The Assessment of Prednisone In Remission Trial (TAPIR) - Patient Centric Approach
Phase: PHASE3
Conditions: Granulomatosis With Polyangiitis, Wegener Granulomatosis, Vasculitis
Sponsor: University of South Florida

The Assessment of Prednisone In Remission 
Trial (TAPIR) – Patient Centric Approach 
Vasculitis Clinical Research Consortium (VCRC) 
Protocol Number 5526B
          NCT01933724  
Version Date 04April2017
Study Chairs: 
Jeffrey P. Krischer, Ph.D. 
Peter A. Merkel, M.D., M.P.H. 
University of South Florida 
University of Pennsylvania  
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this 
protocol are intended only for use by Consortium investigators in 
carefully controlled settings.  The Chair of this study should be 
consulted before using or attempting any procedure in this protocol. 
TAPIR 
THE ASSESSMENT OF PREDNISONE IN REMISSION TRIAL 

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Participating Institutions/Investigators Table (contact information) 
 
 
Co- Principal Investigator:  Peter A. Merkel, MD, MPH 
Contact:  Carol McAlear, MA 
Institution: University of Pennsylvania 
Address: 8th Floor Penn Tower, 3400 Spruce St., 
Philadephia, PA 19104 
Phone: 781-321-4567 
Email: cmcalear@upenn.edu 
 
Co- Principal Investigator:  Jeffrey P. Krischer, Ph.D. 
Contact:  Cristina Burroughs 
Statistician: David Cuthbertson, M.S. 
Institution/ 
Department: 
Data Management and Coordinating Center (DMCC); Health Informatics 
Institute; University of South Florida 
Address: 3650 Spectrum Blvd; Suite 100 
Tampa, FL  33612 
Phone: 813-396-9237 
Fax: 877-775-7987 
Email: cristina.burroughs@epi.usf.edu 
 
 

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Table of Contents 
1. 
Protocol Synopsis Table .............................................................................................4 
1a.  Brief Summary ....................................................................................................7 
1b.  Detailed Description ............................................................................................7 
2. 
Study Endpoints ..........................................................................................................8 
2a.  Primary Outcome ................................................................................................8 
2b.  Secondary Outcomes ...........................................................................................8 
3. 
Background and Rationale ..........................................................................................8 
3a.  Background .........................................................................................................8 
3b.  Rationale ............................................................................................................10 
4. 
Study Design and Methods .......................................................................................11 
4a.  Overview ...........................................................................................................11 
4b.  Study Diagram ...................................................................................................11 
4c.  Recruitment .......................................................................................................12 
4d.  Eligibility Criteria ..............................................................................................13 
4di.  Inclusion Criteria .............................................................................................13 
4dii.  Exclusion Criteria ............................................................................................14 
4e.  Randomization Procedures ................................................................................14 
4f.  Visit Frequency/Visit Schedule .........................................................................14 
4g.  Data Elements for Collection ............................................................................15 
4h.  Retention Strategies ...........................................................................................15 
5. 
Safety Monitoring and Adverse Event Reporting .....................................................16 
5a.  Nature of Study .................................................................................................16 
5b.  Adverse Events ..................................................................................................16 
6. 
Data Analysis and Statistical Considerations ...........................................................18 
6a.  Sample Size .......................................................................................................18 
6b.  Stratification ......................................................................................................19 
6c.  Secondary outcomes ..........................................................................................19 
7. 
Data Management .....................................................................................................19 
7a.  Registration/Online Consent .............................................................................19 
7b.  Data Entry ..........................................................................................................19 
7c.  Data Quality Control .........................................................................................20 
8. 
Protection of Human Subjects ..................................................................................20 
9. 
References .................................................................................................................21 
 
 
 

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1. Protocol Synopsis Table 
Protocol Number: 5526B 
Protocol Title: The Assessment of Prednisone In Remission Trial (TAPIR) 
– Patient Centric Approach 
Study Chairs: Jeffrey P. Krischer, Ph.D. 
Peter A. Merkel, M.D., M.P.H. 
Statistician: David Cuthbertson, M.S. 
Participating Sites: University of Pennsylvania 
University of South Florida 
Activation Date: February 17, 2014     
Sample Size: A maximum of 79 randomized participants for a total 
sample size of 159 evaluable randomized participants 
between the Centers of Excellence (CoE) and Patient 
Centric (PC) study arms. 
Target Enrollment 
Period: 
5 years 
Study Design: Randomized controlled trial to evaluate the effects of using 
low-dose glucocorticoids as compared to stopping 
glucocorticoid treatment entirely.  Participants will be 
randomized 1:1 to: 
 taper their prednisone dose down to 5 mg/day using 
a tapering schedule determined by their treating 
physician and stay at 5 mg/day of glucocorticoids 
for the duration of the study (approximately 6 
months), or  
 taper their prednisone dose down to 0 mg/day using 
a tapering schedule determined by their treating 
physician and stay at 0 mg/day for the duration of 
the study (approximately 6 months). 
 
Target enrollment is randomization of a maximum of 79 
eligible patients.  Participant data collected via this study 
will be combined with that from a complementary study 
conducted at VCRC clinical centers (N=159 evaluable 
participants between the two study arms). 
 
