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Building the Case for Novel Clinical Trials in Pulmonary Arterial
Hypertension
John J. Ryan1, Jonathan D. Rich2, and Bradley A. Maron3
1Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City,
UT, United States
2Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of
Medicine, Chicago, IL, United States
3Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital
and Harvard Medical School, Boston, MA, United States
Keywords
randomized controlled trials; N-of-1 study; heart failure; pulmonary vasculature; factorial design
Introduction
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular
resistance due to remodeling of distal pulmonary arterioles that occurs as a consequence of a
complex interplay between molecular and genetic factors1. The incidence of PAH is
estimated at 7–10 individuals per million people2, with a prevalence of up to 50 cases/
million3. The most recent World Health Organization (WHO) clinical classification of
pulmonary hypertension (PH)4 distinguishes Group 1 PH from pulmonary vascular disease
related to lung disease, left atrial hypertension or venothromboemoblism by including PAH
in association with anorexigen exposure, connective tissue disease, Human
Immunodeficiency Virus (HIV), or portal hypertension, among other specific co-
morbidities. In turn, idiopathic PAH (iPAH) is diagnosed in patients without a hereditary or
other identifiable cause of PAH. Owing to the diversity of diseases implicated in the
pathogenesis of PAH, a central goal among PH care centers5 is pathophenotyping patients
with pulmonary vascular disease to calibrate suitable therapy6.
Prior to “PAH-specific” drug treatment availability, diagnosing PAH functioned principally
to inform (a dismal) patient prognosis as treatment was relegated primarily to the careful use
of warfarin, digoxin, diuretics, and oxygen7. The discovery of calcium channel blocker
efficacy in this disease was a breakthrough, but this therapy was deemed to be appropriate
Address for correspondence: John J. Ryan MB BCh, FAHA, FACC, Assistant Professor, Division of Cardiovascular Medicine,
University of Utah Health Science Center, 30 North 1900 East, Room 4A100, Salt Lake City, UT 84132, john.ryan@hsc.utah.edu;
(P): 801-585-2341; (F): 801-587-5874.
Disclosures
Dr. Maron is an awardee of the Gilead Research Scholars Program from Gilead Sciences Inc. to study pulmonary hypertension.
NIH Public Access
Author Manuscript
Circ Cardiovasc Qual Outcomes. Author manuscript; available in PMC 2016 January 01.
Published in final edited form as:
Circ Cardiovasc Qual Outcomes. 2015 January ; 8(1): 114–123. doi:10.1161/CIRCOUTCOMES.
114.001319.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
for only a minority of patients and this remains true today8, 9. However, subsequent seminal
discoveries of key signaling pathways implicated in the pathogenesis of PAH in some
patients exposed for the first time disease-specific treatment targets10. In turn, results from
conventional randomized clinical trials (RCTs) validated their translational relevance and
introduced four novel drug classes to clinical practice that improve incrementally quality of
life and/or longevity in PAH patients8, 11–17. Even in the era of contemporary PAH
therapies, progressive heart failure and diminished quality of life remain common and are
associated with a one-year mortality rate of 7–17%18, 19. The persistently elevated rates of
PAH-associated morbidity and mortality raise speculation that currently used tactics to
identify optimal treatments and predict therapeutic responsiveness in PAH are insufficient,
and that additional molecular treatment targets remain unidentified20.
With the maturation and enhanced availability of applied clinical genomic- and proteomics-
based research, the defining features of PAH biology is in continual flux. Over the previous
few years, numerous molecules that contribute to PAH pathophysiology have been
identified in at least two experimental animal models of PAH in vivo or in affected
patients21–24. Moreover, the pool of potential monogenetic forms of PAH has expanded
through the recent identification of novel gene mutations in PAH family clusters25. The
ramifications of these advances are not inconsequential: the current methods for clinical
diagnosis of PAH, which hinge primarily on achieving hemodynamic metrics without regard
to other clinical variables, such as right ventricular function or patients’ molecular
pathophenotype, is increasingly recognized as antiquated and insufficient26–28.
The National Institutes of Health announced recently a major funding initiative to stimulate
investigations that leverage proteomics and genomics for the characterization of pulmonary
vascular disease phenotype29. Collectively, momentum is shifting in the PAH field toward a
personalized medicine approach to disease categorization, diagnosis, and, ultimately,
treatment implementation30. The barriers to achieving truly individualized care are
extensive, complex, and may not be surmountable. Nevertheless, in the spirit of this aim we
believe that PAH is a disease model well suited for smaller trial designs that selectively
target patients based on pathobiology (rather than general hemodynamic data alone) and
maintain adequate statistical fidelity. Additional potential virtues of these alternative clinical
research approaches in PAH include maneuverability between therapies to improve the
identification of effective drugs or drug combinations31.
