A Randomized, Controlled Trial to Evaluate the Role of Oral Azithromycin in the Treatment of Symptomatic Meibomian Gland Disease and Its Effect on the Ocular Surface Microbiome
Phase: PHASE4
Conditions: Dry Eye, Neuropathic Eye Pain, Ocular Microbiome, Depression, Anxiety
Sponsor: University of California, San Francisco

 
A Randomized, Controlled Trial to Evaluate the Role of Oral Azithromycin in the 
Treatment of Symptomatic Meibomian Gland Disease and its effect on the Ocular 
Surface Microbiome 
 
 
NCT Number NCT03953118 
 
Date: January 2, 2018 
 
 

 
Principal Investigator: Julie Schallhorn, MD 
Co-Investigator: Thuy Doan, MD PhD 
 
i. 
Background and Significance 
 
Dry eye syndrome (DES) is a persistent feeling of ocular discomfort that encompasses dryness, 
irritation, foreign body sensation and burning.  In the United States, it is the most common non-
refractive cause of visits to eye care providers1, and has been shown to have a significant 
impact on quality of life of patients who suffer from this condition2.  It is not one disease state, 
but rather is composed of multiple different entities whose end stage results in the symptoms 
encompassed by DES.  The most common cause of DES is Meibomian gland disease (MGD).3   
 
The Meibomian glands are modified sebaceous glands that line the upper and lower eyelids and 
have orifices opening onto the eyelid margin.4  The secretory product of the Meibomian glands 
is a finely tuned mixture of lipids with high spreadability and low surface tension that coat the 
ocular surface and provide an evaporative barrier against aqueous tear loss.5  A change in the 
composition of the lipids can cause the tear film to become unstable, either breaking up 
prematurely or failing to spread properly after blinking, which leaves the underlying corneal 
epithelium exposed.6   
 
Numerous treatments for MGD have been proposed, ranging from heating the glands7 to topical 
anti-inflammatories8, 9, oral omega-3 fatty acids10, 11, and topical12 or oral13, 14 antibiotics.  The 
role of topical anti-inflammatories as effective has been well-established, but the role of 
antibiotics is less clearly defined.  Some clinicians advocate using antibiotics to reduce the 
burden of bacteria on the ocular surface15, but the utility of this has never been established16, 
nor have there been any causal relationship demonstrated between a bacterial pathogen and 
MGD17.   
 
A competing theory for the use of antibiotics to treat MGD is that they exhibit an anti-
inflammatory effect on the Meibomian glands, thereby improving the composition of secreted 
lipid.  The macrolide and tetracycline antibiotics have been shown to have a anti-inflammatory 
effects in addition to their antimicrobial action.18   Azithromycin has also been shown to affect 
the lipid composition of cultured human Meibomian gland cells.19, 20   
 
The use of antibiotics in the treatment of MGD is an important question to address, as MGD is 
both an extremely common and chronic disease, and patients are often treated repeatedly.  It 
has been well established that the use of topical and oral antibiotics can induce resistance in 
bacteria, and thus use of antibiotics should be limited only to cases where there is a definite 
treatment benefit.  Given the widespread use of antibiotics in treatment of MGD, one would 
hope that there is solid evidence as to the benefit of oral antibiotics as compared to placebo, 
however evidence based on well-designed clinical trials is sorely lacking.16   
 
The pathogenicity of bacteria in MGD has never been demonstrated.17  It may be because MGD 
is a non-infectious disease, or it may be because the organism is difficult to identify using 
standard culture techniques.  With the dawn of 16s ribosomal DNA amplification techniques, it 
has become apparent that the microbiological inhabitants of the ocular surface are far more 
diverse and numerous than what has been identified using standard culture techniques.  
Although studies on the ocular microbiome are still in their infancy, differences in microbiological 
populations have been identified in patients with DES and in contact lens wearers.  The 
microbiome in patients with MGD and in patients who have been treated for MGD remains 

unstudied using modern DNA-based techniques and is a ripe area for research, which this 
project proposes to address.   
 
