. Results of clinical observations, laboratory tests, and reported events form the basis for
evaluating the safety profile of this therapy. At all contacts, patients will be questioned regarding side
effects or symptoms associated with the study medication which are as follows:
#
Dizziness at rest
#
Dizziness on standing (postural hypotension)
#
Abnormal ejaculation (in men)
#
Gastrointestinal disorder
#
Peptic ulcer disease
#
Gastrointestinal bleeding
#
Urinary tract infections
#
Facial flushing
#
Headache
#
Tachycardia
#
Other side effects
The clinical center will report adverse events to the coordinating center in a timely fashion. The
coordinating center will summarize and report adverse events to the DSMB.
Additional procedures are warranted for cases of serious adverse events which is defined by the FDA as a
patient outcome that is: (1) death; (2) life-threatening, i.e., the patient was at substantial risk of dying at
the time of the adverse event or it is suspected that the use or continued use of the product would result in
the patient's death; (3) hospitalization (initial or prolonged); (4) disability, i.e., resulted in a significant,
persistent, or permanent change, impairment, damage or disruption in the patient's body
function/structure, physical activities or quality of life; (5) congenital anomaly, i.e., there are suspicions
that exposure to a medical product prior to conception or during pregnancy resulted in an adverse
outcome in the child; (6) requires intervention to prevent permanent impairment or damage. Serious
adverse events will be reported immediately to the NIDDK project office, the BCC and the local IRB.
The BCC will notify the DSMB chair; and the entire DSMB will confer if needed.
The only indication for breaking the randomization code is when it is medically necessary to unmask the
study drug assignment to be able to treat the patient, such as an allergic reaction or severe side effect that
appears to be related to the medication.
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September 4, 2015
5 Statistical Considerations
Our data analysis is designed to evaluate the following goals of the study: 1) to determine the efficacy of
tamsulosin with respect to primary and secondary outcomes in patients with urolithiasis, 2) to ensure that
such treatment is safe 3) to determine if benefit is equally evident across a range of clinically relevant
subgroups. The principal analyses of primary and secondary outcomes employ the intent-to-treat (ITT)
approach. Although data may be missing at points in time, all relevant data available from each
participant will be employed in all analyses. An ITT analysis more closely reflects actual conditions and
experiences of clinical practice than analyses based on the subset of ‘complete’ or ‘totally compliant’
participation and, therefore, does not overestimate the impact of an intervention. Treatment group
assignments are not altered based on adherence to the assigned treatment regimen. Furthermore, applying
ITT maintains the benefits of randomization; if dropouts and non-compliers are ignored, then the study
design becomes more observational and bias due to post-randomization subset selection is introduced.
All significance tests will be 2-sided, with alpha=0.05.
5.1
Data Relevant to the Primary Outcome
A power analysis was conducted for the primary outcome measure, reduction in time to stone passage.
Two published studies6, 9 provide data on the time from diagnosis to either passage of the kidney stone or
complete relief of pain under current standard treatment procedures. Although this time interval varies
directly by stone size and location at time of diagnosis, a weighted average of the patient groups in
Miller’s work6 showed an overall mean time interval of about 14 days, and a 30 day passage rate of 90%.
In recent Italian studies16, 46 using tamsulosin and nifedipine in urolithiasis, the overall passage rate of the
control arm is much lower. In the control arm of these studies, the 30 day expulsion rate was only 35-
43%. We cannot account for this wide variation in overall passage rate between the American and Italian
data sets. In order to perform a reliable power analysis, we have used an estimated passage rate of 70% in
the placebo group.
As mentioned above in the Background section 2.1.2, in his meta review in 2006, Hollingsworth
suggested the need for a definitive clinical study which suggested a sample size very similar to that
calculated for our own study.
5.2
Interim Analysis
Interim statistical analyses of clinical trials are a requirement of all National Institutes of Health (NIH)
sponsored clinical trials. The Data and Safety Monitoring Committee (DSMC) meets at least once a year
to review trial results; however, the exact timing of the interim analyses is at the discretion of the
committee. Before each meeting, a formal detailed statistical report will be written by the Biostatistical
Coordinating Center (BCC) which presents the results of every aspect of the study, including all baseline
variables, protocol adherence, all outcome variables, adverse events reported and center performance in
terms of recruitment, data quality, loss to follow-up and protocol violations. However, the main emphasis
is on the primary outcome. For this evaluation, a cohort of patients is chosen consisting of all patients
randomized before a certain date so that the analysis cohort does not depend on time to stone expulsion.
The main statistical issue relevant to interim analysis is the problem of performing multiple tests of
significance on accumulating data. A number of procedures have been developed to handle this
situation50, 51 Most techniques52, 53 entail adjusting the nominal significance level at the interim
evaluations to some value less than ", such that the overall probability of committing a type-I error is
maintained at ". For this trial, the group sequential method of Lan and DeMets54 will be used to
characterize the rate at which the type I error is spent. This method is flexible with regard to the timing of
16