Primary Study Objective: Physician decision to increase prednisone for disease 
relapse  
Primary Outcome 
Measure: 
The proportion of participants who increase prednisone for 
disease relapse within 6 months of randomization 
Secondary Study 
Objective: 
 
 
 
 Rates of flare sub-types: severe vs. non-severe within 6 
months of randomization 
 Time to event (flare) 
 Health-related quality of life 
 Safety outcomes   

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o Serious adverse events 
o Infections  
 Protocol performance 
o Patient characteristics 
o Protocol compliance 
o Participant retention 
o Data completeness 
o Timeliness of data entry 
o Data accuracy 
Secondary Outcome 
Measures 
1. Flare type (severe or non-severe) 
2. Duration of remission  
3. Patient-reported outcomes (PROMIS measures) 
4. Frequency of adverse events 
 
Eligibility/ Exclusion 
Criteria: 
 Inclusion Criteria 
1. Established diagnosis of granulomatosis with 
polyangiitis (GPA) (verified by medical record review 
by Protocol Oversight Management team) where 
patients will need to meet at least 2 of the 5 modified 
ACR criteria, at least one of which must be d or e: 
a. Nasal or oral inflammation, defined as the 
development of painful or painless oral ulcers or 
purulent or bloody nasal discharge 
b. Abnormal chest radiograph, defined as the 
presence of nodules, fixed infiltrates, or cavities. 
c. Active urinary sediment, defined as microscopic 
hematuria (>5 red blood cells per high power field) 
or red blood cell casts) 
d. Granulomatosis inflammation on biopsy, defined 
as histologic changes showing granulomatous 
inflammation within the wall of an artery or in the 
perivascular or extravascular area.  Note: Pauci-
immune glomerulonephritis seen on kidney biopsy 
will suffice for this criterion. 
e. Positive anti-neutrophil cytoplasmic antibody 
(ANCA) test specific for proteinase-3 measures by 
enzyme-linked immunoassay 
Patients who are MPO positive or ANCA negative are 
still eligible for this study if they meet the criteria 
above and are felt to have GPA. 
2. Active disease within the prior 12 months (initial 
presentation or relapse) that at time of active disease 
required treatment with prednisone ≥ 20 mg/day 
3. Disease remission at time of enrollment 
4. Prednisone dose at time of enrollment of  ≥ 5 mg/day 
and ≤ 10 mg/day 

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5. Participant age of 18 years or greater 
6. If the patient is taking an immunosuppressive 
medication agent other than prednisone (maintenance 
agent) then the maintenance agent must be at a stable 
dose for one month prior to enrollment with no plans 
by the treating physician to change the dose (other 
than for safety purposes/toxicity) for the duration of 
the study (through the month 6 visit or early 
termination).  Acceptable maintenance agents include 
azathioprine, leflunomide, 6-mercaptopurine, 
methotrexate, mycophenolate mofetil,  mycophenolate 
sodium, or rituximab.  Patients may be on 
trimethoprim/sulfamethoxazole (TMP/SMX) for use 
as either a maintenance agent or for prophylaxis for 
infection.  TMP/SMX may be used in combination 
with other drugs. 
6.1 If the patient is regularly taking 
trimethoprim/sulfamethoxazole at any dose then 
the patient is eligible if there no plans by the 
treating physician to change the dose after 
enrollment (other than dose reduction or 
discontinuation for safety purposes/toxicity) for 
the duration of the study 
7. Agreement from Treating Physician that randomized 
treatment assignment is standard of care 
8. Participant’s Treating Physician is located in the 
United States  
 
Exclusion Criteria 
1. Comorbid condition that has moderate likelihood of 
requiring a course of prednisone within one year of 
enrollment (e.g. COPD, asthma, adrenal insufficiency) 
 
Statistical 
Considerations 
(analysis plan): 
Participant data collected via this study will be combined 
with that from a complementary study (N=159).  The 
percent of participants whose physician decided to increase 
glucocorticoid dose for disease relapse will be compared 
between those randomized to receive 0 mg prednisone and 5 
mg prednisone by a Z test with pooled variance.  
Descriptive statistics with appropriate 95% confidence 
intervals will be calculated for all secondary outcomes. 
Differences in maintenance regimens (i.e., 
immunosuppressive agents other than glucocorticoids, such 
as azathioprine, methotrexate, or rituximab) will be 
included as covariates in assessing the study end point. 
Sponsors:  National Heart Lung and Blood Institute (NHLBI)  

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National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) 
 
1a. Brief Summary 
 
This study is a novel approach to conducting a randomized clinical trial in the 
community setting. 
 
This study is funded through the National Institutes of Health with the purpose of 
exploring novel methods of conducting clinical trials.  The study will be 
conducted by the Vasculitis Clinical Research Consortium (VCRC) and the Data 
Management and Coordinating Center (DMCC). 
 
1b. Detailed Description 
 
Patients with granulomatosis with polyangiitis (GPA) will be recruited via the 
Rare Disease Clinical Research Network (RDCRN) VCRC Contact Registry, 
social media, and the study public website.  The VCRC contact registry consists 
of over 3,000 subjects with vasculitis, of which over 1,600 have reported a 
diagnosis of GPA.  Several social media sites including Facebook and Twitter 
will have an information page about the study. 
 