ii. 
Preliminary Studies 
 
There have been two published studies looking at oral azithromycin in the treatment of MGD.  
Oral azithromycin dosed at 1 gram per week for 3 weeks, has been previously studied in a 
retrospective case series conducted at the F.I. Proctor Foundation at UCSF.  In this study, 
seventy-five percent of subjects reported symptomatic improvement in ocular surface discomfort 
at a mean follow up time of 5.6 weeks.13  This was a retrospective analysis, and subjects were 
on multiple different medications during the study period, which may have affected the outcome.  
Oral azithromycin has also been studied at a dose of 500mg/day for 3 days, repeated every 7 
days for 3 cycles, in a prospective, open-label trial of 13 patients.  In this study, the authors 
reported improvement in both the symptoms and signs of MGD at an undefined end point.21 
 
Topical azithromycin has been studied in several open-label studies which demonstrated a 
benefit in improvement of both the signs and the symptoms of MGD.22, 23   However, a well-
designed randomized controlled double-masked trial of 904 patients comparing topical 
azithromycin alone to topical azithromycin plus dexamethasone to dexamethasone alone to 
placebo both demonstrated no additional benefit of azithromycin to dexamethasone in the 
treatment of MGD, but did show that dexamethasone was effective in improving the signs of 
MGD.12  The differing results of these trials demonstrate the need for well-designed randomized 
controlled trials in evaluating interventions for MGD.   
 
iii. 
Study Design 
 
 
Randomized, controlled, double-masked clinical trial of oral azithromycin vs placebo in the 
treatment of symptomatic Meibomian gland disease. 
 
Patient will be randomized with a 1:1allocation ratio into two groups.   
 
- 
Group 1 will receive oral azithromycin, 1 gram per week for 3 weeks, plus instruction to 
perform warm compresses.   
- 
Group 2 will receive oral azithromycin, 1 gram per week for 3 weeks, plus instruction to 
perform warm compresses.   
 
 
IV. Study Location:  
 
1. Ophthalmology clinic at the University of California, San Francisco  
2. Ophthalmology clinic at the F.I. Proctor Foundation, San Francisco 
 
V. Criteria 
 
 
Inclusion 
1. Symptomatic Meibomian gland disease, defined as patient-reported ocular surface 
symptoms such as dryness, grittiness, foreign body sensation, or eye fatigue in 
combination with clinically identifiable Meibomian gland disease with Grade 2 or 
greater involvement on the Meibomian Gland Grading Scale (Section XV, item 2). 
2. OSDI Score ³ 20 

3. Ability to give informed consent 
 
 
Exclusion 
1. Age less than 18 years 
2. Allergy or intolerance to oral azithromycin or topical dexamethasone 
3. Allergy or intolerance to the preservatives used in topical ophthalmic 0.1% 
dexamethasone: sodium bisulfite, phenylethyl alcohol, benzalkonium chloride  
4. History of prolonged QT interval, history of torsades des pointes, congenital long QT 
syndrome, bradyarrhythmias, heart failure 
5. Patients currently taking medications that prolong the QT interval (Table 1) 
6. Aqueous deficiency dry eye defined as Schirmer’s strip testing without anesthesia 
with £ 5mm of tears on two separate tests. 
7. Ocular surface inflammatory disease, including cicatrizing conjunctivitis, graft versus 
host disease, Stevens Johnson syndrome 
8. Atopic disease with ocular involvement 
9. Limbal stem cell deficiency 
10. Oral or topical ophthalmic antibiotic use within the last 90 days 
11. Oral prednisone use >5mg per day 
12. Topical ophthalmic steroid use within the past 30 days 
13. Topical ophthalmic anti-inflammatory (including non-steroidal anti-inflammatories, 
lifitegrast, or cyclosporine) use within the past 30 days 
 
Table 1: Medications that Prolong QT Interval 
 
Medication 
Use 
Medication 
Use 
Amiodarone 
Antiarrhythmic 
Flecainide 
Antiarrhythmic 
Amisulphride 
Antipsychotic 
Haloperidol 
Antipsychotic 
Amitryptyline 
Antidepressant 
Hydroxychloroquine Anti-Malarial 
Astemizole 
Antihistamine 
Imipramine 
Antidepressant 
Chloroquine 
Anti-Malarial 
Loratadine 
Antihistamine 
Chlorpromazine 
Antipsychotic 
Nortriptyline 
Antidepressant 
Clarithromycin 
Antibiotic 
Olanzapine 
Antipsychotic 
Desipramine 
Antidepressant 
Procainamide 
Antiarrhythmic 
Diphenhydramine Antihistamine 
Quetiapine 
Antipsychotic 
Disopyramide 
Antiarrhythmic 
Quinidine 
Antiarrhythmic 
Doxepin 
Antidepressant 
Quinine 
Anti-Malarial 
Droperidol 
Antipsychotic 
Sotalol 
Antiarrhythmic 
Encainide 
Antiarrhythmic 
Terfanadine 
Antihistamine 
Erythromycin 
Antibiotic 
Thioridazine 
Antipsychotic 
 
 
 
VII. Main Outcome Measure 
 
The primary outcome will be change in OSDI score from enrollment to 1 month. 
 

