Treatment of Acute Sinusitis With High-Dose vs. Standard-Dose Amoxicillin/Clavulanate: A Confirmation Study
Phase: PHASE4
Conditions: Sinusitis, Acute
Sponsor: Paul Sorum, MD

 
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Research Protocol and Statistical Analysis Plan 
 
Treatment of Acute Sinusitis with High-Dose vs. Standard-Dose 
Amoxicillin/Clavulanate: A Confirmation Study 
 
NCT03431337 
 
February 11, 2028 
 
 
 

 
Version 11-Feb-2018 
 
 
Background and Purpose 
Acute sinusitis is a common out-patient diagnosis and is commonly treated with 
antibiotics even though the current recommended regimen, amoxicillin/clavulanate 
875/125,1 has been shown in clinical trials to provide only minimal benefit beyond 
placebo.2 Evidence from studies in children of the penetration of amoxicillin into middle 
ear fluid3 and of the treatment of acute sinusitis4 suggested that a higher dose of 
amoxicillin would provide more benefit to adults without increasing side effects. We 
performed in 2014-17, therefore, a double-blind placebo-controlled trial of high-dose vs. 
standard-dose amoxicillin/clavulanate for clinically diagnosed acute bacterial sinusitis.5 
The study drug was the extended-release formulation of amoxicillin/clavulanate. Midway 
through the trial, the manufacturer stopped producing both the brand-name and the 
generic forms of the study drug. We were forced, therefore, to use instead for the high-
dose arm a combination of standard immediate-release amoxicillin/clavulanate plus 
immediate-release amoxicillin. To our surprise, we found that the extended-release 
formulation provided no significant benefit, but the immediate-release formulation did; 
with 52% rating their symptoms as “a lot better” at the end of 3 days of treatment (the 
primary endpoint) vs. 34% (p = 0.04). 
This finding needs, however, to be replicated because 1) it was, arguably, the 
result of an analysis not initially planned and of a sub-group; 2) the number of 
participants in the immediate-release part of the study was not large (less than half of the 
whole cohort), even if enough for statistical significance; 3) the secondary outcome, the 
change in the rating of 16 symptoms (the validated SNOT-16) from baseline to the end of 
3 and 10 days of treatment, did not show a significant improvement; 4) the biological 
explanation of the difference in outcomes (that the high concentration achieved, if only 
for a short time, by the immediate release might be needed for penetration of amoxicillin 
into sinus fluid) was only hypothetical; and 5) the percent of patients reporting “severe” 
diarrhea at day 3 was higher for the immediate-release high-dose group than for the 
others (which was also a surprise since other studies suggested that diarrhea is largely 
caused by the clavulanate, which was the same for all groups). The balance for patients 
between more rapid clinical improvement versus more common and severe adverse 
effects needs to be explored further. One problem is that patients with adverse effects 
from high-dose amoxicillin may not be able to appreciate that their sinus symptoms 
improved faster than if they had taken standard-dose. 
The Infectious Disease Society of America (IDSA) recommends using high-dose 
amoxicillin/clavulanate when the prevalence in the community of penicillin-resistant 
pneumococci is >10%.1 Few primary care clinicians will know this prevalence. By 
performing anterior nasal cultures on the first two-thirds of our participants in the initial 
trial, we confirmed our expectation that very few of our patients are colonized with 
penicillin-resistant pneumococci. We will not need to repeat this part of the study. 
If we confirm that supplementing standard, immediate-release amoxicillin-
clavulanate 875/125 bid with standard, immediate-release amoxicillin 875 bid results in 
as substantial a benefit as in the initial study, we will be able to provide patients with a 
treatment that is clearly more efficacious than placebo and that is also quite inexpensive 
and easily available. If we find that the increase in adverse effects caused by the 

 
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supplemental amoxicillin does not outweigh, in patients’ judgments, the added benefits of 
treatment, we may change the way acute bacterial sinusitis is treated. 
 