The RDCRN VCRC Contact Registry and the social media sites will direct 
patients to the study public website.  The study public website will be developed 
and maintained by the Data Management and Coordinating Center at USF.  The 
website will provide information about the study including inclusion/exclusion 
criteria, whom to contact with questions, requirements for participation in the 
study, and the study design of tapering to 0 mg/day of prednisone or 5 mg/day of 
prednisone.  The public website will also contain the interactive informed consent 
form to enroll in this study. 
 
Potential participants will be presented with a video about the study that explains 
the goals of the research and the risks and benefits of the study.  Participants will 
be able to access this video continually during the consenting process and after 
enrollment.  The participant will be able to contact study staff through multiple 
channels including phone, email and social media. 
 
At time of enrollment, participants will need to be taking prednisone at a dose ≥ 5 
mg/day and ≤ 10 mg/day.  Once the participant has enrolled in the study, the 
participant will have access to a study website that is personalized for each 
participant.  Participants can keep track of their progress in the study, access the 
online consent form, and access study forms.  Participants will receive their 
treatment randomization assignment via the Participant website as well as a 
Physician packet that the participant will take to his/her treating physician 
explaining the research study and the participant’s involvement in the study.  The 
Physician will have the option to consent to be contacted to answer questions 
about the research study. 

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In order for the participant to be eligible for the study, the treating physician 
needs to agree that a prednisone dose of 5 mg/day or 0 mg/day is standard of care.  
The Protocol Oversight Management Team will review the patient’s medical 
records to determine if the participant meets the eligibility requirements.  
Participants will taper his/her prednisone under the guidance of his/her treating 
physician.  Once the participant reaches a prednisone dose of 5 mg/day, the 
participant will be randomized to continue prednisone at 5 mg/day or taper 
prednisone to 0 mg/day.  The Participant’s treating physician will be notified of 
the participant’s randomized dose.  Participants will be followed for 6 months 
from randomization.  Throughout the study, participants will have the option to 
consent to be contacted via phone to answer additional study questions.  At the 
conclusion of the study participants will be thanked for their participation. 
 
2. Study Endpoints 
 
2a. Primary Outcome 
 
The primary study endpoint will be the physician decision to increase 
prednisone for disease relapse. 
 
2b. Secondary Outcomes 
 
The secondary study endpoints include: 
 Rates of flare sub-types: severe vs. non-severe within 6 months of 
randomization  
 Time to event (flare) 
 Health-related quality of life 
 Safety outcomes   
o Serious adverse events 
o Infections  
 Patient characteristics 
 Protocol Performance 
o Protocol compliance 
o Subject retention 
o Data completeness 
o Timeliness of data entry 
o Data accuracy 
 
3. Background and Rationale 
 
3a. Background 
 
The Rare Diseases Clinical Research Network (RDCRN) 
(www.RareDiseasesNetwork.org) is a highly successful and innovative 
international clinical trials network of 17 distinct clinical research consortia led by 

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the Office of Rare Diseases Research with collaboration from NCI, NINDS, 
NIAID, NIAMS, NICHD, NIDCR, NIDDK, and NHLBI, and central 
coordination provided by the Data Management and Coordinating Center at the 
University of South Florida. 
 
The Data Management and Coordinating Center (DMCC) houses all RDCRN 
data and coordinates all protocol activity for the Vasculitis Clinical Research 
Consortium centrally via in-house scalable and customizable electronic data 
capture systems.  The DMCC will design and implement all facets of data 
collection and develop and manage the web tools (Facebook presence, etc.) for 
recruitment and consenting. 
 
The Vasculitis Clinical Research Consortium (VCRC) 
(www.RareDiseasesNetwork.org/vasculitis) is a founding member of the RDCRN 
and the major clinical research infrastructure in North America for the study of 
vasculitis.  The research conducted by the VCRC includes clinical trials, outcome 
measures development, large cohort and clinical epidemiologic studies, specimen 
collection and repository, translational investigations including biomarker 
discovery and genomics, and research training.  The VCRC includes 11 major 
vasculitis clinical centers in the US and Canada and dozens more partner sites in 
the US, Europe, Asia, and Australia.  Each US VCRC site coordinates its research 
activities with a CTSA program.  The VCRC has substantial funding from the 
NIAMS, FDA, NINDS, and various private foundations and industry partners.  
The VCRC investigators include nearly every major researcher involved in 
vasculitis in the US and Canada.  Several of the VCRC investigators will make up 
the Protocol Oversight Management Team. 
 
The RDCRN VCRC Contact Registry 
The RDCRN VCRC Contact Registry is an online mechanism for patients to 
register themselves or a member/members of their family who have been 
diagnosed with Vasculitis.  The Contact Registry provides ongoing email contact 
to each registrant, providing information when studies are activated.  The 
RDCRN VCRC Contact Registry has over 1,600 participants with GPA enrolled.  
 