Secondary Outcome Measures 
 
1. Difference in alpha diversity of ocular surface microbiome as assessed by Shannon’s 
diversity index between azithromycin and placebo groups at 1 and 3 months. 
2. Change in alpha diversity of ocular surface microbiome as assessed by Shannon’s 
diversity index between azithromycin and placebo groups between 0 and 1 month. 
3. Change in OSDI score from enrollment to 3 months 
4. Change in Neuropathic Pain Score Inventory for the Eye (NPSI-E) from enrollment to 1 
and 3 months 
5. Change in 5-Item Dry Eye Questionnaire (DEQ-5) from enrollment to 1 and 3 months 
6. Change in meibomian gland grading from enrollment to 1 and 3 months 
7. Change in SICCA score from enrollment to 1 and 3 months 
8. Change in OSI (Ocular Surface Index) score at 1 and 3 months 
 
VIII. 
Statistical Analysis 
 
For continuous outcomes, a two-tailed t test for significance will be used.  
 
For microbiome outcomes, the alpha diversity (local species pool) of the population will be 
analyzed and compared pre-and post-treatment within and between the azithromycin and 
control groups.  The difference between the bacterial microbiome in the azithromycin and 
placebo arm will be assessed using a PERMANOVA with an L2 norm distance measure.  
Secondary analyses will include L1 and L0 norms, as well as a phylogenetic distance. In 
addition, we will assess whether bacterial alpha diversity is decreased in the antibiotic treated 
arm with the primary outcome being the Simpson’s index (L2), with secondary analyses 
assessing Shannon’s (L1) and Richness (L0).   
 
IX. Study Sizing 
 
The number of patients was calculated by assuming a 20% difference in Ocular Surface 
Disease Index (OSDI)24 score at the primary outcome between treatment and placebo groups, 
with 80% power and a significance level of 0.05.  This yielded a total of 16 patients per arm.  To 
account for loss to follow up, a total of 19 patients per arm will be recruited.   
 
X. Placebo 
 
The oral azithromycin placebo will be a sugar pill, and will be made by the UCSF Investigational 
Pharmacy.   
 
XI. Non-Medication Intervention 
 
All patients will receive education regarding non-medication interventions for their Meibomian 
gland disease.  This will be instruction to perform warm compresses over both eyes for 10 
minutes twice per day.  The handout that will be given to patients is available in the Manual of 
Procedures (MOP). 
 
XII. Masking 
 
The UCSF Investigational pharmacy will perform randomization according to randomization 
schedule.  All masking of investigational medications will be performed by the UCSF 
Investigational Pharmacy.   

 
Azithromycin tablets will be over-encapsulated for masking purposes to match the placebo pills.  
Artificial tears will be used as the placebo for dexamethasone, and both will be in identical eye 
dropper vials.   
 
Both patients and physicians will be masked as to study assignment.  The clinical coordinator 
and the Investigational Pharmacy will have access to the randomization key. 
 
XIII. 
Schedule of Procedures 
 
The initial visit will be at enrollment.  The 1 month visit will be 21-35 days after the initial visit, 
and the 3 month visit will be 76-96 days after the initial visit.   
 
Procedure 
Initial 
1 Month 
3 Months 
Visual Acuity 
x 
x 
x 
Refraction 
x 
 
 
IOP 
x 
x 
x 
Schirmer’s 
x 
x 
x 
TBUT 
x 
x 
x 
MGE 
x 
x 
x 
SICCA Score 
x 
x 
x 
NSPI-E 
x 
x 
x 
DEQ-5 
x 
x 
x 
OSDI 
x 
x 
x 
PHQ-9 
x 
 
 
 
