Clinical trial NCT01461668
Conditions: Methicillin-Resistant Staphylococcus Aureus
Keywords: MRSA MRSA resistant to mupirocin
Sponsor: University of California, Irvine
Start date: 2012-07-01; Completion date: 2017-12-01
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators will conduct a randomized placebo-controlled double-blinded study of nasal decolonization with retapamulin vs. placebo for the eradication of MRSA nasal carriage among adult carriers with low-level (MIC 8-256) and high-level mupirocin resistant (MIC \>256) strains.

Objectives:

1. To determine the percent of intervention vs. control patients with successful MRSA nasal decolonization as determined by bilateral nares swabs following a 5-day twice-a-day regimen of retapamulin.
2. To determine the time to decolonization based upon interim and final bilateral nares swabs.
3. To determine the acceptability of retapamulin by surveying participants about their experience and adverse events experienced during this study.

The duration of participant follow-up is expected to last up to 7 weeks.

This study will evaluate the safety and effectiveness of Altabax (retapamulin) during decolonization of MRSA carriers with mupirocin-resistant strains, stratified by low-level and high-level resistance to mupirocin. Mupirocin resistance is increasingly common and there is no approved substitute topical agent for decolonization of the MRSA nasal reservoir.

Detailed description:
This study will evaluate the utility of retapamulin, a topical ointment FDA approved for skin infection, as a novel agent for MRSA decolonization and prevention of healthcare-associated MRSA infection. Retapamulin is a first-in-class semi-synthetic pleuromutilin antibiotic that inhibits protein synthesis by interacting with the bacterial ribosome 50S subunit. It received FDA approval in 2007 for the topical treatment of impetigo in adults and pediatric patients.

We propose to evaluate retapamulin as an investigational agent for the nasal decolonization of MRSA carriers whose strains demonstrate low-level and high-level resistance to mupirocin. Mupirocin resistance is increasingly common and there is no approved substitute topical agent for decolonization of the MRSA nasal reservoir.

We will conduct a randomized placebo-controlled double-blinded study of nasal decolonization with retapamulin vs. placebo for the eradication of MRSA nasal carriage among adult carriers with low-level (MIC 8-256) and high-level mupirocin resistant (MIC \>256) strains. Randomization will be stratified by low vs high level resistance.

Consenting adult (at least 18 years old) subjects will be randomized to 1% retapamulin or placebo ointment intra-nasally twice a day for 5 days (D1-5) with follow up bilateral nares swab one week following completion of therapy (\~D12) to assess clearance. If follow up swabs are positive for MRSA, patients will be given a second course of the same agent (retapamulin or placebo) to begin one week following swab collection (\~D19-23) so that up to two decolonization attempts will be made. A final set of bilateral nares swabs will be obtained from all subjects six weeks from the completion of initial treatment (\~D47).

Consenting adult (at least 18 years old)subjects will be given retapamulin or placebo. At the time of recruitment, all subjects will complete a detailed survey administered by trained research staff. This survey will include questions related to self care, home hygiene practices, and known risk factors for MRSA acquisition. Subject follow up will include repeat bilateral nares swabs and follow up surveys related to compliance, experience (side effects/concerns) with the assigned regimen, and ongoing risk factors will occur either during a home visit (or facility visit if the patient is admitted to a hospital or nursing home at the time of the required visit) or at the University of California Irvine (UCI) Institute for Clinical and Translational Science (ICTS), a Clinical and Translational Science Award (CTSA) site which provides clinic visit support for pilot studies.

Outcomes will include successful nares decolonization at the end of the follow up period (D47). We will detail the sequence of clearance or re-colonization based upon the two follow up nares swabs, as well as any adverse events, which are expected to be related to local irritation in a small percent of subjects.