Granulomatosis with polyangiitis (Wegener’s) (GPA) is a primary systemic 
vasculitis, predominantly involving microscopic blood vessels with no or scanty 
immune deposits.  GPA is strongly associated with circulating auto-antibodies to 
neutrophils (ANCA) and is one of a group of conditions known as ANCA-
associated vasculitis (AAV) (1).  The cause of AAV is unknown. AAV has an 
annual incidence of 20 per million and an approximate prevalence of 200/million 
(2).  It is a multi-system autoimmune disease that causes tissue damage especially 
to the respiratory tract and kidneys, and causes early mortality, organ failure 
including end stage renal disease, and chronic morbidity (3). 
 
Prior to the availability of effective treatment, AAV was almost universally fatal, 
with a 93% mortality within 2 years due to pulmonary and renal failure (4).  The 

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introduction of what is now termed conventional immunosuppressive treatment 
transformed survival (5).  Administration of cytotoxic immunosuppression 
(cyclophosphamide, rituximab, methotrexate) and glucocorticoids (GC) for at 
least one year induces remission in approximately 80% of patients.  GC are a 
standard of care in the treatment of AAV.  High doses of GC early in disease 
although undeniably reduce disease activity due to their anti-inflammatory and 
immunosuppressive properties also increase the risk of infection particularly in 
the elderly and in the presence of uremia.  There is a major unmet need for safer 
therapy that leads to sustained treatment free remission in patients with relapsing 
disease, which will reduce drug toxicity that results from cumulative exposure to 
immunosuppression and glucocorticoids. 
 
Clinical Manifestations 
Classic GPA involves the upper respiratory tract, the lungs, and the kidneys.  
Distinctive features may also occur in the eyes, ears, and other organs.  
Approximately 90% of patients with GPA have nasal involvement, including 
crusting, bleeding, and obstruction, erosive sinus disease and subglottic stenosis 
(6). Two principal forms of ear disease, conductive and sensorineural hearing 
loss, are typical of GPA.  Orbital masses (“pseudotumors”) and scleritis are the 
signature ocular lesions of GPA.  The clinical manifestations of GPA in the lung 
range from asymptomatic nodules to fulminant alveolar hemorrhage.  The most 
common radiographic findings are pulmonary infiltrates and nodules.  Renal 
involvement is the most ominous clinical manifestation of GPA.  The clinical 
presentation of renal disease in GPA is that of rapidly progressive 
glomerulonephritis with: hematuria, red blood cell casts, and proteinuria.  Without 
appropriate therapy, end-stage renal disease may ensue within days to weeks.  
Sixty percent of patients with GPA have musculoskeletal symptoms during their 
disease courses. Arthralgias/arthritis are frequently the presenting complaint of 
GPA.  Skin lesions in GPA include the full panoply of lesions associated with 
cutaneous vasculitis such as purpura, nodules, and other lesions.  Neurologic 
manifestaions of GPA include mild-severe sensory and motor peripheral 
neuropathy (especially mononeuritis multiplex), cranial neuroapthies, and rarely, 
central nervous system disease. 
 
3b. Rationale 
 
Treatment of GPA includes the combination of high-dose glucocorticoids (GC) 
and an immunosuppressive agent, including cyclophosphamide, rituximab, 
methotrexate, azathioprine, or other drugs. Remission is usually achieved within a 
short time (1-2 months) and glucocorticoid taping is begun within one month of 
initiation.  A major unanswered question is what tapering regimen to use for GC 
and whether patients with GPA are better off being maintained on low-dose 
prednisone or attempting to come off of glucocorticoids altogether.  Patients 
successfully treated for GPA continue, however, to have high rates of relapse 
associated with the accrual of organ damage and exposure to toxic medications.  
Optimal treatment strategies for patients with GPA remain to be defined. Studies 

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in the last 20 years have addressed the use of immunosuppressive medications in 
GPA (7, 8).  Unlike immunosuppressive medications, the use of GC has not been 
rigorously evaluated.  There is little evidence to guide the use of GC and there is 
considerable practice pattern variation, especially after the induction of remission.  
Of particular debate is whether low-dose GC contributes to maintaining the 
remission of GPA.  Some experts support the use of long-term, low-dose GC, 
claiming improved disease control, a subsequent reduction in the exposure to 
toxic immunosuppressive medications, fewer periods of exposure to high-dose 
GC, and a reduction in the accumulation of disease-related scarring.  Others argue 
that the use of long-term, low-dose GC is ineffective at reducing relapses and 
exposes patients to the potential toxicity of high cumulative doses of GC.  The 
efficacy of long-term, low-dose GC for the treatment of AAV to prevent relapses 
or reduce treatment-related toxicity is a matter of continued debate, even within 
the Vasculitis Clinical Research Consortium, and is of great interest to patients.  
This issue is considered quite important for its clinical implications as well as its 
potential impact on design of randomized clinical trials in GPA since both the 
“taper to 0 mg/day” and ”maintain at 5 mg/day” prednisone schedules have been 
used in the major randomized clinical trials in this field.  
 