Study Design and Methods 
Randomized, double-blind, comparative-effectiveness trial 
Site: the Albany Medical College Internal Medicine and Pediatrics primary care practice 
in Latham, NY 
Duration of study: 2 ½ years (November 2017-April 2020) 
 
Investigators 
Faculty: Paul Sorum, MD, PhD; Danielle Wales, MD, MPH; Gina Garrison, PharmD 
Medicine-Pediatrics residents: Jennifer Gregory, MD; Bichtram Huynh, MD 
Albany Medical College student volunteers: Jennifer Cha; Chaitali Korgaonkar; Laura 
Stanfel 
 
Participants 
Adults 18 years and older who are patients at the Albany Medical Center Internal 
Medicine and Pediatrics Practice in Latham, NY. 
Inclusion criteria 
1. Clinical diagnosis of acute bacterial sinusitis in accordance with the guidelines of 
the Infectious Disease Society of America, i.e., fitting into one of 3 categories: 
a. Persistent symptoms of rhinitis, purulent secretions, and/or pain in face or teeth 
and not improving (lasting for > 10 days); or 
b. Severe symptoms or signs of fever > 102 degrees F and nasal discharge or facial 
pain (lasting for > 3-4 days); or 
c. Worsening symptoms or signs characterized by a new onset of fever, headache, 
or increase in nasal discharge following a typical viral URI that lasted 5-6 days 
and was initially improving (“double-sickening”). 
2. Patients who participated in the initial study will be eligible. Having chronic or 
recurrent sinus infections was, and will again be, an exclusion criterion, but it 
would decrease external validity to exclude patients who occasionally get sinusitis 
and might, therefore, have participated in the past 3 years. We are able to obtain 
different looking antibiotic and placebo pills, so that we can include even patients 
who knew or who think they knew which formulation they took in the first study. 
We will, however, plan a secondary analysis of those who were and were not in 
the initial study. 
Exclusion criteria 
1. Patients who were enrolled previously in the current study 
2. Allergy or intolerance to any penicillin (oral penicillin, amoxicillin, or 
dicloxacillin or IV penicillin, ampicillin, oxacillin, nafcillin, carbenicillin, 
ticarcillin, or piperacillin) or to amoxicillin/clavulanate 
3. Serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) 
to any beta lactam 
4. Elevated risk of amoxicillin-resistant bacteria 
a. Amoxicillin, penicillin, or other beta-lactam within the past month (not, as 
in the IDSA guidelines [2012], any antibiotics) 
b. Known to have had MRSA 

 
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5. Chronic or recurrent “sinus” problems. Defined as persistent symptoms of “sinus” 
congestion, not attributed to nasal allergies, for 8 weeks or more (Mayo Cinic, 
2014) or 2 or more episodes of antibiotic-treated “sinusitis” in past 3 months. 
These patients are at risk of anatomical or immunological abnormalities and of 
harboring antibiotic resistant organisms. 
6. Need to use high-dose amoxicillin/clavulanate or levofloxacin or to send to ED or 
to hospitalize because of 
a. Signs of severe infection 
b. Immunocompromise 
7. Cognitive impairment, so unable to give reliable symptom ratings (even if a 
health proxy can give consent) 
8. Pregnant women and nursing mothers.  Pregnancy is Category B, so we do not 
need to perform a pregnancy test prior to enrolling pre-menopausal women; but 
known pregnancy will be an exclusion because amoxicillin/clavulanate has been 
demonstrated as safe in pregnant animals but not yet in pregnant women, and in 
practice (as in the previous trial), both clinicians and pregnant women hesitate to 
participate in experiments unless it is important to include pregnant women as a 
category.  Nursing will be an exclusion because of lack of information even 
though it is not likely to cause a problem. 
9. Drug warnings 
a. Taking allopurinol (which increases substantially the risk of rash) 
b. Current mononucleosis (because of amoxicillin-induced rash) 
c. Chronic kidney disease stage 4 with estimated GFR <30 
d. Hepatic impairment (not including isolated transaminase elevated < 2 
times upper limit of normal) 
e. History of antibiotic-associated colitis (C. diffiile) 
Time in study 
10-11 days (or a few days longer if difficult to make telephone contact at day 10) 
Drop-outs 
Participants can exit the study at any time: a) by going to Urgent Care or the Emergency 
Department if very sick (calling our office beforehand if possible, in accordance with 
office policy); b) by indicating this at the day 3 telephone call; or c) by calling the office 
or (after hours) the physician on call at any time 
If appropriate, the office or on-call physician can switch the antibiotic (in accordance 
with ISDA guidelines) to doxycycline or levofloxacin 
 