Arms: arm 1: Participants in this arm will be instructed to complete a decolonization regimen that will involve a 5-day application of retapamulin with follow up bilateral nares swab one week following completion of therapy (\~D12) to assess clearance. If follow up swabs are positive for MRSA, patients will be given a second course of the same agent (retapamulin) to begin one week following swab collection (\~D19-23) so that up to two decolonization attempts will be made. A final set of bilateral nares swabs will be obtained from all subjects six weeks from the completion of initial treatment (\~D47). arm 2: Participants in this arm will be instructed to complete a decolonization regimen that will involve a 5-day application of a placebo with follow up bilateral nares swab one week following completion of therapy (\~D12) to assess clearance. If follow up swabs are positive for MRSA, patients will be given a second course of the same agent (placebo) to begin one week following swab collection (\~D19-23) so that up to two decolonization attempts will be made. A final set of bilateral nares swabs will be obtained from all subjects six weeks from the completion of initial treatment (\~D47).
Interventions: intervention 1: Retapamulin intervention 2: Placebo
Intervention descriptions: intervention 1: Two times a day for 5 days intervention 2: Two times a day for 5 days

Protocol documents:
Prot_000.pdf: 
Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
Retapamulin for Reducing MRSA Nasal Carriage 
Study Protocol 
January 27, 2012 
ClinicalTrials.gov ID: NCT01461668 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
2 
 
I. BACKGROUND 
Methicillin-Resistant Staphylococcus aureus (MRSA or also known as “mer-sa”) is bacteria 
(germ) that can be found living on the body, especially in the nose.  MRSA infections are 
common among people who have weak immune systems and are in hospitals, nursing homes, 
and other health care centers.  Infections can appear around surgical wounds or invasive 
devices, like catheters or implanted feeding tubes. Rates of infection in hospitals, especially 
intensive care units, are rising throughout the world.  Though most MRSA infections are not 
serious, some can be life-threatening. Many public health experts are alarmed by the spread of 
antibiotic-resistant bacterial strains like MRSA, which are also known as "super bugs."   
Currently, prevention for MRSA is restricted to education for the public and patients who harbor 
MRSA. Currently, some physicians will attempt to rid MRSA from the body to prevent later 
infection using special soaps and medicines. Use of these strategies is variable since no 
definitive guidance exists for their use. Currently, one of the medications to eradicate MRSA 
from its most common body reservoir, the nose, is a drug known as mupirocin. Mupirocin is an 
ointment approved for MRSA removal. However, in recent years, resistance to mupirocin is 
rising among MRSA strains. A second drug, retapamulin has been shown in the laboratory to be 
highly active against all MRSA strains, even mupirocin resistant ones. While retapamulin is FDA 
approved for use in open wounds and skin infections, it is not currently approved for use in the 
nose. The purpose of this study is to evaluate whether retapamulin (an FDA approved topical 
ointment for treatment of staphylococcus) which is commonly used to treat MRSA wound 
infections, may work in clearing MRSA from the noses of people who have MRSA types that are 
resistant to mupirocin.  The route of administration that will be investigated is to apply the 
ointment via the nasal passage twice daily for up to 5 days.  The effects of retapamulin will be 
compared to placebo (inactive similar ointment) in a randomized placebo controlled double-
blinded trial. 
 
II. INVESTIGATIONAL PRODUCT 
Altabax (retapamulin) has been FDA approved since April 2007 for use in the topical treatment 
of impetigo due to susceptible strains of Staphylococcus aureus or Streptococcus pyogenes, the 
two most common types of bacteria in this kind of infection. 
Altabax (retapamulin) is a semisynthetic pleuromutilin antibiotic. 
The chemical name of retapamulin is acetic acid, [[(3-exo)-8-
methyl-8-azabicyclo[3.2.1]oct-3-yl]thio]-, 
(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-
hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9propano-3aH-
cyclopentacycloocten-8-yl ester. Retapamulin, a white to pale-
yellow crystalline solid, has a molecular formula of C30H47NO4S, 
and a molecular weight of 517.78.  
Altabax (retapamulin) has not been withdrawn from investigation or marketing in the United 
States or any other country for any reason related to safety or effectiveness. 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
3 
 
III. PURPOSE & OBJECTIVES 
The purpose of this study is to evaluate altabax (retapamulin) as an investigational agent for 
decolonizing MRSA carriers with high-level resistance to mupirocin. Mupirocin resistance is 
increasingly common and there is no approved substitute topical agent for decolonization of the 
MRSA nasal reservoir.   
Objectives 
1. Evaluate the proportion of patients treated with retapamulin vs placebo who clear nasal 
carriage with a mupirocin-resistant strain of MRSA  
2. Evaluate the time to MRSA clearance among patients treated with retapamulin vs 
placebo for nasal carriage with a mupirocin-resistant strain of MRSA (one treatment 
course or two)  
3. Evaluate side effects reported with nasal administration of retapamulin compared to 
placebo 
 