The RCT is the principle clinical research method to assess efficacy of novel treatment in
PAH, and has been instrumental for identifying the vast majority of Food and Drug
Administration-approved therapies for this disease. By recruiting clinical resources from
PAH centers of excellence worldwide, RCTs have been successful at providing outcome
data relevant to this pulmonary vascular disease patient population despite the (relatively)
low prevalence of PAH. However, RCTs in PAH trials generally do not incorporate the
totality of clinical, genetic, and molecular data when designating inclusion/exclusion criteria
for enrollment20. This, in turn, increases the probability that a study cohort includes a
heterogeneous range of PAH substrates, which we believe accounts for inconsistent rates of
clinical benefit reported within RCTs, across similarly designed RCTs, and, ultimately limits
the translation of clinical trial observations to “real world” practice. One often cited
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justification for the use of conventional RCT design includes unavailability of suitable
alternative study designs. Here, we discuss clinical trial designs for the forthcoming era of
advanced molecular and genomic PAH diagnosis that maintain rigorous analysis of outcome
despite lower patient volume, which we believe are necessary elements of contemporary
clinical research studying this heterogeneous and uncommon disease. Although RCTs will
continue to play a vital role in PAH research, we feel that we must pivot and start
incorporating other designs that will better answer certain questions when a conventional
RCT is unlikely to.
PAH and Randomized Controlled Trials: An Imperfect Strategy to Study a
Complex Disease
Applying randomized clinical trial data to patient care in PAH
The traditional RCT design hinges on a reductionist approach to establishing patient
appropriateness for study consideration, which often involves 20 or more patient inclusion/
exclusion criteria for study enrollment11–14, 16, 32,33. Still, this approach does not appear to
offset the heterogeneity of PAH, as poor generalizability of findings from RCT to clinical
practice are reported26. Additional factors specific to traditional study design that are likely
to contribute to this dilemma include trial duration variability and flawed study end-points34.
Optimal therapy duration and ethical consideration of placebo use in PAH trials
The optimal duration of therapy in PAH clinical trials is unresolved. While RCTs completed
over the last two decades have demonstrated that a 12-week end-point correlates positively
with outcomes assessed in longer extension studies,35 a number of PAH studies have
included time points ranging from 8–26 weeks. Moreover, other trials have demonstrated a
benefit at 12 weeks only to observe diminished benefit at 9 months36. Data to systemically
characterize PAH-specific treatment efficacy as a function of time are unavailable; however,
the rapid trajectory of clinical decline in many patients is an important consideration to trial
design, especially in the setting of delayed clinical presentation and diagnosis that often
characterizes PAH in clinical practice37. Recent estimates indicate that despite the
availability of PAH-specific therapy, 1-year mortality rates in untreated PAH7, 38 rival
patients with moderate or severe congestive heart failure due to advanced left-sided heart
disease (New York Heart Functional Class III/IV)(Figure 1)2, 18, 39. However, clinical trials
in systolic heart failure use follow-up periods on a scale of years compared to the much
shorter durations commonly used in PAH trials40, 41.
In light of the progressive (and generally poor) natural history of untreated PAH, concern
has been raised regarding the ethical implications of placebo use in RCTs, which adds to the
complexity of performing controlled clinical studies in this disease42. Although the
association between placebo use and unanticipated mortality during RCTs in PAH is
unresolved38, withholding active treatment for the duration of RCTs (12–18 weeks) is
associated with a significantly increased short-term risk of morbidity43, including clinical
worsening. It is notable, however, that, despite these data, up to 50% of patients randomized
to placebo in the most recent PAH RCTs were not on background pulmonary vasodilator
therapy at all13, 15.