 
XIV. 
Patient-Reported Instruments 
 
 
1. NPSI-E – Neuropathic pain inventory 
i. Number of Questions – 12 
ii. Time to Complete -  
 
2. DEQ-5 – Dry eye questionnaire 5 
i. Number of Questions –  
ii. Time to Complete –  
 
3. OSDI – Ocular surface disease index 
i. Number of Questions – 12 
ii. Time to Complete - 5 minutes 
 
4. PHQ-9 –  
i. Number of Questions – 9 
ii. Time to Complete – 5 min 
 
 
XV. Ocular Surface Evaluation Procedures 

The evaluation procedures should be performed in the order specified below to minimize 
disruption of the ocular surface. 
1. Tear Breakup Time 
Two people are required to measure tear breakup time, one who does the examination and one 
who holds timer.  The tear breakup time should be measured prior to instillation of any 
anesthetic drops.  A dry fluorescein strip should be touched lightly to the tear meniscus, and the 
patient instructed to blink several times.  After even distribution of the fluorescein, the patient 
should be asked to blink again and then hold the eye open.  The instant the patient holds their 
eye open an assistant should start a stopwatch.  The examiner will remain looking at the ocular 
surface with the cobalt blue light at the slit lamp, and signal to the timer when the first break in 
the tear film occurs.  This should be repeated a total of three times, and all three times 
recorded.   
 
2. Meibomian Gland Grading 
Meibomian glands will be evaluated using the handheld Meibomian gland expression device 
(MGED)25 using the procedure described in Meadows, et al.26  
Two areas of the lower lid will be used for Meibomian gland grading – the temporal lower lid 
from the 4th-9th observable Meibomian gland orifice (counting from the lateral canthus) and the 
central lower lid from the 15th- 20th Meibomian gland orifice (counting from the lateral canthus).   
The first step is observation of the glands, with assignment of a morphology score (Table 2). 
Following this, the glands will be expressed using the MGED, and meibum quality score will be 
assigned (Table 2).  
Lid Morphology 
Assigned Grade 
Meibum Quality 
No plugged glands 
0 
Clear, fluid meibum 
Mild (1-2 glands plugged) 
1 
Granular or yellowish meibum 
Moderate (3-4 glands 
plugged) 
2 
Whitish, semi-solid meibum 
Severe (5+ glands plugged) 
3 
Solid, toothpaste-like meibum 
- 
4 
No expressible meibum 

Table 2: Meibomian gland scoring system, adapted from Meadows, et al26 
3. Schirmer Testing 
Schirmer testing will be performed using commercially available filter paper Schirmer strips.  
The strips should be placed at the outer canthus with the tip of the strip tucked between the 
lower lid and the bulbar conjunctiva, with both eyes being tested at the same time.  The strips 
should be left in place for 5 minutes or until the length of the strip is saturated.  The result 
should be recorded in mm of paper wetted by tears.  No anesthetic drops should be given prior 
to testing. 
4. SICCA Scoring 
A drop of 0.25% fluorescein should be administered to the conjunctiva of each eye and the 
patient allowed to wait for approximately 5 minutes.  Following this, the corneal epithelium 
should be examined for staining following the method of Whitcher, et al27, and the number of 
puncate epithelial erosions (PEE) counted.  A Lissamine green strip should then be saturated 
with 0.05% proparicaine and the proparicaine allowed to sit on the surface for 30 seconds, this 
should then be applied to the conjunctiva and the number of conjunctival PEE counted.  A score 
will be assigned according to the following system, from Whitcher, et al27.  The scores will range 
from 0 (no staining) to 12 (severe dry eye findings). 

 
Figure 1: SICCA scoring system27 
 
5. HD Analyzer 
The HD Analyzer is a FDA approved device to measure ocular surface light scatter.  As the tear 
film is the first surface that light encounters as it enters the eye, disruption of the tear film from 
Meibomian gland disease can have optical sequelae.   
Subjects will receive HD Analyzer measurements of the OSI (ocular surface index) at 
enrollment, 1 month, and 3 month timepoints per manufacturer instructions.   
 
XVI. 
Safety and Data Monitoring 
a. Adverse Events 
All adverse events will be recorded and reported via the Adverse Event Reporting Form 
(AERF, MOP), and entered into an Adverse Event Log for the patient (MOP).  Below is a list 
of adverse events (AE) and serious adverse events (SAE). 