September 4, 2015
the interim analyses. Asymmetric stopping boundaries will be used for the Lan-DeMets procedure. The
upper boundary which describes the stopping rule for benefit will be based on 1-sided type I error of .025
and the Lan-DeMets generalization of the O’Brien-Fleming boundary. The lower boundary will be based
on a less stringent stopping rule: 1-sided type 1 error of .05 and the Lan-DeMets generalization of the
Pocock type boundary. However, this should not preclude the Data and Safety Monitoring Committee
recommending termination earlier if there is evidence of harm.
Sometimes, a surprising development may lead to extra looks or even continuous monitoring of the data,
such as on a monthly basis. The Lan-DeMets procedure is flexible, in that one can switch from
occasional to continuous monitoring of the data, with negligible effect on the type I error level. 55 In some
instances the Lan-DeMets boundary for statistical significance may be crossed, but due to other
considerations the DSMC decides that the trial should continue. In this case, the type I error previously
spent under by the " spending function can be retrieved to be distributed over future looks without
inflating the total type I error probability.56
It is often useful to calculate conditional power given the observed data to date, and conditional on the
future data showing the originally assumed design effect.57 If this conditional power is low (under 10
percent) the DSMC may consider termination for futility if the accrual rate is slow with confidence that
the Type II error is not greatly inflated.)
It is recognized that any decision to terminate the study would not be reached solely on statistical grounds
but on a number of complex clinical and statistical considerations.58
5.3
Analysis Plan
5.3.1
Preliminary Analyses
To assess the efficacy of tamsulosin for the treatment of urolithiasis, the BCC will employ a systemic
statistical analysis strategy. The first analytic step will be to compile descriptive statistics (e.g. mean,
standard deviation, range, proportion) of patient demographics. This activity, while not directly
addressing any of the study hypotheses, will serve to describe central tendencies and the variability of
outcome variables and co-variables.
Then a series of interactive data analyses will be conducted, which will be used to characterize data
distributions, detect any missing data patterns, examine associations and redundancies among
independent variables, and generally watch for unusual or unexpected data patterns. This will help verify
whether the assumptions of the proposed statistical models are reasonably met and if necessary to choose
alternative analytic methods such as non-parametric tests or transformations.
The second step will be to compare treatment groups with respect to important suspected covariates,
specifically age, gender, stone location and size, and the number of prior episodes of renal colic. Any
variables found to have substantial imbalance (either statistically significant or large in magnitude)
between the study groups will be included as covariates. The third step will be to analyze the data
according to our specific aims.
5.3.2
Testing of efficacy and safety outcomes
One of the secondary endpoints is whether the patient requires a more complicated treatment within 90
days of the index emergency visit. This would be evidenced by the need for surgical intervention or
lithotripsy. Based on the practice characteristics of the research site we expect a low number of these
cases. In addition, work by Yilmaz36 described above lends strong evidence to our expectation that the
17