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The clinical outcome dilemma in PAH clinical research
The cornerstone outcome measure to assess intervention efficacy in PAH RCTs has
historically been distance achieved on the 6-minute walk test.11 Completion of a RCT
powered sufficiently to measure drug effect on other primary end-points, such as survival, is
uncommon due to the low prevalence of this disease and high costs associated with extended
length studies to achieve sufficient statistical power12–14, 16, 17. Although 6-minute walk
distance (6-MWD) is proposed as a marker of global health and baseline 6-MWD is an
established predictor of survival in PAH, a consistent relationship has never been observed
between change from baseline in 6-MWD and survival, PAH-associated hospitalization, or
PAH therapy escalation44. In addition, while most therapies affect mean 6-MWD to a
similar, albeit modest magnitude (approximately 20–50 m), studies evaluating the effect of
an exercise program on 6-MWD in PAH demonstrate superior improvements in 6-MWD as
compared to PAH pharmacotherapy. These findings underscore the potential bias of the
training effect on assessing functional capacity as an outcome measure in this (and other)
cardiopulmonary diseases and raises the question of the true clinical impact that a small
improvement in 6-MWD achieved actually has on PAH outcomes45. For these reasons,
many contemporary study designs in PAH have transitioned away from utilizing 6-MWD as
the sole primary end-point15, 46. Instead, other clinical endpoints have been introduced in
recently published trials, such as time to the first clinical event related to PAH and time to
general clinical worsening15.
Time-to-clinical-worsening, however, may conflict with patients’ clinical care goals by
illuminating treatment failure as inevitable. In fact, many professional societies are now
underscoring the importance of integrating patient-reported outcomes in clinical research47.
With this in mind, many PAH trials now emphasize patient reported outcomes
measurements (PROMs), such as dyspnea or quality of life. Recently, the Cambridge
Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire was demonstrated
to predict clinical deterioration at study enrollment in PAH, even after adjusting for
functional class and 6-MWD48. If validated in subsequent studies, the integration of
CAMPHOR or similar tools into future trials should be considered.
Investigational endpoints can inform the pathophysiological basis for treatment success or
failure. Often, the unavailability of technology and costs limits the widespread use of these
endpoints within RCTs when studied across large populations and different centers. While
such endpoints are unlikely to serve as the basis for drug approval, utilization of
investigational end-points in future trial designs can help further understand the relevance of
basic science or pre-clinical observations to iPAH patients. Examples of this might include
changes in pulmonary vascular metabolic status using fluorodeoxyglucose (FDG) uptake,49
or distinguishing adaptive from maladaptive RV structural changes using cardiac magnetic
resonance imaging (CMRI). Such an approach to including investigational secondary
endpoints is not without precedent; for example, many historic trials in myocardial
infarction and heart failure were designed to achieve the primary clinical endpoint while also
providing information on disease epidemiology through surrogate end-points50.
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Clinical Research Designs for PAH: Alternative to the Randomized Clinical
Trial
Factorial Design
Factorial studies allow investigators to test multiple hypotheses at once. The simplest
example is a 2×2 design where two treatments are studied. For example, if studying drug A
and drug B, a factorial design would comprise four groups: (1) active drug A plus placebo
drug B, (2) placebo drug A plus placebo drug B, (3) placebo drug A plus active drug B, (4)
active drug A plus active drug B (Table 1). When deciding on the various therapies to be
tested using a factorial design, it is important to consider the potential for drug-drug
interaction(s) between each therapy as a confounder.
Using this design, Kawut and investigators conducted a randomized, double-blind, placebo-
controlled 2×2 factorial clinical trial of simvastatin and aspirin in PAH patients receiving
background PAH therapy (Figure 2)51. Subjects were randomly assigned in a 1:1:1:1 ratio to
aspirin 81 mg once daily/simvastatin 40 mg once daily, aspirin 81 mg once daily/simvastatin
placebo once daily, aspirin placebo once daily/simvastatin 40 mg once daily, or aspirin
placebo once daily/simvastatin placebo once daily. Subjects were then evaluated at baseline,
week 6, month 3 and month 6. The study was both informative and instructive: despite
demonstrating no significant benefit from either aspirin or statin therapy on 6-MWD at 6
months, findings highlighted the feasibility and role of performing a factorial study in PAH,
particularly when different mechanistic pathways are under investigation.
Crossover study
The crossover study design is divided into specific phases. In phase I, the dependent variable
(i.e., end-point) is assessed at baseline and following randomization to treatment with study
drug or placebo for a pre-determined duration of time. In phase II, patients are administered
therapy opposite to Phase I and the end-point is re-assessed at the completion of the study
(Figure 3). Within-subject analyses are performed to compare differences in outcome
between the study drug and placebo. Advantages of this trial design include blinding and use
of a smaller sample size compared to parallel trial design20.