IV. STUDY DESIGN 
This is a randomized placebo-controlled double-blind study of nasal decolonization with 
retapamulin vs. placebo for the eradication of MRSA nasal carriage among adult carriers with 
mupirocin resistant strains. Randomization of eligible patients will be stratified by participants 
with low-level (MIC 8-256) and high-level mupirocin resistant (MIC >256) strains. 
Eligible subjects will be randomized to 1% retapamulin or placebo ointment intra-nasally twice a 
day for 5 days (D1-5) with follow up bilateral nares swab one week following completion of 
therapy (~D12) to assess clearance. If follow up swabs are positive for MRSA, subjects will be 
given a second course of the same agent (retapamulin or placebo) to begin one week following 
swab collection (~D19-23) so that up to two decolonization attempts will be made. A final set of 
bilateral nares swabs will be obtained from all subjects six weeks from the completion of initial 
treatment (~D47).  
Overview for Study Participants 
Consent Date 
Swab nares, complete survey 
Day 0 
Swab confirms mupirocin-resistant MRSA, provide 5-day protocol 
(retapamulin vs placebo) 
Day 1 
Initiate 5-day protocol (retapamulin vs placebo) 
Day 12 
Follow Up Visit 1, complete survey, swab nares 
 
If nares from day 12 still shows MRSA, repeat 5-day protocol 
Day 47 
Follow Up Visit 2, complete survey, swab nares 
 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
4 
 
Consenting subjects will be given retapamulin or a placebo. Additionally, all subjects will be 
given an education material to follow standard-of-care for patients harboring MRSA. At the time 
of recruitment, all subjects will complete a detailed survey administered by trained members of 
research team. This survey will include questions related to comorbidities and presence of 
wounds or central lines. Subject follow up will include repeat bilateral nares swabs and follow up 
surveys related to compliance with the assigned regimen and will occur either during a home 
visit (or facility visit if the patient is admitted to a hospital or nursing home at the time of the 
required visit) or at the University of California Irvine (UCI) Institute for Clinical and Translational 
Science (ICTS), a Clinical and Translational Science Award (CTSA) site.   
 
V. OUTCOMES 
Primary outcome will be successful nares decolonization at the end of the follow up period 
(D47). The members of the research team will also detail the sequence of clearance or re-
colonization based upon the two follow up nares swabs with and without re-treatment by 
assigned protocol. We will define any adverse events, which are expected to be related to local 
irritation in a small percent of subjects (1.4% reported site irritation when applied to lesions, as 
per package insert). As a potential corollary, use of the nasal product mupirocin, which is FDA 
approved for intranasal use for MRSA clearance resulted in <1% of patients in clinical trials 
withdrawing due to adverse events. With mupirocin, the most frequently reported adverse 
events were as follows: rhinitis (1.0%), taste perversion (0.8%), and pharyngitis (0.5%). 
 
VI. DURATION OF INDIVIDUAL SUBJECTS EXPOSURE TO DRUG  
Eligible subjects who are randomized to 1% retapamulin intra-nasally will be directed to apply it 
twice a day for 5 days. For those that fail to clear MRSA by their first follow up visit, a second 
course directing application of retapamulin twice a day for an additional 5 days will be provided 
to allow up to two decolonization attempts to be made.  
 
VII. DESCRIPTION OF THE OBSERVATIONS AND MEASUREMENTS TO BE 
MADE TO FULFILL THE STUDY OBJECTIVES  
 
At the time of recruitment, all subjects will complete a detailed enrollment survey administered 
by trained research staff. This survey will include enrollment information (demographic, contact), 
questions related to self care, home hygiene practices, high contact sports or other activities, 
comorbidities, and presence of wounds or central lines. They will also have a nasal swab 
performed to confirm the presence of MRSA carriage with a strain resistant to mupirocin. Once 
swab cultures confirm the presence of MRSA resistant to mupirocin, subjects will be 
randomized to receive 5-days of either placebo or retapamulin with the first treatment day being 
Day 1. Subject follow up will include repeat bilateral nares swabs (Day 12 (range 9-15), Day 47 
(range 37-57) and follow up surveys related to compliance and experience (side 
effects/concerns) with the assigned regimen and will occur either during a home visit (or facility 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
5 
 
visit if the patient is admitted to a hospital or nursing home at the time of the required visit) or at 
the University of California Irvine (UCI) Institute for Clinical and Translational Science (ICTS).  
All study subjects will have subject enrollment and follow-up data maintained in a secure 
electronic database that only authorized members of the study team will have access to. 
 