September 4, 2015
surgical intervention rate will be low. These cases will be described descriptively. The two study groups
will be compared using the Pearson chi-square test or the Mantel-Haenszel procedure if covariate
adjustment is necessary. An additional secondary outcome is the number of days of work missed. These
will be tested by t-test or (or ANCOVA with covariates), or if necessary because of distributions
requirements, by the Wilcoxon test.
To examine whether the treatment groups experience comparable rates of complications we will monitor
patients for several unlikely but potential complications of tamsulosin as outlined above. Events not
typically associated with patients with acute urolithiasis will be classified as adverse effects. Adverse and
serious adverse events are expected to occur at a very low rate in both study conditions. These will be
analyzed descriptively.
5.3.3
Exploratory Analyses
It is possible that the beneficial effects of the study drug, if observed, will be more evident in one subset
of patients than another. To assess this possibility, we will conduct a series of analyses, categorizing
patients into a variety of clinical sub-groups: first episode vs. recurrent episode of ureterolithiasis; small
stones (<1.9mm) vs. moderate stones (2-5.9mm) vs. large stones (>6mm); location of stone; male patients
vs. female patients; age. These will be tested as interactions with treatment group, using cross-product
terms, in a Cox proportional hazards model to assess the duration of symptoms.
5.3.4
Statistical Complications
Because of the brief treatment and follow-up period and the expected very low rate of side effects, it is
anticipated that the attrition rate will be low. However, if any patients end their treatment early while still
providing outcome information, the primary outcome will be analyzed according to the intention-to-treat
principle. It is possible that some outcome data may be missing for some patients. For example, some
patients may not be reachable by telephone, may refuse to provide follow-up information or may have
unreliable recall. If the number missing is low these patients will be dropped from the analysis; otherwise
multiple imputation methodology59 will be employed to reduce statistical bias and make efficient use of
all of the data.
5.4
Sample Size and Power
5.4.1
Sample size
The primary outcome for the STONE study is the proportion of patients who pass stones within 28 days.
Data on stone passage rates is summarized in a meta-analysis by Hollingsworth et al37 who found the
baseline occurrence of stone passage in the control group across nine studies to be 47% with rates ranging
from 20% to 73%. The lower confidence limit of the passage rate in the treatment group across the nine
studies was 68%. A two group chi-squared test with a 0.05 two-sided significance level will have 90%
power to detect the difference between a placebo proportion of 0.45 and a tamsulosin proportion of 0.60
when the sample size in each group is 250 accounting for losses to follow-up.
Due to concerns that the passage rate might be inappropriate, this sample size will be achieved in a two-
stage approach. After the outcomes of the treatment of the first 100 patients were obtained, the passage
rate in the placebo group was calculated by the BCC. The DSMB reviewed the data and agreed that the
total sample size of 500 was accurate. Therefore, the remainder of the sample will be collected in a multi-
center trial. There will be approximately 200 more patients randomized to each treatment group along
with the 109 patients randomized in the pilot study, would achieve the total sample size of 500 patients.
18

September 4, 2015
5.5
Statistical Analyses
The principal analyses of primary and secondary outcomes employ the "intent-to-treat" approach as
described by Peduzzi.60 The intent-to-treat analyses include all randomized patients with all patients
included in their randomly assigned treatment group; treatment group assignment is not altered based on
the patient’s adherence to the assigned treatment regimen. All statistical tests are two-sided with the
DJ;F6AA G?=C?<?86C8; A;J;A D< H>; EF?B6FL DIH8DB; R*$#$'# .DK;J;F" H>; G?=C?<?86C8; A;J;AG IG;9 ?C H>;
interim and final analyses of the primary outcome are adjusted to account for the interim analyses.
#
Baseline characteristics: Comparison of the baseline characteristics (e.g., age, gender, stone
location and size) between the two treatment groups uses standard parametric and nonparametric
statistical techniques, such as the Pearson chi-square test and Fisher's exact test for categorical
data and ANOVA and the Kruskal-Wallis test for continuous data.
#
Primary outcome: The principal analysis of STONE will be a comparison of the proportion
passing stones in the two groups using the Pearson chi-square test. Logistic regression will be
used if covariate adjustment is necessary.
#
Secondary outcomes: Secondary time to event outcomes (e.g., time to passage of stone; time to
pain relief) are analyzed using life-table analysis of the time to event. A proportional-hazards
regression model is used to evaluate potential covariates that may modify the secondary time to
event outcomes (e.g., size and location of stone). Graphical procedures are used to assess the
proportionality assumption. If the proportionality assumption is found to be unreasonable, then
other models such as the accelerated failure time model or the proportional odds model are used
to evaluate the covariates.
#
Secondary dichotomous outcomes (e.g., need for surgical intervention or lithotripsy) are analyzed
using the same methods as described for the primary outcome. Ordinal outcomes (e.g., number
of days lost from work) are analyzed using Poisson regression with adjustment for covariates if
necessary. Continuous variables will be analyzed using general linear models.
#
Subset analysis: It is possible that the beneficial effects of the study drug, if observed, are
stronger in one subset of patients than another. Subsets based on sex, age, stone size, stone
location and stone recurrence may receive differential benefit. To assess this possibility, these
groups are tested as interactions with treatment group, using cross-product terms, in the
appropriate model (e.g., Cox proportional hazards, logistic regression, Poisson regression).
If the two groups show a difference in the incidence of the primary outcome, interactions will be
evaluated and subgroup analyses conducted to determine whether the effect prevails throughout
particular subgroups of patients. Indeed, NIH guidelines require investigators to evaluate
consistency between the genders and across racial subgroups. It should be noted, however, that
subgroup analyses have been greatly abused,61 particularly when there is no overall treatment
difference. There is a strong temptation to search for a specific subpopulation in which the
therapy is nevertheless effective. Yusuf et al62 concluded “the overall ‘average’ result of a
randomized clinical trial is usually a more reliable estimate of the treatment effect in the various
subgroups examined than are the observed effects in individual subgroups.” Thus subgroup
analyses will be interpreted with care.
#
Interim analysis: The Lan-DeMets55 spending function approach is used to adjust the probability
of a type I error for testing the primary outcome when interim ‘looks’ of the data are taken by the
19