As discussed previously, PAH is often characterized by rapid clinical deterioration and
symptom transition across various stages of disease natural history (i.e. exertional
intolerance at early stages versus syncope and progressive right heart failure at advanced
stages). Thus, crossover studies, in which a proportion of patients are randomized to upfront
placebo generally involve patients with moderate symptom burden and do not control for
timing of drug initiation. Additionally, owing to the observation that PAH-specific therapies
appear more efficacious in patients with more severe disease, delayed drug therapy may be a
confounding factor in the interpretation of cross-over study design results in demonstrating
drug efficacy in PAH.
Singh and colleagues randomized patients with PAH (n=10) and Eisenmenger syndrome
(n=10) to receive sildenafil or placebo for 6 weeks and then crossed over to opposite therapy
after a washout period of 2 weeks52. Sample size calculation was based on a predetermined
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definition of improvement in 6-MWD by 50 m as clinically relevant, and the primary
outcome was compared using repeated-measures analysis of variance. The authors also
recorded and compared cardiopulmonary hemodynamic changes with Friedman tests.
Individual changes in mean pulmonary artery pressure, New York Heart Association
functional status, and metabolic equivalents achieved during exercise were analyzed using
the Wilcoxon signed rank test. A benefit for sildenafil use was observed in the studied
patient populations, which was later confirmed in larger RCTs12.
Randomized discontinuation trial and Withdrawal studies
A randomized discontinuation trial (RDT) is optimal for studying long-term, non-curative
therapies, especially when the use of placebo is deemed unethical53. The RDT consists of
two-phases. In the first phase, all patients are treated with the study drug, and in the second
phase, drug therapy responders are randomly assigned to switch to placebo or continue the
same treatment53. Predictive enrichment techniques are used to select subjects for study who
have the greatest chance of benefit, as medication non-adherent patients or those reporting
adverse events are generally not considered for study enrollment20. Withdrawal studies,
which are similar to RDTs in principle, aim to determine if patients may be transitioned
safely to an alternative form of therapy. Such a randomized, placebo-controlled withdrawal
trial was performed by Rubenfire and colleagues, in which clinically stable PAH patients on
epoprostenol (PGI2) therapy were randomized to transition to subcutaneous treprostinil
(PGI2) or placebo in a 2:1 manner over a period of up to 14 days (Figure 4)54. In this study,
of the 8 patients withdrawn to placebo, seven (88%) had clinical deterioration, while only 1
of 14 patients (7%) withdrawn to treprostinil deteriorated (p<0.001).
More recently, Channick and colleagues used a RDT to assess outcomes following transition
from parenteral prostacyclin to inhaled iloprost55 (Figure 5). In this study of 37 consecutive
patients, the transition period began on the first day of inhaled iloprost with intent of
discontinuing parenteral prostacyclin, and completed on the first day of treatment with
inhaled iloprost free of parenteral prostacyclin. Almost 92% of patients had an overlapping
transition with a mean transition period of 10.5 ± 13.9 days. At one year follow up, 78% of
the patients remained on inhaled iloprost alone, and 81% were free of clinical worsening. It
should be noted, however, that successful transition in this study appeared related to
concomitant oral medication use, which must be considered during RDT planning.
An important consideration of this study design in PAH is the possibility for adverse events
to occur upon therapy withdrawal. Therefore, the RDT planning phase requires particular
consideration to the individual patient’s clinical profile, particularly disease severity, when
determining appropriateness for RDT trial enrollment.
The N-of-1 Clinical Trial
A common N-of-1 trial design involves multiple crossover experiments performed over pre-
defined time periods to compare the effects of different treatments on outcome measure(s)
within an individual patient (Figure 6). Although under-represented in the cardiovascular
disease literature, Gabler and colleagues identified 108 N-of-1 trials involving 2,154 patients
published between 1985–201056, which include chronic diseases such as insomnia, attention
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deficit hyperactivity disorder, chronic obstructive pulmonary disease, and sleep disordered
breathing. Generally, following informed consent, a patient enrolled in an N-of-1 trial
undergoes baseline measurement of a specific outcome measure. The patient is randomized
to receive placebo or a therapeutic intervention for a pre-specified time period, after which
performance on the outcome measure(s) is reassessed. Following a drug washout period, the
same experimental design is repeated to measure the effect of a second therapy on the same
outcome measure(s). Ultimately, a comparison of the effect of each treatment on outcome is
performed to characterize drug efficacy. Similar to RCTs, clinicians and patients are
generally blinded to the therapeutic agent (or placebo) during the study to avoid the
introduction of bias on outcomes. Various permutations in study design involving the
number of therapy cycles, duration of therapy, role of blinding, sequence of randomization,
and potential for co-therapy is considered according to the disease process and
pharmacokinetics of the drug(s) under investigation. Overall, a favorable cost value of an N-
of-1 trial compared to RCT is likely, but hinges on the complexity of the selected end-points
and scale of the comparator RCT (Table 2).