Interventions 
Randomization: 
Participants will be randomized 1:1 by the pharmacist (GG) and her pharmacy students, 
who will prepare the study medication in bottles labeled only by study # and who will 
keep a list of study # and dosage that will be revealed to the investigators only after the 
completion of the study. 
Treatment arms: 
1. Standard dose: amoxicillin/clavulanate 875/125 + placebo tablet (OTC lactase) 
bid x 7 days 
2. High dose: amoxicillin/clavulanate 875/125 + amoxicillin 875 bid x 7 days 

 
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Measurements: 
1. Global rating of improvement: on the scale 1=a lot worse, 2= a little worse, 3=the 
same, 4=a little better, 5=a lot better, 6=no symptoms (at telephone calls at the 
end of days 3 and 10) 
2. SNOT-16: rating of current condition of 16 symptoms on a scale of 0 = no 
problem to 4 = severe problem (at enrollment and at telephone calls at days 3 and 
10) 
3. Additional question at bottom of baseline SNOT-16: do you often have trouble 
with a) constipation, b) diarrhea, c) (for women) vaginal yeast infections (yes or 
no)? 
4. Rating of adverse effects (diarrhea, abdominal pain, [for women] vaginal itching 
and discharge, and rash on a scale of 0=none to 3=severe (at days 3 and 10) 
5. Were you treated for vaginal yeast infection (if so, when and how, and did it help) 
and for diarrhea (if so, when and how, and did it help)? (at day 10) 
6. How many doses of antibiotic did you not take? If you stopped early, why? (Felt 
so much better, side effects, forgot, lost medication) (at day 10) 
7. How would you balance the good effects and the bad effects of the antibiotic on a 
scale of -3=bad effects MUCH greater than good effects; -2=bad effects 
SOMEWHAT greater than good effects; -1= bad effects A LITTLE greater than 
good effects: 0=bad effects and good effects about equal; +1=good effects A 
LITTLE greater than bad effects; +2=good effects SOMEWHAT greater than bad 
effects; +3=good effects MUCH greater than bad effects (at day 10) 
8. Would you take this antibiotic again (yes, no, uncertain). Any further explanation 
of response beyond the previous question? (at day 10) 
9. What dosage do you think you took? And why? (looked up or recognized pills, 
degree of beneficial effect on sinus symptoms, level of severity of side effects) (at 
day 10) 
10. Drop-outs will be asked how many doses they took and why they are dropping out 
of the study (fear of adverse effects, actual experience of side effects, quick 
improvement, no improvement) 
Endpoints 
1. Primary efficacy endpoint: percent giving a global rating of improvement of 5 or 
6 after 3 days of treatment 
2. Secondary efficacy endpoints:  
a. Percent giving a global rating improvement of 5 or 6 at day 10 
b. Change in SNOT-16 average score from baseline (at enrollment) to 3 and 
10 days after enrollment (with minimal clinically important change = 0.5 
units of the scale from 0 to 4)) 
c. Percent having change in mean SNOT-16 item score at day 3 and 10 > .5 
(minimal clinically significant difference) 
3. Adverse effect endpoints: 
a. Percent having each of adverse effects and having level 3 (severe) of each 
of side effects 3 and 10 days after enrollment 
b. Percent having side effects in a) of those declaring themselves prone or 
not to have 1) diarrhea and 2) vaginitis (predictive power) 
4. Overall judgments:: 