4. Study Design and Methods 
 
4a. Overview 
 
This open label pilot study will randomize a maximum of 79 participants (for an 
evaluable total sample size of 159 participants between this study and a 
complementary VCRC study) with GPA in remission affecting the sinonasal tract, 
oral mucosa, skin, musculoskeletal system, pulmonary parenchyma, or other 
disease features that warranted an administration of 20 mg/day within the last 12 
months.  At the time of enrollment, participants will need to be taking prednisone 
at a dose of ≥ 5 mg/day and ≤ 10 mg/day.  All enrolled participants will be 
instructed to reduce the daily dose of prednisone according to their treating 
physician.  Once participants reach a prednisone dose of 5 mg/day, they will be 
randomized at a 1:1 ratio to continue prednisone at 5 mg/day or to taper 
prednisone to 0 mg/day.  Participants will be followed for approximately six 
months from reaching a prednisone dose of 5 mg/day. 
 
It is recognized that patients who receive repeated doses of rituximab will usually 
receive an intravenous dose of glucocorticoids on the days they receive an 
infusion of rituximab as part of usual care; these additional doses of 
glucocorticoids will be allowed for under this protocol and receipt will not be 
considered criteria for achieving a relapse/primary endpoint. The doses of 
glucocorticoids given on days of administration of rituximab will be recorded. 
 
4b. Study Diagram 

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4c. Recruitment 
 
Potential research participants will be recruited online through the RDCRN 
VCRC Contact Registry, social media outlets and a study public website.  Social 
media pages will be created on Facebook, Google+, Twitter and other social 
media outlets to advertise for this study.  The RDCRN VCRC Contact Registry 
and social media outlets will direct patients to the study public website. 
 
Vasculitis patient advocacy groups will promote this randomized clinical trial at 
in-person meetings and in newsletters. 
 
An additional avenue to identify and recruit participants will be for the TAPIR 
trial to partner with two separate Clinical Data Research Networks (CDRNs), part 
of the Patient-Centered Outcomes Research Network (PCORnet). Each CDRN 
has access to the electronic health records (EHR) of > 1 million patients.  A 
validated computable phenotype for granulomatosis with polyangiitis will be run 
through the CDRN health system databases to identify patients that are potentially 
eligible for this trial.  These patients will be sent correspondence referring them to 
the main TAPIR website to consent and enroll in the trial.  Since the CDRNs have 
access to these patient’s electronic health records, this partnership would also 
make EHR data available on drug dosing and outcomes for individuals who 
consent and join the study.  These CDRN networks will obtain separate IRB 
approval for their identification and referring activities.  This new approach is 
consistent with patient-centric approach to this study and the goal of exploring 
novel methods to conducting clinical trials. 
 
All recruitment material will be reviewed by the appropriate oversight bodies 
(Institutional Review Boards (IRBs), Research Ethics Boards (REBs), Data and 
Safety Monitoring Board (DSMB), etc.).   
   

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 Prior to protocol version 04Apr17, participants receiving rituximab for induction 
of remission were not eligible to participate in this study while patients receiving 
rituximab for maintenance of remission were allowed to participate if the last dose 
of rituximab for maintenance of remission was administered at least one month 
prior to enrollment and no additional doses were planned for future 
administration. With the approval of the amended protocol dated 04Apr17, 
participants receiving rituximab at the time of screening will be allowed to 
participate in the study regardless of any planned future additional administrations 
of rituximab.  The dose of rituximab and glucocorticoids given with the rituximab 
infusion will be prescribed by the local physician. The study team will collect 
information about the dose of rituximab and the dose of glucocorticoids given 
with each infusion of rituximab for data analysis purposes. 
 
4d. Eligibility Criteria 
 
4di. Inclusion Criteria 
1. Established diagnosis of granulomatosis with polyangiitis (GPA) 
(verified by medical record review by the Protocol Oversight 
Management Team) where patients will need to meet at least 2 of the 5 
for the classification of GPA, at least one of which must be criterion d or 
e. 
The modified ACR criteria are: 
a. Nasal or oral inflammation, defined as the development of painful or 
painless oral ulcers or purulent or bloody nasal discharge 
b. Abnormal chest radiograph, defined as the presence of nodules, fixed 
infiltrates, or cavities. 
c. Active urinary sediment, defined as microscopic hematuria (>5 red 
blood cells per high power field) or red blood cell casts 
d. Granulomatosis inflammation on biopsy, defined as histologic 
changes showing granulomatous inflammation within the wall of an 
artery or in the perivascular or extravascular area.  Note: Pauci-
immune glomerulonephritis seen on kidney biopsy will suffice for 
this criterion. 
e. Positive anti-neutrophil cytoplasmic antibody (ANCA) test specific 
for proteinase-3 measures by enzyme-linked immunoassay 
Patients who are MPO positive or ANCA negative are still eligible for this 
study if they meet the criteria above and are felt to have GPA. 
2. Active disease within the prior 12 months (initial presentation or 
relapse) that at time of active disease required treatment with prednisone 
≥ 20 mg/day (verified by medical record review by the Protocol 
Oversight Management Team) 
3. Disease remission at time of enrollment (verified by medical record 
review by the Protocol Oversight Management Team) 
4. Prednisone dose at time of enrollment of  ≥  5 mg/day and ≤ 10 mg/day 
5. Participant age of 18 years or greater 