Ocular Adverse 
Event 
Non-Serious 
Serious 
Ocular Irritation 
Mild to moderate irritation 
treatable with adjuvant 
lubricant drops.   
Impairs patient’s ability to complete 
activities of daily living, after normal 
surgical recovery period.   
Ocular Hypertension 
≥ 24 mm Hg 
Surgery required (laser or incisional) 
Subconjunctival 
hemorrhage 
Subconjunctival hemorrhage 
greater than 5mm indiameter 
after injection 
 
Cataract 
Visually significant cataract, 
cataract surgery indicated 
 
Infectious scleritis or 
keratitis 
 
Any occurrence is a serious adverse 
event 
Corneal or scleral 
perforation 
 
Any occurrence is a serious adverse 
event 
 
Systemic Adverse 
Event 
Non-Serious 
Serious 
Nausea 
Any nausea 
Severe discomfort, minimal food 
intake for 3 or more days or at least a 
2.5 kg weight loss resulting from 
nausea 
Vomiting 
Any vomiting 
Severe: vomiting all food or fluids in 
24 hours or orthostatic hypotension or 
at least a 2.5 kg weight loss resulting 
from vomiting 
Diarrhea 
Any diarrhea 
Severe, bloody diarrhea or 8-9 loose 
stools in 24 hours or orthostatic 
hypotension or at least a 2.5 kg 
weight loss resulting from diarrhea 
Dyspnea 
Breathlessness on significant 
exertion or breathlessness at 
normal level of activity 
Breathlessness at rest 
Headache 
Moderate, non-narcotic 
analgesic therapy required 
Severe, requires narcotic therapy 
Fatigue 
Self-reported fatigue 
Normal activity reduced >50%; cannot 
work or unable to care for self 
Fever for 12 hours 
> 100.6 to 103°F/39.5°C 
≥ 103°F/39.5°C 
Muscle strength 
Subjective weakness, no 
objective symptoms or mild 
objective weakness, no  
decrease in function 
Objective weakness, function limited, 
or worse 

Mood 
Self-reported mood changes 
or psychiatric diagnosis not 
requiring medical therapy 
(specify):_ 
_______________ 
Psychiatric diagnosis requiring 
medical treatment or hospitalization 
Cardiac function 
Mild congestive heart  
 failure (CHF) or 
arrhythmia  
not requiring treatment or 
moderate CHF or worse, 
arrhythmia requiring 
treatment, stable angina 
Unstable angina, severe CHF, 
myocardial infarction, or arrhythmia 
requiring hospitalization 
Neurologic function 
Numbness or tingling 
Total loss sensation 
Allergic reaction* 
Pruritis without rash or 
erythema or localized 
urticaria, diffuse 
maculopapular rash, dry 
desquamation 
Generalized urticaria, angioedema or 
worse, vesiculation, moist 
desquamation, ulceration up to and 
including: exfoliative dermatitis; 
mucous membrane involvement; or 
Stevens-Johnson Syndrome, or 
erythema multiforme, or necrosis 
requiring surgery 
Systemic infection 
Any systemic infection.  
 
Systemic infection requiring 
hospitalization.  
Other systemic 
No treatment required and 
no limitations or mild  
impairment of usual 
activities       
   
Vigorous treatment, hospitalization 
usually required, immediate risk of 
death  
 
Seizure 
 
Any occurrence is a serious adverse 
event 
Cancer 
 
Any occurrence is a serious adverse 
event 
Congenital 
Anomaly/Birth Defect 
 
Any occurrence is a serious adverse 
event 
Disability or Permanent 
Damage 
 
Any occurrence is a serious adverse 
event 
Hospitalization 
 
Any occurrence is a serious adverse 
event 
Life-threatening event 
 
Any occurrence is a serious adverse 
event 

 
 
Serious adverse event collection begins after the patient has signed informed consent and 
has undergone pterygium excision. If a patient experiences an SAE after signing informed 
consent, but prior to undergoing surgery, the event will be treated as unrelated to the study 
unless the investigator feels the event may have been caused by a protocol procedure. 
Adverse events (SAEs) occurring after a patient has received the last injection of the study 
drug will be collected for 30 days after the last dose of study drug, regardless of the 
investigator’s opinion of causation.  Thereafter, SAEs are not required to be reported unless 
the investigator feels the events were related to the study drug or a protocol procedure. 
 