 
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a. Mean rating on balance of good and bad effects at day 10 
b. Distribution of ratings of balance (using different cutoffs) 
c. Distribution of judgments about whether they would take the antibiotic 
again 
5. Impact of using the web: if any significant number of participants use the web to 
enter their responses, we will compare the answers to the endpoints of web vs. 
non-web participants 
6. Impact of potentially confounding factors: 
a. Use of nasal steroids (which can improve symptoms6  
b. Use of other antibiotics in the past month (altering nasal flora) 
c. Discovery of the identity of the pills (unblinding) 
 
Study Materials 
1. Posters in waiting and examining room 
2. Enrollment form (filled out by enrolling physician) 
3. Day 0 SNOT-16 questionnaire (given by nurses to all patients with respiratory 
symptoms and, if not filled out already, filled out by participants at enrollment)\ 
4. Consent Form 
5. Day 3 and Day 10 telephone or web questions [except for the additional day 10 
questions asked over the telephone or on the website] (handed out to participants 
at enrollment) 
6. Directions for nasal saline and contact information (handed out at enrollment) 
7. Telephone scripts or web forms at end of days 3 and 10 
8. Drop-out form 
 
Study Flow 
1. Nurse gives the patient with respiratory symptoms a SNOT-16 form to fill out and 
mentions the study to the patient. 
2. Physician does the standard clinical assessment; decides if the patient is likely to 
have sinusitis (according to IDSA guidelines) and might benefit from antibiotics; 
determines if the patient meets inclusion criteria for the study and has no 
exclusion criterion (as shown on the Enrollment Form); and explains the study to 
the patient. 
3. If the patient will be treated with antibiotics for acute sinusitis but will not be a 
participant in the trial, the physician will fill out the Treated Outside of Study part 
of the Enrollment Form and leave it on the designated spot in the Pod. 
4. If the patient is willing, the physician gives the Consent Form to the patient, 
explains what involved, and allows the patient to read it, ask questions, and decide 
to enter the study or not. 
5. If the patient enrolls in the study, the physician, nurse, or pharmacy student 
a. Puts a patient sticker on the next study # in the Participant List in the 
locked study room; 
b. Obtains the bag of study medications with that study # (prepared in 
advance by the pharmacist [GG]) and, as required by NYS law, writes on 
the bottles the patient’s name and address, the physician’s name, and the 
date; 

 
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c. Fills out the Enrollment Form: writes the study # on it, on the SNOT-16 
form, and on a study folder; puts the forms in the study folder and leaves it 
in the locked study room; and brings the bag of study medications back to 
the examining room. 
6. The physician then 
a. Gives the participant the study medication, with directions how to take the 
pills; gives the participant the Day 3 and Day 10 telephone questions with 
the study # written on them (without the questions added to the Day 10 
form) with a request to fill them out after 3 and 10 days just in case the 
study personnel do not succeed in making contact on time; 
b. Gives the participant the option of filling out the forms online, using 
AMC’s membership in Qualtrics (in which the participant is identified by 
study number only), and, if desired, has the participant write down his or 
her email address and tells the participant that we will send by email the 
directions for the secure website (but also will telephone him or her); 
c. Asks the participant if he or she wants a text message reminder and, if so, 
has him or her to write down the telephone number for the text (if different 
from the main number); 
d. Shows the participant the directions for symptomatic treatment. 
7. The residents are responsible for making the telephone calls themselves or 
assigning them to the medical student members of the team. The residents 
telephone or send AMC emails to the students to provide the names, telephone 
numbers and dates of required telephone calls. 
8. At the ends of day 3 and 10, the participant is called by a member of the study 
team and asked the questions on the day 3 and day 10 telephone forms. If the 
participant wants a text reminder and/or wants to fill out the form online, the 
study team member sends the text and/or email with the link. The study team 
member enters the data from the web-based form or from the telephone call into 
the restricted database on the AMC Med-Ped Y drive (with participants identified 
only by study number) and also fills out the forms to be placed with the other 
study materials. 
9. If the participant sends to us (by e-mail, fax, or mail) a completed day 3 or 10 
questionnaire and also provides answers over the telephone and if the written and 
verbal answers differ, we will use the written version (unless the participant 
directs us not to). 
10. If the participant asks the study team member for a call from the office, that 
request is communicated to the on-call physician for the Medicine-Pediatrics 
practice. 
11. If a participant indicates at the day 3 call or at another time that he or she is 
dropping out of the study, the clinician, medical student, or staff member asks 
why, fills out the Drop-out form in paper and on the shared electronic database on 
the Y drive, and (if needed) notifies one of the study team members. 
12. After the study has been completed, the data analyzed, and a study report 
accepted for publication, we will mail to each participant a summary of the study 
results and an indication of the dosage she or he took. We will then destroy the 
patient registry with its identifying information. 