VIII. MEASURES TAKEN TO MONITOR THE EFFECTS OF THE DRUG IN HUMAN  
SUBJECTS AND TO MINMIZE RISK 
 
This topical agent is already FDA approved for application to the skin. The novel use requested 
here is application to the nasal mucosa. An FDA IND has been received for its use in this study 
as a nasal product. Previous studies with retapamulin on abraded skin failed to show sufficient 
absorption to raise concerns about the drug itself or interaction with systemic agents (see 
package insert). Thus, in this, there will be no direct testing of the systemic levels of this drug. 
To determine if retapamulin is effective in reducing MRSA clearance, serial bilateral nares 
swabs will be taken to confirm MRSA mupirocin resistance and to assess persistence of MRSA 
carriage during this study. A toll free number and 24/7 pager that will be answered by the study 
team will be available to subjects for the reporting of any side effects. In addition, a survey 
assessing compliance and side effects/concerns with the assigned regimen will be performed 
during all follow up visits. 
 
IX. RECRUITMENT METHODS  
The recruitment process will be initiated by study staff who have experience recruiting 
patients into clinical trials and are familiar with the protocol and the consenting process. This 
study to evaluate the safety and efficacy of intra-nasal retapamulin for decolonization of 
mupirocin-resistant MRSA carriers will be conducted in our California regional trial 
environment where patients will be recruited through one of the following methods:  
1) Subjects previously enrolled in a randomized clinical trial (Clinicaltrials.gov ID: 
NCT01209234) found to have low-level (MIC 8-256) or high level (MIC >256 mcg/ml) mupirocin-
resistant MRSA strains at the end of their follow up period will form one source of recruitment 
into the retapamulin study. Willing subjects would consent to a current screening MRSA swab at 
the time of recruitment to confirm the presence of a mupirocin resistant isolate. Patients will be 
randomized within strata of low level and high level mupirocin-resistant strains. 
2) Patients with MRSA isolates processed for mupirocin resistance at the University of California 
Irvine Medical Center clinical microbiology laboratory will also be eligible for recruitment if 
harbored MRSA strains show low level or high level resistance. Patients will be similarly 
randomized based upon strata of low level and high level mupirocin-resistant strains. 
To ensure that a subject has the option to speak with a physician at the end of the consent 
process, a study doctor will be available via pager or phone to answer any questions or 
concerns a subject might have prior to finalizing consent. 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
6 
 
Review and approval of this human protocol will be conducted by the UCI Institutional Review 
Board (IRB) Human Subjects Review Committee.  Subjects must be able to understand and 
sign an informed consent form. Consent forms must comply with U.S. regulations (U.S. 21 CFR 
50) and ICH guidelines to be eligible for this trial.  All study materials, including consent forms 
will be provided in the patient’s primary language.  In addition, each subject will be given a copy 
of the consent form, the Experimental Subjects’ Bill of Rights, and HIPAA Release form, all of 
which will be explained to the subject. 
 
X. INCLUSION AND EXCLUSION CRITERIA  
Inclusion Criteria 
 
1. Adult, at least 18 years of age or older 
2. MRSA carrier of a mupirocin resistant strain  
3. Must be able to provide consent 
 
Exclusion Criteria 
 
1. Known allergy to retapamulin 
2. Inability to use an intranasal product (e.g. recent nasal surgery, anatomic defects) 
3. Pregnant or breastfeeding 
 