September 4, 2015
Data Safety Monitoring Board. The spending function corresponding to an O’Brien - Fleming
boundary is used. The Lan-DeMets procedure is flexible, in that the number of looks does not
have to be specified in advance and the time interval between looks does not have to be the same
throughout the study. The rate at which the type I error is spent is a function of the fraction of
total information available at the time of the interim analysis (i.e., information time).63 Prior to
taking any ‘looks’ at the data, the study Steering Committee and the DSMB will develop study-
specific procedures for interim analyses and stopping rules.
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September 4, 2015
6 Data Collection and Management
6.1
Data Collection Forms
Data will be collected on standardized forms on which nearly all responses have been pre-coded. Each
form is briefly described below:
#
Screening Log lists all patients screened for the study and some demographic data.
#
Eligibility and Randomization Form is completed for all randomized patients and records
assigned study drug code number, and information on the study drug administration.
#
Screening Form is completed for all randomized patients. This form includes detailed medical
data obtained during screening for the study.
#
Adverse Event Form records adverse events.
#
Follow-up Form for all contact calls for follow-up of randomized patients.
#
Radiologic Imaging Forms for radiologic imagining at screening and at follow-up.
6.2
Web Data Entry System
For this protocol, web data entry screens corresponding to the study forms listed above will be developed
and maintained by the staff of the BCC. Clinical center staff will enter data into the MySQL database
located at the BCC through a web data management system (MIDAS). The data are edited on-line for
missing, out of range and inconsistent values. A Users’ Manual documenting this system is provided to
the centers by the BCC.
6.3
Centralized Data Management System
Daily data conversions from the MySQL database create up-to-date SAS datasets. Data are reviewed
weekly using edit routines similar to those implemented on-line during data entry, as well as additional
checks for data consistency within or across forms. A database of resulting potential data problems is
generated in MIDAS for initial review by BCC staff, who then evaluate the comments keyed in
association with edits on missing or unusual values. Valid edits will be flagged in MIDAS for resolution
at the clinical centers.
At regular intervals, specialized data reviews comparing data availability and consistency across forms
are run by the BCC staff on the entire database or on a specific subset of data. These reports are also
submitted to the centers for correction or clarification.
An audit trail, consisting of all prior versions of each data form as entered in the computer for each
patient, is maintained so that the succession of corrections can be monitored.
6.4
Performance Monitoring
The BCC will present regular reports to the Steering Committee, and the Data and Safety Monitoring
Board. These include:
#
Monthly Recruitment Reports - reports of the number of people screened and enrolled by month
and by clinical center are provided monthly to the Steering Committee.
#
Steering Committee Reports - reports detailing recruitment, baseline patient characteristics, data
quality, incidence of missing data and adherence to study protocol by clinical center, are provided
the Steering Committee.
21

September 4, 2015
#
Data and Safety Monitoring Board Reports - for every meeting of the DSMB a report is prepared
which includes patient recruitment, baseline patient characteristics, center performance
information with respect to data quality, timeliness of data submission and protocol adherence (in
addition to safety and efficacy data). The reports also include adverse events, loss to follow-up
and all outcome variables as described previously in this protocol.
22