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6. If the patient is taking an immunosuppressive medication agent other 
than prednisone (maintenance agent) then the maintenance agent must 
be at a stable dose for one month prior to enrollment with no plans by 
the treating physician to change the dose (other than for safety 
purposes/toxicity) for the duration of the study (through the month 6 
visit or early termination).  Acceptable maintenance agents include 
azathioprine, leflunomide, 6-mercaptopurine, methotrexate, 
mycophenolate mofetil, mycophenolate sodium, or rituximab.  Patients 
may be on trimethoprim/sulfamethoxazole (TMP/SMX) for use as either 
a maintenance agent or for prophylaxis for infection.  TMP/SMX may 
be used in combination with other drugs. 
6.1 If the patient is regularly taking trimethoprim/sulfamethoxazole at 
any dose then the patient is eligible if there no plans by the treating 
physician to change the dose after enrollment (other than for dose 
reduction or discontinuation for safety purposes/toxicity) for the 
duration of the study.  
7. Agreement from Treating Physician that 0 mg/day of prednisone or 5 
mg/day of prednisone is standard of care 
8. Participant’s Treating Physician is located in the United States  
 
4dii. Exclusion Criteria 
1. Comorbid condition that has moderate likelihood of requiring a course 
of prednisone within one year of enrollment (e.g. COPD, asthma, 
adrenal insufficiency) 
 
4e. Randomization Procedures 
 
At randomization, all participants will be on prednisone dose of 5 mg/day.  All 
participants with GPA confirmed by the Protocol Oversight Management Team 
will be randomized to continue their prednisone at 5 mg/day or to taper their 
prednisone to 0 mg/day.  If necessary, the treating physician will have 5 weeks to 
taper patients from 5 mg/day to 0 mg/day. 
 
4f. Visit Frequency/Visit Schedule 
 
This study will occur primarily online.   
 
Participants will enroll online.  After enrollment, participants will have access to a 
personalized participant website.  Participants can keep track of their progress in 
the study and access the online consent form and study materials including a 
packet that the participant will send to his/her treating physician.  The packet 
explains the research study and notifies the treating physician of the participant’s 
interest in participating in the study.  The treating physician will confirm (or not 
confirm) that the participant is eligible for the study and confirm (or not confirm) 
that 5 mg/day or 0 mg/day of prednisone is standard of care for that patient.  The 
participant may provide the study packet to their treating physician in person or 

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may send the packet to their treating physician to complete via mail/fax/etc.  An 
in-person visit with the participant’s treating physician is not required for any 
study related reasons (participant may still need to visit physician for clinical 
care.) 
 
Participants will reach the end of the study participation when the participant has 
completed the duration of the study. 
 
Participants will be informed that they are free to withdraw from the study at any 
time without compromising the relationship with their physician or their future 
medical care. 
 
4g. Data Elements for Collection 
 
Participants will be asked to send or to authorize their treating physician to send 
the DMCC medical history data including physical examination data, blood 
results, chest radiographs and other diagnostic images.  This information is 
collected as part of routine clinical practice and is not mandated by the protocol.  
The information will be used to confirm eligibility by the Protocol Oversight 
Management Team. 
 
 
*Participants may consent to be contacted to answer additional study related questions 
†AE and/or Flare Verification may not be required for all participants 
±Treating Physicians may consent to be contacted to answer study questions 
 
 
4h. Retention Strategies 
Data Collection Points 
Time Period 
Completed by Participants 
Start of 
Study 
During 
Study 
End of Study 
Participation 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Disease Information 
X 
X 
 
Disease Activity, Medication history 
(including rituximab usage) and/or 
Adverse Symptoms 
X 
X 
X 
Quality of Life questionnaires 
X 
X 
X 
Prednisone Dose 
X 
X 
X 
Qualitative Measures* 
X 
X 
X 
Completed by Protocol Oversight 
Management Team 
 
 
 
GPA Diagnosis Verification 
X 
 
 
AE and/or Flare Verification† 
 
 
     X 
Completed by Treating Physician± 
 
 
 
Qualitative Measures± 
 
 
 X 
 
 
 
 

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Retention will be encouraged by frequent electronic contact with the participant.  
Contact can be made to the participant via email, social media outlets, text 
messaging, mobile phone applications, etc.  These messages can be study specific 
and remind the participant to report disease activity, prednisone dose, etc., disease 
specific including information about GPA, prednisone use, etc. and other items 
that patients with GPA are often interested about such as rare diseases.  
 
5. Safety Monitoring and Adverse Event Reporting 
 
5a. Nature of Study 
 
Participant enrollment may only begin with IRB approved consent forms. 
 
This study meets the federal definition of low risk. 
 
5b. Adverse Events 
 
Participants will be encouraged to report disease activity and adverse symptoms 
throughout their participation on the study.  The Protocol Oversight-Management 
Team will review reported disease activity and adverse symptoms.  The 
participant will remain under the care of his/her treating physician during the 
study and will be instructed to consult his/her treating physician for any event 
requiring medical attention. 
 
Only those events associated with the conduct of the study and as defined above 
are reportable. Adverse events believed to be related to other medications 
provided to the participants (such as rituximab) for the purpose of maintaining 
remission, are not considered reportable as they are not considered a study 
medication in this protocol. 
 