 
Version 11-Feb-2018 
 
Data Analyses 
Sample size: 
To have a power of 80% to find again an increase in the primary endpoint from 34% to 
52% with an alpha of 0.05 %, we would need 230 patients (115 in each group). To find 
an increase only to 50%, we would need 292 patients (146 in each group). Our aim is, 
therefore, to enroll at least 240 and ideally 300 patients. We enrolled 315 patients in the 
previous study during an equivalent time period. 
Outcomes: 
Using SPSS, we will calculate 
1. Chi-square analyses of the differences between the two arms in percentages of 
global ratings, adverse effects, balance between good and bad effects, willingness 
to take the antibiotic again, use of nasal steroids, and correct guesses of the dose 
(with alpha set at 0.05). 
2. T-test analyses of the differences between the two arms in the changes of average 
SNOT-16 item rating from baseline to the end of day 3 and to the end of day 10 
and in the mean rating of balance between good and bad effects at day 10 (alpha 
0.05) 
3. Subgroup analyses for 1) and 2) of those who did vs. did not participate in the 
initial study. 
4. Repeat analyses combining a) the participants in this study and b) the participants 
in Time Period 2 of the initial study. 
 
Human subjects 
Risks 
1. Adverse physical effects 
In the initial study the primary adverse effects were diarrhea and (in women) 
vaginal discharge or itching. In the second time period, comparing the antibiotic 
formulations used in the current study, the increases in these adverse effects 
associated with a doubling of the amoxicillin were: 
a. Diarrhea 
i. At day 3; any diarrhea 47.37 % vs. 30.65% (p=0.06); severe 
diarrhea 15.79% vs. 4.84% (p=0.05) 
ii. At day 10: any diarrhea 17.32% vs. 12.00% (p=0.45); severe 
diarrhea 3.85% vs. 0 (p=0.16) 
b. Vaginal itching or discharge 
i. At day 3: any symptoms 15.91% vs. 7.84% (p=0.22); severe 
symptoms 2.27% vs. 1.96% (p=0.92) 
ii. At day 10: any symptoms 23.68% vs 17.50% (p=0.50); severe 
symptoms 0 vs. 2.56% (p=0.33) 
2. Flaws in decision making 
a. Under-treatment: the risk of enrolling in the study a very sick patient who 
should be either treated with levofloxacin or sent to the ED. To guard 
against this, the enrolling physician must attest that the patient is not too 
sick to receive out-patient amoxicillin/clavulanate. 
 

 
Version 11-Feb-2018 
b. Over-treatment: the risk of enrolling patients who ought not to receive 
antibiotics. To minimize this, the enrolling physician must indicate to 
which of the 3 IDSA categories of acute bacterial sinusitis the patient 
belongs. 
c. Coercion: the risk that, because we are their primary care office, patients 
who prefer not to be in a study will allow themselves to be enrolled. In the 
previous study, however, we found many patients not afraid to say no.  
3. Breach of confidentiality 
This is very unlikely to be a problem (see below). Nonetheless, since the 
study database indicates the presence or absence of the comorbidities of 
smoking, asthma or COPD, diabetes, and heart disease, it is conceivable, 
though unlikely, that someone might use this information to target the 
participant for marketing or other purposes. If a data breach does take 
place, we will immediately notify the AMC risk management office. 
 