September 4, 2015
7 Study Administration
7.1
Organization and Funding
The trial management is composed of study staff from the NIDDK project office, the George Washington
University Biostatistics Center, and the principal investigator. Organizationally:
#
The clinical centers at the Emergency Departments of the George Washington University
Hospital, the University of Pittsburgh and the Thomas Jefferson University Hospitalare
responsible for recruiting and enrolling patients and for collecting and entering data.
#
The NIDDK project office participates in all decision-making activities, has selected and will
oversee the activities of the Data Safety Monitoring Board.
#
The Biostatistical Coordinating Center (BCC) is responsible for statistical aspects of study design
and conduct, designs and monitors quality control systems. The BCC produces performance
reports, including periodic tracking reports and reports to the Steering Committee and Data Safety
Monitoring Board.
7.2
Committees
7.2.1
Steering Committee
The Steering Committee is the primary decision making body for the study, and convenes periodic
meetings and conference calls to review scientific issues and study progress. Members of the Steering
Committee are the Principal Investigators from each of the clinical centers, the Principal Investigator at
the Data Coordinating Center and the NIDDK project office representatives.
7.2.2
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) consisting of appropriately qualified independent experts has
been appointed by the NIDDK to provide review of data on patient safety and study progress. The
membership roster is maintained by NIDDK and is available from them as needed. The Data
Coordinating Center will provide reports to the DSMB including adverse events. A summary of DSMB
deliberations will be prepared by NIDDK and distributed to the clinical center to submit to their IRB.
23

September 4, 2015
8 Study Timetable
8.1
Training and Certification
Figure 2. Timeline
With funding beginning in September 2012 and the first 4 months will be spent on final preparations of
the protocol, acquisition of study drugs and training and certification of study coordinators and staff.
Screening will begin in April 2013.
8.2
Data Collection Period
The recruitment and follow-up period begins in April 2013 and continues through February 2016. Data
queries are generated and resolved during this time period through April 2016. Data close-out will be
performed during the final 6 months of funding starting in January 2016 through June 2016.
8.3
Final Analysis
After a period of approximately three and a half years for completion of data acquisition for the trial and
close-out, the data set will be locked and ready for analysis. A few months will be required to complete
the final report to the Steering Committee and to submit the study’s primary report for publication.
24

September 4, 2015
Appendix A
DESIGN SUMMARY
Study TamsulOsiN for urolithiasis in the Emergency Department (STONE)
OBJECTIVE
To determine if the administration of tamsulosin after the clinical and radiographic diagnosis of acute urolithiasis produces an increase in the proportion of patients passing their stone at 28 days.
ORGANIZATION
Clinical Centers:
George Washington University Hospital, Thomas Jefferson University
Hospital, University of Pittsburgh Medical Center (Presbyterian Hospital
and Mercy Hospital), University of Alabama at Birmingham Medical Center
Data Coordinating
Center:
George Washington University Biostatistics Center
Steering Committee:
Clinical center PIs, data coordinating center PI and the NICHD Program
Scientist
DESIGN
Type:
Randomized clinical trial
Inclusion Criteria:
#
Age >= 18 years
#
Radiologic evidence of kidney stones
#
Has telephone
#
Informed consent
Major Eligibility
Criteria:
#
Require surgical intervention
#
Pregnancy
#
Hypersensitivity to tamsulosin or current use of medications which
affect stone expulsion or contraindication to tamsulosin
#
Renal insufficiency or kidney malformation
#
Stone located in bladder only
#
Current urinary tract infection
Groups:
#
Experimental: Tamsulosin 0.4 mg
#
Standard care: Placebo tamsulosin
Random Allocation:
Standard urn design
Level of Masking:
Double-blinded
Stratification:
Clinical center
Sample Size:
Trial goal = 500 (250/group)
Assumptions:
1) Type 1 error = 5% (2-sided); Power >= 90%
2) Outcome event = passage of symptomatic stone at 28 days post -
randomization
#
Placebo group event rate = 45%
#
Tamsulosin group event rate = 60%
Interim Analysis:
Group sequential method
SCHEDULED EVALUATIONS / DATA COLLECTION
Pre-randomization:
#
Informed consent
#
Eligibility
#
Medical history
#
Physical exam
#
Labs: urinalysis
#
Labs: hematology, serum chemistry*
#
CT scan
Management Protocol
#
Study medications are taken for 30 days post-randomization
#
Stone passage documentation
Post-randomization
Contacts on Days
2,7,15,20,29,90
#
Medications taken including study drug
#
Kidney stone passage
#
Side effects
#
Hospitalizations and doctor visits
#
Return to work
OUTCOME MEASURES
Primary:
#
Kidney stone passage <= 28 days
Secondary:
#
Reduction in the length of time in pain
#
Reduction in the number of days lost from work
#
Reduction in the need for surgical intervention or lithotripsy
#
Cost savings
#
Crossover to open label tamsulosin/Flomax
TIMETABLE
Pilot Study
April 1, 2006 – December 31, 2010
Planning Grant
September 30, 2010 – August 31, 2012
Training/Certification
February 1, 2013 – March 30, 2013
Randomization:
April 1, 2013 –December 31, 2015
Data Processing:
April 2, 2013 – April 30, 2016
Closeout/final analysis:
January 1, 2016 – June 30, 2016
25