Children (under the age of 18 years old) will be excluded since post-carriage MRSA risks have 
not been studied among those <18 years old and there is insufficient data to estimate the effect 
or potential benefit in this age group. This also translates to an inability to calculate power or 
sample size needs to answer the questions in this trial for children <18.  
In addition, there are several reasons to believe that the risk in children <18 will be different 
from those in adults. First, and most importantly, they have a much lower frequency of risk 
factors for MRSA disease, including comorbidities, medical devices and procedures. Second, 
their risk of MRSA carriage has been found to be lower than in adults. Third, children 
experience a much higher proportion of disease due to community-associated MRSA infection 
(and strains) versus healthcare associated infections (and strains). These differences suggest 
that the mechanisms for MRSA acquisition may be different in children compared to adults. 
Fourth, children also experience much more skin and soft tissue disease and less of other types 
of infections, again suggesting substantial differences in children and adults that would support 
a separate trial in this age group. For all these reasons, we will exclude children under the age 
of 18. 
Women who are pregnant or breastfeeding will be excluded from the study.  Retapamulin is 
Pregnancy Category B drug, defined by the FDA as an agent in which animal reproduction 
studies have failed to show a risk to the fetus. The effects of retapamulin on fertility or a human 
fetus are not known, however absorption is deemed so minimal that pharmacokinetic studies 
were not deemed necessary by the FDA.  Animal studies have been performed and have not 
shown concerns; however since animal studies are not always predictive of human response, 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
7 
 
retapamulin should only be used on pregnant women if clinically necessary. Despite minimal 
absorption, as a precautionary measure, we will not be recruiting patients known to be pregnant 
or breastfeeding into this study. In addition, we will recommend abstinence or contraception for 
those who wish to participate. However, since the current FDA approved usage of retapamulin 
on open wounds does not require a pregnancy test nor contraception, we will only recommend, 
but not require, that all subjects abstain from sexual activity or use birth control while taking 
study product. 
 
XI. RISKS AND DISCOMFORTS 
Subjects are informed of the risks and side effects that are known to possibly occur due to 
Retapamulin and procedures involved during this study. Subjects are also instructed to contact 
their study doctor or a member of the study team immediately if they experience any problems 
during the course of the study. All subjects will be closely monitored throughout the study and 
may be asked to come into UC Irvine for an unscheduled visit, at the discretion of the lead 
researcher. In addition, all subject data will be de-indentified with a key-code and only the study 
team and authorized individuals involved with the study will have access to the code.  All 
measures will be taken by the study team to protect the confidentiality of every subject’s 
personal health information. 
 
XII. ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
All adverse events will be tracked until resolved or participation in the study has ended, 
whichever comes first. All serious adverse events will be tracked until resolved. In accordance 
with UCI IRB’s guidelines, all adverse events and unanticipated problems will be reported per 
policy. There will be a Data Safety Advisory Committee to oversee the number and composition 
of adverse events, and assess any need for intervention or discontinuation of study protocols 
 
Study coordinators will be available from 8am-5pm via a toll-free phone number. Should a 
subject require immediate assistance after hours (5pm – 8am) or on weekends, the Senior 
Project Coordinator and Supervisor will be available via pager. The Senior Project Coordinator 
and Supervisor can assist the subject with any questions and concerns and can promptly put 
them in contact with study investigators as needed. In addition, study staff will query for adverse 
events or other unanticipated problems via phone calls and during scheduled follow up visits. If 
adverse events are identified, subjects may be referred for a phone conversation or in person 
visit with a nurse of physician at ICTS. If an adverse event is serious, the subject is instructed to 
contact 911 or go to the nearest Emergency Department for immediate care. 
 
 
XIII. PARTICIPANT COMPENSATION AND REIMBURSEMENT 
 
Subjects will be required to have two follow-up visits at 2 weeks and 6 weeks from 
randomization. Subjects will be compensated $25 for the first follow-up visit and $25 for the 


Retapamulin Protocol  - Version 1.0 
January 27, 2012 
 
8 
 
second follow-up visit with cash payment. Total payment for participation in this study is $50. If 
subjects cannot attend the follow-up visits, recruiters will drive to their location and perform the 
follow-up procedures there. If subjects decide to withdraw from the study or are withdrawn by 
the study team, they will receive compensation for the visits that they have completed. 
 

SAP_001.pdf: 
 
 
 
Randomized Placebo Controlled Trial of Retapamulin in Mupirocin Resistant Patients: Page 1 of 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retapamulin for Reducing MRSA Nasal Carriage 
Statistical Analysis Plan 
October 28, 2011 
ClinicalTrials.gov ID: NCT01461668 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Randomized Placebo Controlled Trial of Retapamulin in Mupirocin Resistant Patients: Page 2 of 4 
 
 
 
Statistical Analysis Plan for Randomized Placebo Controlled Trial of Retapamulin in 
Mupirocin Resistant Patients 
D. L. Gillen 
October 28, 2011 
 