Benefits 
1. Patients receiving the extra dose of amoxicillin may benefit from a more rapid 
rate of improvement. 
2. Other patients are likely to benefit if clinicians know whether or not to treat acute 
sinusitis with high-dose amoxicillin/clavulanate. 
 
Confidentiality 
1. The enrolling physician, office nurse, or pharmacy student will place the patient’s 
label next to the study # in the study patient registry.  The patient number will be 
written on a study folder as well as on the enrollment form, the Consent form, and 
the baseline SNOT-16 that will be placed in that study folder (along with the day 
3 and 10 telephone forms, as well as the Drop-out form if needed). The study 
patient registry and the files will be kept in a locked room. 
2. Communication between team members of patient names and telephone numbers 
will be either verbally or via Albany Med email (hence secure). 
3. The participants who chose to enter their answers to the day 3 and 10 
questionnaires electronically will receive an email from the study team member 
with directions on how to access the secure Qualtrex website with their study 
number and will enter their data on it, identified only by study #. The study team 
member will be able to access this data and transfer it to the study-wide database 
on the Y drive. 
4. The study-wide shared electronic database for the entry of day 3 and 10 responses 
will be kept in the sinusitis study folder on the AMC Med-Ped Y drive, with 
access limited to members of the study team only, and will identify participants 
by study # only i.e. will contain no personal identifying information. 
5. The material in the participant’s study file will contain no information that is at all 
likely to be embarrassing or compromising to the patient. 
6. The study team members are clinicians (physicians, office nurses, the pharmacy 
professor (GG), and pharmacy students) who are part of the practice and already 
have routine access to the patients’ full medical records. The students from the 
Albany College of Pharmacy and Health Sciences have full access to patient 

 
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records during their blocks in the office and, under the supervision of the 
pharmacy professor, regularly review and counsel patients about their 
medications. The medical students will not have access to the patient registry or 
the study files, although they will of course know the names of the participants 
whom they contact. 
7. Study data will ultimately be entered into an Excel database. Individual 
participants will be identified by study #, not by name; data will include sex and 
age (but not date of birth). The database will be kept in the sinusitis study folder 
of the AMC Y drive, with access limited to study team members. 
8. When the trial is complete, the data analyzed, and the report accepted for 
publication, we plan to notify participants of the study results and of the dosage 
they received and then to destroy the patient registry. We will not destroy the files 
and database, identified only by study #, so that, if needed, we can do further 
analyses. 
 
Costs 
Funds will come from the AMC Med-Ped Research Fund 
1. Medications (for 300 participants) 
a. Amoxicillin/clavulanate 875/125: 4200 pills = $840 
b. Amoxicillin 875: 2100 pills = $525 
c. Placebo (lactase): 2100 pills = $300 
d. Medication bottles and caps: 600 = $210 
2. Duplication of forms = $350 
3. Letters to participants after publication of study results = $300 
4. Total: $2,175 
 
References 
1. Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for 
acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 
2012;54(8):e72-e112. 
2. Lemiengre MB, van Driel ML, Merenstein D, Young J, De Sutter AIM. 
Antibiotics for clinically diagnosed acute rhinosinusitis in adults. Cochrane 
Database Syst Rev. 2012;10:CD006089. 
3. Canafax DM, Yuan Z, Deka K, Russlie HQ, Giebink GS. Amoxicillin middle ear 
fluid penetration and pharmacokinetics in children with acute otitis media. Pediatr 
Infect Dis J. 1998;17(2):149-156. 
4. Wald ER, Nash D, Eickhoff J. Effectiveness of amoxicillin/clavulanate potassium 
in the treatment of acute bacterial sinusitis in children. Pediatrics. 2009;124(1):9-
15. 
5. Matho A, Mulqueen M, Tanino M, et al. High-dose versus standard-dose 
amoxicillin/clavulanate for clinically-diagnosed acute bacterial sinusitis: a 
randomized clinical trial. 2017; unpublished manuscript. 
6. Zalmanovici Trestioreanu A, Yaphe J. Intranasal steroids for acute sinusits. 
Cochrane Database of Systematic Reviews 2013, Issue 12, Art No CD005149.