Appendix B
Sample Informed Consent
Research Consent Form
Tamsulosin for Urolithiasis
IRB Reference number: ___________
Principal Investigator: ______________________
Telephone number: ____________
Sponsor: NIDDK
I.
INTRODUCTION
You are invited to participate in a research study of tamsulosin for kidney stones because you have a
kidney stone. Your participation is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time. In either case, you
will not lose any benefits to which you are otherwise entitled. You do not have to take part in this study
to receive care at (university/hospital). You may not receive any benefit from taking part in this study;
however, the research may give us knowledge that may help people in the future.
This study is being conducted by the investigators listed above from the Department of Emergency
Medicine at the (university/hospital). The costs of this research study are paid for by the National
Institutes of Health.
Before you decide to participate, please take as much time as you need to ask any questions and discuss
this study with anyone at (university/hospital), with family and friends, and your personal physician or
other health professional. Before you sign this form, be sure you understand what the study is about,
including the risks and possible benefits to you.
Please tell the Principal Investigator or study staff if you are participating in another research study.
II.
WHY IS THIS STUDY BEING DONE?
The Department of Emergency Medicine at (the university/hospital) and the National Institutes of Health
are carrying out a research study to find out if tamsulosin can reduce the time you are in pain with kidney
stones, and possibly help the stones pass, which would reduce the need for surgery. The investigator
(person in charge of this research study) is Dr. (local PI). About 400 patients will be enrolled. This
research is funded by the government through the National Institutes of Health.
III.
WHAT IS INVOLVED IN THIS STUDY?
The research will be conducted by giving you the medications and seeing how long it takes you to
improve, and whether or not you required any surgery to remove the stone. The medication being studied
is tamsulosin which used to relax the muscle in the ureters where the stone is. There will be no need to
come back to the hospital for any special visits, other than the visits you would normally make because of
your kidney stone. You have a 50-50 chance of getting either the medication or a sugar pill, called a
placebo. There is no way of knowing whether or not you got the real medications or the sugar pill until
the end of the study, unless there is an emergency in which case we can tell you immediately.
If you see a urologist, we may ask that doctor to share information about the visit with us.
HOW LONG WILL I BE IN THIS STUDY?
The total amount of time you will spend in connection with this study is three months. You will take the
study medicines for 30 days and will be called by the researchers over the first thirty days and again after
26

three months to see how you are doing and to collect information about how many pain pills you have
been taking.
You always can choose to stop participating at any time. However, if you decide to stop
participating in the study, we encourage you to talk to your doctor first.
IV.
WHAT ARE THE RISKS OF PARTICIPATING IN THIS STUDY?
The medication you may be given has been used for many years to treat other problems and has been
shown to be very safe. It has been used for years to treat patients with prostate problems. The most
common side effects are dizziness and abnormalities of ejaculation. Once you stop the medication any
side effects rapidly end.
Reproductive Risks
Pregnant women may not take part in this research study because of the risk the fetus from radiation from
the CT. To determine if you are pregnant, pregnancy testing will be performed on all women capable of
becoming pregnant before and during participation in this study. Even if not sexually active, all female
participants will be given a pregnancy test. The only exceptions are when female participants have
stopped having menstrual periods at least one year after menopause (change of life); or have undergone
sterilization surgery (tubes were tied or had a hysterectomy). The effect of the study drug on a child
conceived (created) while a female participant is taking the study drug, are not known. If female
participants become or suspect that they are pregnant during the study, the study doctor must be notified
immediately. Also, breastfeeding mother may not take part in the study.
V.
ARE THERE POTENTIAL BENEFITS TO TAKING PART IN THIS STUDY?
If you agree to take part in this study, there may be direct medical benefit to you. If you get the study
pills and they work, you may get better much quicker than you would without them. This means that you
will be in less pain for fewer days. In addition the pills may prevent you from needing surgery later.
However we do not know if the treatment will work.
We hope the information learned from this study will benefit other individuals with kidney stones
in the future.
We cannot and do not guarantee or promise that you will receive any benefits from this study.
VI.
WHAT ARE MY OPTIONS?
You do not have to take part in this study if you do not want to participate. Should you decide to take
part and later change your mind, you can do so at anytime. There are no other medical alternatives that
are currently offered for those patients who have kidney stones, other than pain relieving medications. If
the stone does not pass within a few weeks, you may be offered interventions by urologists, such as
lithotripsy (using shock waves to break up the stone) or removing the stone directly. These interventions
are considered if the stone fails to pass despite medications. You may chose not to take part in this study.
If you do not take part you will be offered all of the standard medications for this condition which are
pain relieving medications (analgesics like Motrin or Percocet). You also have the right to refuse all
treatment.
Your study doctor can explain these options in detail or refer you to the appropriate doctor for more
information.
VII.
WILL I RECEIVE PAYMENT FOR BEING IN THIS STUDY?
You will not be paid for taking part in this study.
27