A limitation of the N-of-1 trial in PAH is the potential rapid nature of disease progression as
well as the perils of drug withdrawal. Indeed, N-of-1 trials may be suited better for chronic,
progressive diseases characterized by a predictable mortality and event rate, as demonstrated
in a recent N-of-1 analysis of statin therapy57. Nevertheless, certain PAH patients may
warrant consideration for N-of-1 trial protocols when the disease pathophenotype is known
in order to characterize individualized response to therapy. Consider these three patients
with PAH (i) a loss of function BMPR-2 mutation that promotes angioproliferative
pulmonary vascular injury58, (ii) a loss of function KCNK3 mutation that impairs potassium
channel function to promote pulmonary vascular dysfunction21, or (iii) pulmonary vascular
inflammation and fibrosis in the setting of scleroderma-associated pulmonary arterial
hypertension. Despite an overlapping histopathology between these three patients,
interchangeability of directed therapy to restore BMPR-2-dependent signaling is unlikely to
abrogate pulmonary hypertension in the latter two patients, and vice versa for drugs that
target pulmonary vascular inflammation to treat scleroderma-associated PAH in the first two
cases. Therefore a trial of individualized therapy in an N-of-1 setting may play a role in
these patients. The N-of-1 clinical trial design is well-positioned to identify therapies that
are beneficial for specific PAH sub-pathophenotypes, but is unlikely to lend insight to the
management of PAH patients broadly, which is where investigational endpoints play a role,
i.e., by correlating the clinical improvements with changes in novel markers of disease59. A
thorough discussion of the various statistical methods used to analyze data from N-of-1 trials
is reviewed in reference60.
Limitations of novel trials in PAH
There are important characteristics of PAH that may influence use or success of novel trial
designs. PAH is a progressive disease with a variable clinical trajectory, which may
confound drug efficacy within a single patient to generate both false positive and false
negative results. Along these lines, since currently available therapies for PAH have never
been shown to reverse disease pathobiology, the assessment of drug efficacy within a patient
across different clinical stages of PAH is challenging. Thus, the timing of PAH-specific
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therapy initiation, which is controversial among experts, is unlikely to be resolved by these
alternative trial designs. Additionally, drug withdrawal is associated with acute clinical
worsening in some PAH patients, and, therefore, RDTs, withdrawal studies, and N-of-1 trial
planning should be well within the framework of expert consensus guidelines for good
clinical practice in PAH, including access to expert PAH care providers and specialized
clinical PAH systems61.
Conclusions
In summary, PAH is a rare and heterogeneous disease characterized by elevated rates of
mortality and heart failure-associated morbidity. Variability in PAH pathophenotype is a
likely contributing factor to difficulty generalizing RCT findings to patients in clinical
practice44. By contrast, we believe that crossover, RDT, and N-of-1 study designs are well
positioned to study outcomes in selected PAH patient cohorts defined by converging genetic
or molecular PAH pathophenotypes, and provide hypothesis-generating data for future study
in large RCTs (Table 1). We anticipate that achieving individualized treatment strategies in
PAH ultimately hinges on the application of the novel clinical trial strategies discussed.
Furthermore, we believe these strategies are necessary for developing cost-effective methods
that identify PAH patients likely to benefit from disease-specific pharmacotherapies
Acknowledgments
Funding Sources
This work was supported, in part, by the US NIH (1K08HL111207-01A1), the Center for Integration and
Innovative Technology (CIMIT), Pulmonary Hypertension Association, and Lerner and Klarman Foundations at
Brigham and Women’s Hospital to B.A.M..
The authors thank Dr. Stephen Archer, Queen’s University, Kingston, Ontario and Dr. Stuart Rich, University of
Chicago, for their review of this article. The authors also thank Barbara J. Stephan, Hallside Gallery curator at the
University of Utah for assistance with the figures.