b. Adverse Event Reporting 
Study personnel must alert the medical monitory of any SAE within 24 hours of investigator 
awareness of the event. Alerts issued via telephone are to be immediately followed with 
official notification on the Serious Adverse Event Reporting form (MOP).  All serious or 
unexpected Adverse Events judged to be definitely, possibly, or probably related to study 
participation will be reported to the UCSF CHR (Committee on Human Research) within 5 
working days of their occurrence.  All reporting will be performed following CHR guidelines.   
The study physician must report new significant follow-up information for these events to the 
principal investigator immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
  
c. Determination of Causality 
Causality of the adverse event will be determined by the study investigators and the 
DSMB.  Events will be determined to be one of the following: 

- 
Definitely Related: if it is clear that the event was caused by study 
participation. A definitely related event has a strong temporal relationship 
and an alternative cause is unlikely. 
- 
Probably Related: If there is a possibility that the event is likely to have 
been caused by study participation. The AE has a timely relationship to the 
study procedure(s) and follows a known pattern of response, but a potential 
alternative cause may be present. 
- 
Possibly Related: If there is a reasonable possibility that the event might 
have been caused by study participation. A possibly related event may follow 
no known pattern of response and an alternative cause seems more likely. 
An event may also be considered possibly related if there is significant 
uncertainty about the cause of the event, or a possible relationship to study 
participation cannot reasonably be ruled out. 
- 
Unrelated: The cause of the AE is known and the event is in no way related 
to any aspect of study participation.  
 
Uncertain Causality: If there is any uncertainty regarding AE causality then 
the event must be assessed as possibly related to research participation and 
reported to the IRB as indicated. 
 
d. Emergency Medical Contacts 
Principal investigator: Julie Schallhorn.   
Email: Julie.schallhorn@ucsf.edu 
Phone: 310-709-6105 
 
 
e. Investigator Follow-Up: 
The investigator will follow all unresolved treatment-related adverse event until the event 
has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
new therapy is initiated, the patient is lost to follow-up, or the patient withdraws consent. 
Every effort will be made to follow all serious adverse events considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. 

During the study period, resolution of adverse events (with dates) should be documented on 
the patient’s Adverse Event Log (MOP) and in the patient’s medical record to facilitate 
source data verification.  If, after follow- up, return to baseline status or stabilization cannot 
be established, an explanation will be recorded on the patient’s Adverse Event Log. 
f. Data Review 
The DSMC will review of data from enrolled patients at bi-annual committee meetings.  The 
discussion will include the number of patients and any significant adverse events.  If 
necessary, the Study Coordinator will provide unmasked treatment assignment to the 
committee.   
g. Interim Analysis 
Interim analyses of efficacy are not planned for this study.  
h. Early Stopping of the Study 
Stopping for harm will be done at the judgment of the DSMC.  
 
Committee 
 
Ayman Naseri, MD (ayman.naseri@ucsf.edu) 
Michele Bloomer, MD (michele.bloomer@ucsf.edu) 
 
i. Loss to Follow up 
All patients will be offered enrollment in the text-messaging appointment reminder 
service.  Patients that do not show up for scheduled study visits will be contacted by 
the study coordinator the day following their visit via phone and offered rescheduling.  
If they are unable to be contacted that day, repeated attempts will be made weekly 
for 4 weeks to contact patients lost to follow up.  Additional attempts will be made at 
the 6- and 12-month points.   
 
XVII. 
TREATMENT STOPPING RULES 
a. Discontinuation: 
Patients who discontinue one of the study treatments due to intolerability or side effects will 
be observed to the end of the study period unless they are unwilling or unable to return. 

In addition, the investigator will discontinue patients from the study drug in the following 
circumstances: 
• 
The investigator decides that the patient should be withdrawn from the study. If a SAE 
occurs and the investigator deems stopping study therapy is necessary, the investigator will 
discontinue the study therapy and take appropriate measures.  
• 
The patient or attending physician requests withdrawal of the patient from the study. 
• 
The investigator or the study sponsor stops the study or stops the patient’s participation 
in the study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice (GCP). 
• 
The patient becomes pregnant or fails to use adequate birth control (for women with 
reproductive potential). 
• 
The patient is noncompliant with study procedures. 
 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the Patient Dropout Form (MOP). 
Study agents assigned to the withdrawn subject may not be assigned to another subject. 
Subjects who withdraw will not be replaced.   
 
 
 
 
 
 
 
 
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