Glucocorticoid Side Effects: 
Glucocorticoids have been used therapeutically in humans since 1949 and their 
side effects are well recognized. The main toxicities of prednisone include 
infections, hyperglycemia, hypertension, cataracts, osteoporosis, avascular 
necrosis, gastrointestinal irritation, mood disturbances (including psychosis), 
bruising, skin changes including acne and striae, increase in appetite and weight, 
and redistribution of fat. Prednisone is not known to have teratogenic effects on 
the developing fetus and there has been no evidence to date of an effect on 
fertility. However, prednisone can cause problems during pregnancy for both the 
mother (risks of weight gain, gestational diabetes, and infection) and the 
developing fetus as a result of the maternal problems. 
 
The risks as listed on the package insert for prednisone (Deltasone) include  
(http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3735): 

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 Fluid and Electrolyte Disturbances  
  - Sodium retention 
  - Fluid retention 
  - Congestive heart failure in susceptible patients 
  - Potassium loss 
  - Hypokalemic alkalosis 
  - Hypertension 
 Musculoskeletal  
  - Muscle weakness 
  - Steroid myopathy 
  - Loss of muscle mass 
  - Osteoporosis 
  - Tendon rupture, particularly of the Achilles tendon 
  - Vertebral compression fractures 
  - Aseptic necrosis of femoral and humeral heads 
  - Pathologic fracture of long bones 
 Gastrointestinal  
  - Peptic ulcer with possible perforation and hemorrhage 
  - Pancreatitis 
  - Abdominal distention 
  - Ulcerative esophagitis 
  - Increases in alanine transaminase (ALT, SGPT), aspartate transaminase 
(AST, SGOT) and alkaline phosphatase have been observed following 
corticosteroid treatment. These changes are usually small, not associated with 
any clinical syndrome and are reversible upon discontinuation. 
 Dermatologic  
  - Impaired wound healing 
  - Thin fragile skin 
  - Petechiae and ecchymoses 
  - Facial erythema 
  - Increased sweating 
  - May suppress reactions to skin tests 
 Metabolic  
  - Negative nitrogen balance due to protein catabolism 
 Neurological  
  - Increased intracranial pressure with papilledema (pseudotumor cerebri) 
usually after treatment 
  - Convulsions 
  - Vertigo 
  - Headache 
 Endocrine  
  - Menstrual irregularities 
  - Development of Cushingoid state 
  - Secondary adrenocortical and pituitary unresponsiveness, particularly in 
times of stress, as in trauma, surgery or illness 
  - Suppression of growth in children 

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  - Decreased carbohydrate tolerance 
  - Manifestations of latent diabetes mellitus 
  - Increased requirements for insulin or oral hypoglycemic agents in diabetics 
 Ophthalmic  
  - Posterior subcapsular cataracts 
  - Increased intraocular pressure 
  - Glaucoma 
  - Exophthalmos 
 Additional Reactions  
  - Urticaria and other allergic, anaphylactic or hypersensitivity reactions 
 
6. Data Analysis and Statistical Considerations 
 
The primary objective of this study is to compare the physician decision to increase 
prednisone for disease relapse between those randomized to receive 0 mg/day of 
prednisone and those randomized to receive 5 mg/day.  Disease relapse is defined to 
be an increase in BVAS score necessitating an increase in glucocorticoid dose.  
Should an enrolled and randomized study participant increase their dose for any other 
reason after randomization, with the exception of co-administration of glucocorticoids 
as part of re-treatment with rituximab, the participant will remain on study but not be 
included in the primary analysis.  This, therefore, is a modified intent to treat design.  
Insofar as their effect on sample size, they would be treated as among the dropout 
group. 
 
6a. Sample Size 
 
A meta-analysis of 13 published RCTs was performed to examine the question of the 
clinical utility of low-dose prednisone in remission-maintenance of AAV (10).  This 
study suggested that the expected relapse rate among those treated with continued 
low-dose of prednisone is 15% (95% CI:10-19%) before 12 months compared to 43% 
(95% CI:33-52%) among those in whom glucocorticoids was stopped completely 
(10).  It is anticipated that 41% of the participants in the study overall will have 
received rituximab at the time of screening. This number is based on the prediction 
that 70% of the remaining subjects enrolled once the 04Apr17 protocol version is 
implemented will be on rituximab at Screening. Furthermore, it is estimated that the 
six month relapse rates for these participants will be 20% for those on 0 mg 
prednisone and 10% for those on 5 mg prednisone. Based on the combination of these 
populations, the expected relapse rate for those treated with low dose prednisone is 
14% and 35% for those prednisone free.   Based on these estimates, a target accrual of 
142 patients randomized 1:1 to the two treatment arms would have 80% power 
(comparing 6 month flare rates of 13.2% to 32.9%), using a 2-tailed significance level 
of 0.05 and a Z test with pooled variance.  Assuming a maximum 11% drop out rate 
due to subject choice or related to data quality concerns, we plan to enroll 159 
evaluable participants into the trial from the two arms.  (The original 20% drop out 
rate for the entire trial was adjusted to account for the fact that 59 participants have 

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completed the trial at the time of the implementation of the 04Apr17 protocol. Thus, 
the adjusted overall drop-out rate for the entire trial following the 04Apr17 protocol 
amendment is estimated to be a maximum of 11% allowing for the remaining 
enrollees to have a 20% drop out rate). A maximum of 79 of the 159 participants will 
be accrued through this protocol, with the remainder being  obtained from a 
complementary study.  
 