VIII.
WHAT WILL IT COST ME IF I DECIDE TO PARTICIPATE IN THIS STUDY?
There will be no additional costs to you as a result of taking part in this study. However, routine medical
care for your condition (the care you would receive whether or not you were in this study) will be charged
to you or your insurance company. You may be responsible for any co-payments and deductibles that are
standard for your insurance coverage.
You will not be charged for the following that is part of this research study:
•
Tamsulosin or placebo – the study medications
If you have any questions about your insurance coverage or the items you might be required to pay for,
please call your insurance representative to discuss this further before making your decision about taking
part in the study. You also may contact financial services for information. The contact information for
financial services is:
_______________________________________
_______________________________________
IX.
ARE THE RESEARCHERS BEING PAID FOR THE STUDY?
The sponsor of the study is paying (the university/hospital) and the (local PI) and his/her team for their
work in this study.
X.
WHO PAYS FOR MY MEDICAL CARE IF I BECOME ILL OR INJURED
BECAUSE OF THE STUDY?
The researchers have taken steps to minimize the known or expected risks. In spite of all precautions, you
still may experience medical complications or side effects from participating in this study. If you believe
that you have been injured or have become ill from taking part in this study, you should seek medical
treatment from (the university/hospital) or through your physician or treatment center of choice. Care for
such injuries will be billed in the ordinary manner to you or your insurance company. You also should
promptly notify the study doctor in the event of any illness or injury.
You will not receive any financial payments from (the university/hospital) for any injuries or illnesses.
You do not waive any liability rights for personal injury by signing this form.
XI.
WHAT ABOUT CONFIDENTIALITY?
Your records will be confidential. You will not be identified (e.g., name, social security number) in any
reports or publications of this study. It is possible that representatives of regulatory agencies and from the
study’s sponsor may come to (the university/hospital) to review your information. In that situation,
copies of the relevant parts of your records will be released with all identifying information removed.
Except for these entities, research study records will be kept confidential unless you authorize their
release or if the records are required by law (i.e. court subpoena).
Your information will be kept as confidential as possible. Access to study records will be limited to those
who need the information for purposes of this study, as well as your health care providers should they
need access to the information. All records are kept in a secure location and access is limited to research
study personnel.
28

Except as required by law, you will not be identified by name, social security number, address, telephone
number, or any other direct personal identifier. The results of this research study may be presented at
scientific or medical meetings or published in scientific journals. However, your identity will not be
disclosed, unless you give the appropriate authorization.
XII.
HOW WILL MY PRIVACY BE PROTECTED?
Federal law requires that hospitals, researchers and other healthcare providers (like physicians and labs)
protect the privacy of health information that identifies you. This kind of information is known as
“protected health information” or “PHI.” This section tells you your rights about your protected health
information in the study. This section also lists who you let use, release, and get your protected health
information. You are free to not allow these uses and releases by not signing this form. If you do that
though, you cannot participate in the study.
Protected health information that may be used and released (disclosed) in this study includes information
such as:
#
This consent form;
#
Demographic information (like your name, address, date of birth, social security number, etc.);
#
Information about your medical history from your medical records and your doctor’s office;
#
Information obtained from you to be used in the study as a result of tests or procedures;
#
Results of physical examinations; laboratory results obtained on specimens collected from you
(like blood, urine, tissue);
#
Medical images like x-rays, CT scans, and MRIs;
#
Admissions information;
#
Health care expenses and health insurance coverage information;
#
Questionnaires/surveys you complete;
#
Interviews with you conducted by members of the Research Team;
By signing this form, you allow the use, sharing, copying, and release of your protected health
information to carry out the study by: your healthcare providers (like doctors and hospitals) which are not
part of the study, the study doctor and his or her research team, and other healthcare providers such as
labs which are part of the study.
You also allow the study doctor and his or her research team, and other healthcare providers which are
part of the study to release your health information to:
The (university/hospital) Institutional Review Board (“IRB”) or its authorized representatives, as well as
representatives of the Office of Human Research Protections (OHRP) who may review your records to
ensure that your rights as a research subject are protected;
#
The sponsor of the study and any contractors or partners it may have. (Research monitors and
auditors)
#
Research collaborators participating in this multi-site study at other institutions. (Data receiving
center(s) responsible for collecting, monitoring and /or analyzing data from all the sites
participating in this study)
#
Regulatory agencies such as the U.S. Food and Drug Administration (FDA) to review data on the
safety and effectiveness of the product that is being tested in this study and other Federal and
state agencies that regulate research
#
Clinical staff who are not involved in the study who may become involved in your care, if it
might be relevant to your care; and (the university/hospital) workforce who are involved with the
research;
29