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Figure 1. Mortality rates in patients with pulmonary arterial hypertension (PAH), left-sided
heart failure with reduced ejection fraction (HFrEF), and left-sided heart failure with preserved
ejection fraction (HFpEF)
(A) Kaplan–Meier survival analysis of 6,076 patients hospitalized with left-sided heart
failure hospitalized over a 15-year period (1987–2001) at Mayo Clinic Hospital (Olmsted
County, Minnesota). Compared to patients with HFpEF (red line), decreased survival was
observed in HFrEF (black line) at 5 years (adjusted hazard ratio for death, 0.96; P = 0.03).
Adapted with permission from62. (B) Kaplan–Meier analyses compares survival in the
contemporary era (2002–2005) for patients with idiopathic, familial, or anorexigen-
associated PAH (56 incident and 298 prevalent cases) (solid line) with predicted survival
data derived from the original National Institutes of Health (NIH) PAH registry. The
original NIH PAH registry included 194 patients diagnosed between July 1981 and
December 1985 and followed through August 198838. Adapted with permission from18. (C)
Kaplan–Meier analyses from panels A and B were merged using Adobe Illustrator CS5 on
Win7 OS to compare mortality rates from HFpEF (purple dotted line), HFrEF (green solid
line), and PAH (observed, blue dotted line; predicted, red line). Graph derived from 18, 38, 62.
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Figure 2. Factorial study design used in the ASA-STAT trial involving patients with pulmonary
arterial hypertension (PAH)
Patients were randomly assigned in a 1:1:1:1 ratio by a Web-based computerized system to:
(1) aspirin 81 mg once daily plus simvastatin 40 mg once daily, (2) aspirin 81 mg once daily
plus placebo simvastatin once daily, (3) placebo aspirin placebo once daily plus simvastatin
40 mg once daily, or (4) placebo aspirin once daily plus placebo simvastatin once daily.
NSAID, nonsteroidal anti-inflammatory drug; PFT, pulmonary function test; and ASA,
aspirin. Reproduced with permission from51.
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Figure 3. Schematic representation of a crossover study design
In Phase I, patients are randomized to treatment with placebo or study drug and testing
relevant to the study end-points, such as peak volume of oxygen consumption (pVO2),
occurs at study drug day 1 (i.e., baseline) and day 90. Following a 21-day drug wash out
period, subjects enter Phase II of the trial, which is characterized by cross-over to therapy
opposite of Phase I. Repeat end-point assessment will be performed at study drug day 90 of
Phase II. Change in performance on end-points from study drug day 1 at study drug day 90
(Phase I) are compared to change in performance from study drug day 1 at study drug day
90 (Phase II), using a 2-sided, paired Student’s t test.
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Figure 4. Discontinuation and Transition study design in pulmonary arterial hypertension
(PAH)
In this study, PAH patients stable on intravenous epoprostenol therapy were transitioned to
study drug (subcutaneous treprostinil or placebo, 2:1) over a period of ≤14 days. Patients
were hospitalized during the transition period and for at least 24 hr after the epoprostenol
infusions were stopped. Patients who did not complete the transition to study drug or who
had clinical deterioration were returned to continuous intravenous epoprostenol.
Assessments were conducted at baseline, prior to discharge after the transition period, and at
weeks 4 and 8. Reproduced with permission from 54.
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Figure 5. Study design of an 8-week, multicenter, randomized, placebo-controlled withdrawal
trial in pulmonary arterial hypertension (PAH)
In this randomized discontinuation trial, patients were transitioned from parenteral to
inhaled illoprost and the effects of this on safety and outcome was assessed. During time
period (a) parenteral prostacyclins are administered comprising of intravenous epoprostenol
and intravenous/subcutaneous treprostinil. At time point (b) transition Day 1 is defined as
the start day of inhaled iloprost with intent of discontinuing parenteral prostacyclin therapy.
At time point (c) post-transition Day 1 is defined as the first day on inhaled iloprost free of
parenteral prostacyclin therapy. Depending on the clinical site and/or patient, there may be
no period of concurrent (overlapping) administration of inhaled iloprost and parenteral
prostacyclin therapy and, therefore, no transition period. In such cases, transition Day 1 is
synonymous as post-transition Day 1. Po-T: post-transition; PP: parenteral prostacyclin; II:
inhaled iloprost. Reproduced with permission from 55.