Statistical Analysis Plan 
 
The current study seeks to demonstrate the superiority of Retapamulin to Placebo with respect to 
the probability of virus clearance at 6 weeks following hospital discharge.  In making the 
decision to terminate the study, investigators shall be guided by a formal stopping rule based on 
the primary endpoint of the probability of clearance at 6 weeks following hospital discharge. The 
test statistic shall be the normal approximation to the difference in binomial proportions between 
the treatment and control group. In the event that testing is performed at lower than expected 
sample sizes, a more conservative Fisher’s Exact test will also be performed to assess sensitivity 
to the normal approximation under small sample sizes. Additional secondary analyses that adjust 
for covariates will be performed using generalized estimating equations and logistic regression.  
 
The clinical trial may be stopped early either for reasons of demonstrated efficacy (the 
Retapamulin treatment arm has significantly higher probability of clearance at 6 weeks when 
compared to the placebo arm) or for reasons of futility (the probability of clearance at 6 weeks on 
the Retapamulin arm is not sufficiently higher than that on the placebo arm to warrant 
continuation of the trial). 
 
The formal stopping boundaries will be determined by a symmetric one-sided design (Emerson 
and Fleming, Biometrics, 1989), a family also included in the unified family of group sequential 
stopping rules (Kittelson and Emerson, Biometrics, 1999). In the notation of the latter paper, the 
stopping rule will be based on a one-sided group sequential design testing a upper alternative 
hypothesis at a level of significance =.025 with =.975, an upper (efficacy) stopping boundary 
relationship specified by Pd = 1.0 (an O'Brien-Fleming (1979) type boundary),  and a lower 
(futility) stopping boundary relationship specified by Pa =1.0 (an O'Brien-Fleming type 
boundary).  It is envisioned that one formal interim analysis will be performed during the 
monitoring of the study, occurring at 50% of the maximal sample size. Under such a monitoring 
schedule and assuming a baseline probability of spontaneous clearance of 40% at 6 weeks in the 
placebo arm, a maximal sample size of 116 patients (58 patients on the Retapamulin arm and 58 
patients on the placebo arm) will provide approximately 90.2% power to detect a 30% absolute 
difference in the probability of clearance at 6 weeks. The following table provides a more 
detailed description of the power provided by such a sample size for a range of baseline 6 week 
spontaneous clearance rates in the placebo arm. 
 
 
 
 
 
 
 


 
 
 
Randomized Placebo Controlled Trial of Retapamulin in Mupirocin Resistant Patients: Page 3 of 4 
 
 
 
Table 1: Alternatives for which a maximal sample size of 116 subjects provides the specified power as a 
function of the 6 week clearance rate on the placebo arm. 
 
 
Power 
30% Probability of Clearance 
at 6 weeks in the Placebo Arm 
40% Probability of Clearance at 
6 weeks in the Placebo Arm 
50% Probability of Clearance 
at 6 weeks in the Placebo Arm 
Retapamulin 
Probability 
Diff From 
Placebo 
Retapamulin 
Probability 
Diff From 
Placebo 
Retapamulin 
Probability 
Diff From 
Placebo 
50% 
47.57% 
17.57% 
58.08% 
18.08% 
68.13% 
18.13% 
80% 
55.10% 
25.10% 
65.84% 
25.84% 
75.91% 
25.91% 
90% 
59.04% 
29.04% 
69.90% 
29.90% 
79.98% 
29.98% 
95% 
62.30% 
32.30% 
73.25% 
33.25% 
83.34% 
33.34% 
97.5% 
65.13% 
35.13% 
76.17% 
36.17% 
86.26% 
36.26% 
 
Under the planned schedule of one interim analysis at 50% of the maximal sample size and 
assuming a baseline probability of spontaneous clearance at 6 weeks in the placebo arm, Table 2 
presents the stopping boundaries at the interim and final analysis for the specified stopping rule 
expressed as the absolute difference 6 week clearance rates (Retapamulin – Placebo). Also 
presented are the Z statistics and fixed sample upper one-sided P values that correspond to those 
stopping boundaries. 
 
Table 2: Stopping boundaries for a level .025 one-sided symmetric design with Pa = Pd = 1.0, one interim 
analysis at 50% maximal information, a maximal sample size of 116 subjects, and a 6 week clearance rate of 
approximately 55% on both treatment arms combined. 
 