You may request to review or have a copy of your personal health information collected during this study
and placed in your medical record. This right to review and copy your personal health information only
extends to information that is placed in your medical record; it does not extend to information that is
placed in your research record.
This is a clinical trial and it is critical to the interpretation of the results that you not know which
treatment group you are participating. Once the study is finished you may request to review and have a
copy of your personal health information collected during this study and placed in your medical record.
This right to review and copy your personal health information only extends to information that is placed
in your medical record; it does not extend to information that is placed in your research record.
This permission does not end unless you cancel it, even if you leave the study. You can cancel this
permission any time except where a healthcare provider has already used or released your health
information, or relied on your permission to do something. Even if you cancel this authorization, the
researchers may still use and disclose protected health information they already have obtained about you
as necessary to maintain the integrity or reliability of the research. However, no new PHI or new
biological specimens will be collected from you after you revoke your authorization.
To cancel your authorization, you will need to send a letter to (local PI) stating that you are canceling
your authorization. This letter must be signed and dated and sent to this address:
_______________________________________
_______________________________________
A copy of this revocation will be provided to the study doctor and his or her research team. Not signing
this form or later canceling your permission will not affect your health care treatment outside the study,
payment for health care from a health plan, or ability to get health plan benefits.
Your protected health information will be treated confidentially to the extent permitted by applicable laws
and regulations. Federal law may allow someone who gets your health information from this study to use
or release it in some way not discussed in this section and no longer be protected by the HIPAA Privacy
Rule.
By signing this form you authorize the study doctor and members of the research team to use and share
with others (disclose) your PHI for the purpose of this study. If you do not wish to authorize the use or
disclosure of your PHI, you cannot participate in this study because your PHI is necessary to conduct this
study.
XIII.
CAN I WITHDRAW FROM THE STUDY LATER?
You may withdraw from the study at any time. Leaving the study will not affect your current or future
medical care at (the university/hospital). If you choose to no longer be in the study, you should call or
write to the study doctor right away.
XIV.
CAN I BE TAKEN OFF THE STUDY?
The study doctor or sponsor can decide to stop your participation in this study at any time. You could be
taken off the study for reasons related solely to you (for example, not following study-related directions
from the study doctor, circumstances that may develop and offer alternatives, or a serious reaction) or
because the entire study is stopped. The sponsor may stop the study at any time. The sponsor may also
decide to stop the study doctor’s involvement in this study.
30

XV.
WHO DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
The Office of Human Research of (the university/hospital), at telephone number (phone number); can
provide further information about your rights as a research subject. Research related injury should be
reported to the Principal Investigator of this study. His/her telephone number is (phone number). For
problems arising evenings or weekends, you may call (local PI) at (phone number).
XVI.
CONSENT DOCUMENT
After you sign this Consent Form, the research team will provide you with a copy. Please keep a copy of
this document in case you want to read it again.
If you agree to participate in this study, please sign below:
DOCUMENTATION OF CONSENT
I understand the information printed on this form. I have discussed this study, its risks and potential
benefits, and my other choices with ___(person obtaining consent)_________________. All of my
current questions have been answered. My signature below indicates my willingness to participate in this
study and my understanding that I can withdraw at any time.
__________________________________________________
___________
Participant’s Name (printed) and Signature
Date
__________________________________________________
___________
Name (printed) and Signature of Person Obtaining Consent
Date
__________________________________________________
___________
(Local) Principal Investigator’s Signature
Date
DO NOT SIGN AFTER THE EXPIRATION DATE OF:
31

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