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Figure 6. One potential N-of-1 clinical trial design for idiopathic pulmonary arterial
hypertension (iPAH)
This schematic depicts one potential N-of-1 clinical trial, designed to test the efficacy of
drug therapy on change in peak volume of oxygen consumption (VO2) from baseline as the
outcome measure for a 34-year old woman with iPAH. This trial model designation is A-B-
C by virtue of the three experimental phases involving Drug A (placebo), followed by Drug
B (endothelin receptor antagonist), followed by a period of therapy with Drug C
(phosphodiesterase type-V inhibitor). Each drug therapy period is separated by a drug
washout phase in order to avoid potential residual effects of prior therapy on outcome. The
time period for assessment of drug efficacy is 6 weeks, which is within the time frame of
previously published randomized clinical trials demonstrating drug efficacy in iPAH.
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Table 1
Characteristics of proposed and established study designs in pulmonary arterial hypertension (PAH).
Trial type Design Advantage Limitation Example in PAH
Randomized Controlled Trial • Patients
randomized
to study
agent or
placebo and
outcomes
assessed at
follow-up.
•Placebo
control
demonstrates
efficacy.
•Powered
adequately to
determine
effect.
•Expense.
•Ethics of
placebo use.
•Sub-
populations not
well studied.
Reference 11–17.
Factorial Design ≥2 Factors, each with ≥2
levels:
2 × 2 Factorial Design
Drug A + Placebo B
Placebo A + Placebo B
Placebo A + Active B
Active A + Active B
•Test multiple
hypotheses at
once.
•Test
combination
of agents.
•Potential
interaction
between
agents.
Reference 51.
Crossover Study • Each subject
is
administered
a particular
therapy at
different
time points
•Within
subject
analysis
possible.
•Smaller
sample size
necessary.
•Rapid clinical
deterioration
may affect
results and
limit eligibility
of patients.
Reference 52.
Randomized Discontinuation Trial • Responders
to drug
therapy are
randomly
assigned to
placebo or
continued
treatment
•Removal of
patients that
are therapy
non-
responders is
an element of
study design.
•Adverse events
may occur
upon
withdrawal of
drug.
Reference 54.
N-of-1 Clinical Trial • Multiple
crossover
experiments
over a pre-
defined time
period.
•Individualized
therapeutic
response
identified.
•Limited
statistical
power,
generalizability
of findings to
other patients
unknown.
None reported.
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Table 2
Sample cost-analysis for a placebo-controlled, randomized clinical trial in idiopathic pulmonary arterial hypertension (iPAH)
Published cost estimates for a typical randomized clinical trial (RCT) in iPAH vary substantially based on several key factors, including study duration,
complexity of selected end-points, enrollment, and study drug price. Differences in Institutional Review Board (IRB) and study drug fees for an N-of-1
trial compared to a RCT reflect the single center nature of the design and differences in drug treatment duration.
Randomized Clinical Trial N-of-1 Trial
Study Element Baseline Cost (USD) Iterations/Study (N) Total Cost Per Element (USD) Iterations/Study (N) Total Cost Per Element (USD)
Informed Consent Processing 150.00 1 150.00 1 150.00
History and PE 500.00 3 1,500.00 4 2,000.00
Vital sign assessment 50.00 3 150.00 4 150.00
Outcomes questionnaires 100.00 3 300.00 4 400.00
Drug Compliance Assessment 50.00 3 150.00 4 200.00
Study Personnel 700.00 1 700.00 0 0.00
6-MWT 550.00 1 550.00 4 2,200.00
Cardiopulmonary Exercise Test 1,100.00 2 2,200.00 4 4,400.00
Echocardiography 300.00 1 300.00 4 1,200.00
IRB fees 4,000.00 1 4,000.00 1 1,000.00
Study Drug*
ERA (12 wk)
High Dose 12,100.00 1 12,100.00 - -
ERA (12 wk)
Low Dose 12,100.00 1 12,100.00 - -
ERA (6 wk) - - - 1 6,050.00
PDE-V (6 wk) - - - 1 2,700.00
ERA+PDE-V (6 wk) - - - 1 8,750.00
Subtotal Costs 34,200/patient 29,200/patient
Total Costs For Trial 2,052,000.00 29,200
*Value for Study Drug Costs reflects mean costs for daily study drug use and placebo, based on published costs associated with phosphodiesterase type V inhibitor class medication.9 USD, United States
Dollars ($); PE, physical examination; 6-MWT, 6-minute walk test.
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