 
Analysis 
 
Sample Size 
(R, P) 
Futility (lower) stopping boundary 
Efficacy (upper) stopping boundary 
Abs Diff 
(%) 
 
Z statistic 
Fixed P 
(upper) 
 
Abs Diff 
 
Z statistic 
Fixed P 
(upper) 
1 
58 (29, 29) 
0.000% 
0.0000 
0.5000 
36.17% 
2.7897 
0.0026 
2 
116 (58, 58) 
18.08% 
1.9726 
0.0243 
18.08% 
1.9726 
0.0243 
 
Thus, according to the above table, if the 6 week clearance rate on the combined treatment arms 
is 55%, an absolute difference in the probability of 6 week clearance of 0% or less (e.g., 55% 
probability of clearance on the placebo arm and the Retapamulin arm) when 58 subjects have 
been accrued to the study (29 subjects on each arm), the stopping rule would suggest that the 
study be terminated early with a decision that it was futile to continue the trial because there was 
not sufficient evidence that any beneficial effect of Retapamulin was clinically important. On the 
other hand, if at that first analysis there were an absolute difference in the rate of 6 week 
clearance of 36.17% or more (e.g., 36.92% probability of clearance at 6 weeks on the placebo 
arm and 73.09% probability of clearance at 6 weeks on the Retapamulin arm), the stopping rule 
would suggest that the study be terminated early with a decision that treatment with Retapamulin 
results in a statistically significant improvement in the probability of clearance at 6 weeks.  
 
For the setting presented in Table 2 (i.e., a combined 6 week clearance rate of 55%), Table 3 
presents the statistical inference that would be reported if the study were to result in observed 
treatment effects corresponding to the stopping boundaries. The estimates, P values, and 
confidence intervals reported in Table 3 have been adjusted for the stopping rule. (Note that the 
fixed sample P value presented in Table 2 is not appropriate for statistical inference.)  
 


 
 
 
Randomized Placebo Controlled Trial of Retapamulin in Mupirocin Resistant Patients: Page 4 of 4 
 
 
 
Table 3: Statistical inference regarding the effect of Retapamulin on the probability of clearance at 6 weeks 
(measured as the absolute difference in 6 week clearance rates between the Retapamulin and placebo arms) 
which would be reported if observed results corresponded exactly to the stopping boundaries for a level .025 
one-sided symmetric design with Pa = Pd = 1.0, one interim analysis at 50% maximal information, a maximal 
sample size of 116 subjects, and a 6 week clearance rate of approximately 55% on both treatment arms 
combined as presented in Table 2. 
 
 
Analysis 
 
Sample Size 
(R, P) 
Futility (lower) stopping boundary 
Efficacy (upper) stopping boundary 
Adjusted 
estimate 
  
95% conf intvl 
Adjusted 
P value 
Adjusted 
estimate 
 
95% conf intvl 
Adjusted 
P value 
1 
58 (29, 29) 
2.5% 
(-16.2%, 25.6%) 
.375 
33.7% 
(10.5%, 52.4%) 
.003 
2 
116 (58, 58) 
18.1% 
( 0%, 36.2%) 
.025 
18.1% 
(0%, 36.2%) 
.025 
 
The exact stopping boundaries that are appropriate for the group sequential design will depend 
upon the exact schedule of interim analyses and the best estimate of the variability of the test 
statistic as computed from the observed 6 week clearance rates. The intended schedule of interim 
analyses is one analysis at 58 patients and a final analysis at 116 patients. Modifications of the 
stopping rule to account for any changes in the schedule of interim analyses and estimates of 6 
week clearance rates will be made by using the parametric form of the stopping rule as specified 
above, with constraints imposed for analyses previously performed. Boundaries will be 
constrained on the scale of the maximum likelihood estimate of the treatment effect, with the 
current best estimate of the test statistic’s variance used at each analysis (Burrington and 
Emerson, Biometrics, 2003). The one-sided type I error will be maintained at .025, and the 
maximal sample size will be constrained at 116 subjects. 
 
At the formal interim analysis, the study statistician will use the stopping rule computed in the 
above manner as a guideline in evaluating the trial results with respect to the probability of 
clearance at 6 weeks. In making a final decision to terminate the study, study investigators will of 
course also consider information on safety endpoints, as well as consistency of outcomes for 
secondary endpoints and consistency of outcomes within important subgroups as described in the 
protocol.