If the dropout rate exceeds 11% or the relapse rate on the 5 mg. falls below 
expectations such that the study power is compromised, then the target enrollment 
will be increased to maintain the desired detectable effect size.    
 
6b. Stratification 
 
The study will be stratified by whether the subject is newly diagnosed or previously 
experienced a disease flare requiring steroids according to the eligibility criteria. 
Differences in maintenance regimens (i.e., other non-glucocorticoid 
immunosuppressive agents such as azathioprine, methotrexate or rituximab) will be 
included as covariates in assessing the study end point.  Stratification is intended for 
balancing only and the study is not powered for within-stratum comparisons. 
 
Data on disease relapse will be reported by study participants utilizing the web tools 
provided by the DMCC.  
 
6c. Secondary outcomes 
 
Secondary outcomes including rates of flare sub-types (severe vs. non-severe), time 
to event (flare), adverse events associated with prednisone, health related quality of 
life measures (PROMIS), and safety outcomes will be estimated both overall and by 
treatment arm, and appropriate 95% confidence intervals will be calculated. 
 
7. Data Management 
 
All study data will be collected via systems created in collaboration with the DMCC 
and VCRC and will comply with all applicable guidelines regarding patient 
confidentiality and data integrity and security.   
 
7a. Registration/Online Consent 
 
Participants will register for the study online via the study public website.  After 
consenting to the study, the participant will enter an email address and password.  
An email will be sent to the participant.  The participant will not be enrolled in the 
study until after the participant returns to the public website via the link in the 
email. 
 
7b. Data Entry 
 

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The participant will create a username and password to access the secure 
Participant website.  The participant will directly enter demographics, disease and 
prednisone dose information directly online. 
 
7c. Data Quality Control 
 
Data quality begins with the design of the data collection forms and procedures 
and incorporates reasonable checks to minimize transcription and omission errors.  
Internal validity checks for reasonableness and consistency will be built into the 
initial tables and cross tabulations. 
 
8. Protection of Human Subjects 
 
The proposed research project is a randomized clinical trial of 0 mg or 5 mg daily of 
prednisone in patients with GPA.  Prednisone is the only therapeutic intervention of 
any type included in the research plan. 
 
The risks of participating in this study are expected to be low and will be due to the 
use of prednisone.  A potential risk is a risk of loss of privacy.  Participants may find 
the study through social media outlets. If the participant utilizes their name in 
messages or in account names in social media, privacy may be lost.  The investigators 
will not share personal information or identifiers with anyone outside of the research 
team.  The demographic and disease information collected are not anticipated to be 
psychologically harmful or stressful.  
 
If adverse effects from the study are incurred, the participant will be instructed to 
utilize full resources of the hospital or their treating physician.  Throughout the 
informed consent form, when discussing the study with study staff, and in media 
messages, participants will be instructed to seek medical attention from his/her 
treating physician if an adverse event occurs. 
 
There are no benefits to study participants for their involvement in this research.  If 
the study leads to higher quality care or therapeutic trials for vasculitis then study 
patients could theoretically benefit in the future.  All participants will potentially have 
the satisfaction of helping to contribute to medical knowledge of vasculitis.  Further 
understanding of the clinical aspects of vasculitis is of great medical importance.  
Because progress in understanding this disease is expected from this study it is felt 
that the potential benefits of this research outweigh the risks of participation. 
 
Knowledge to be gained from this study could be potentially highly important.  
Understanding the optimum use of low-dose glucocorticoids is important.  This study 
could lead to better care and less toxic treatment regimens.  Insight into the conduct 
of clinical trials in vasculitis could be gained and this might lead to more efficient 
clinical trials for patients with vasculitis. 
 
 

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2. Watts RA, Scott DG, Lane SE. Epidemiology of Wegener's granulomatosis, 
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2002;69 Suppl 2:SII84-6. 
3. Mohammad AJ, Bakoush O, Sturfelt G, Segelmark M. The extent and pattern of 
organ damage in small vessel vasculitis measured by the Vasculitis Damage Index 
(VDI). Scand J Rheumatol 2009;38(4):268-75. 
4. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective 
clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 
1983;98(1):76-85. 
5. Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS. Treatment of 
Wegener's granulomatosis with intermittent high-dose intravenous 
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6. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. 
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7. Mukhtyar C, Guillevi n L, Cid M, Dasgupta B, De Groot K, Gross W, Hellmich 
B, Jayne D, Kallenberg C, Merkel PA, Raspe H, Salvarani C, Scott DGI, 
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EULAR Recommendations for the management of large vessel vasculitis. Annals 
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8. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg 
CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, 
Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, 
Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert 
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ANCA-associated vasculitis. New England Journal of Medicine. 2010; 363:221-
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9. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The 
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Wegener's granulomatosis. Arthritis Rheum 1990;33(8):1101-7. 
10. Walsh M, Merkel PA, Mahr A, Jayne D.  Effects of duration of glucocorticoid 
therapy on relapse rate in antineutrophil cytoplasmic antibody-associated 
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