Clinical trial NCT02552225
Conditions: Laryngeal Diseases
Keywords: laryngeal sensory neuropathy, chronic laryngeal neuropathy
Sponsor: Boston Medical Center
Start date: 2016-04-01; Completion date: 2021-01-15
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, placebo-controlled trial will compare the effectiveness of amitriptyline versus placebo (inactive medication) in treating chronic laryngitis.

Detailed description:
Chronic laryngitis commonly manifests through symptoms including cough, hoarseness, throat clearing, foreign body sensation, throat pain, sensation of excessive phlegm, and difficulty swallowing. A significant minority also present with GERD, rhinosinusitis-induced post-nasal drainage, direct allergic effect, and smoking issues.

Amitriptyline is commonly used for mental/mood problems, but is also prescribed to treat chronic laryngitis because some investigators suggest a neuropathic etiology for idiopathic chronic laryngitis. No trials have compared any treatment for chronic laryngitis to placebo and it is unknown if currently used therapies for chronic laryngitis are effective.

At the baseline visit, subjects will be assigned at random to amitriptyline or placebo, which they will take for 4 weeks each. Subjects will be seen in the clinic at baseline and after 10 weeks. Improvement will be measured using standardized symptom scales, and a self-reported subjective improvement percentage.

Arms: arm 1: Subjects in this arm will receive pills composed of amitriptyline and Avicel (cellulose filler) arm 2: Subjects in this arm will receive pills composed only of Avicel (cellulose filler)
Interventions: intervention 1: Amitriptyline intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects in this arm will receive pills composed of amitriptyline and Avicel (cellulose filler) intervention 2: Subjects in this arm will receive pills composed only of Avicel (cellulose filler)

Protocol documents:
Prot_SAP_000.pdf: 
Protocol for H-34438 DOUBLE-BLIND PLACEBO CONTROLLED 
TRIAL OF THE TREATMENT OF CHRONIC LARYNGITIS WITH 
AMITRIPTYLINE 
 
NCT02552225 
 
Version 4.4 30-APRIL 30, 2017 
 
PI- Pieter Noordzij, MD 
Boston Medical Center 
 
 
Statistical Analysis Plan pages 6-8 
 
 
 
 
 
 
 
 
 
 
 
 


H-34438 Version 4.4 30-APRIL 2017 
 
 
2 
H-34438 DOUBLE-BLIND PLACEBO CONTROLLED TRIAL OF THE 
TREATMENT OF CHRONIC LARYNGITIS WITH AMITRIPTYLINE  
 
 
Background 
Chronic laryngitis can present with a myriad of symptoms including cough, hoarseness, 
throat clearing, foreign body sensation, throat pain, sensation of excessive phlegm, and 
difficulty swallowing. This combination is significantly limiting for many patients, who 
often report impairment of ability to perform their job, embarrassment, discomfort and 
avoidance of social settings. Many patients present to primary care providers and 
specialists with these symptoms. Of these, a significant minority have symptoms not 
amenable to standard therapies. Several causes for this disorder have been identified, 
including GERD, rhinosinusitis-induced post-nasal drainage, direct allergic effect, 
smoking, and other environmental causes. Despite treatments already available for these 
conditions, some patients fail to improve, despite extensive diagnostic testing and a 
variety of therapeutic regimens. These patients are often desperate for any relief, and may 
present to otolaryngologists for consultation. Here at BMC, an otolaryngologist may see 
up to approximately 10 such patients per week, with a more common number between 2 
and 4, of whom about half are prescribed amitriptyline (based on data compiled from 
Logician for a poster presentation, "RETROSPECTIVE ANALYSIS OF USE OF 
AMITRIPTYLINE IN CHRONIC LARYNGITIS", H-29997). 
 
For these cases, some investigators have suggested a neuropathic etiology for idiopathic 
chronic laryngitis without a clear cause, and have speculated that this may occur as a 
post-viral complication (1-4). Diagnosis of this condition, also known as chronic 
laryngeal neuropathy, remains one of exclusion, since there is no diagnostic test for 
chronic laryngitis at this time. Multiple medications used in other specialties for the 
treatment of neuropathic disorders have been tried, with significant clinical relief in many 
patients. As a result, uncontrolled trials of amitriptyline, nortriptyline, gabapentin, and 
pregabalin were conducted and shown to have some benefit (10), but it is unknown if 
improvement seen in these studies was due to placebo effect alone. To date, no controlled 
(prospective, randomized, placebo-controlled) trials have been performed.  
 
As the prescription of amitriptyline for chronic laryngeal neuropathy is an off-label use, 
there is no standardized dose. Literature review shows that doses from 10-100mg have 
previously been well tolerated without serious adverse side effects, with improvement 
noted with doses as low as 10mg daily for 21 days in non-randomized controlled trials 
(Table 1). Therefore, the amitriptyline dosing regimen as described in this protocol (12.5-
50mg nightly) is unlikely to put subjects at risk for either undertreatment or serious 
adverse side effects. Subjects randomized to placebo, however, will be at potential risk 
for undertreatment. 
 
Table 1. Prior dosing regimens for amitriptyline in chronic laryngeal neuropathy (Altman (10)) 
First Author  
 
Study Type  
Intervention  
Outcome  
Side Effect 
Bastian (6) 
Prospective cohort, 
12 consecutive 
10 mg 
amitriptyline daily 
10 of 12 patients 
had ≥ 50% 
None noted. 
 


H-34438 Version 4.4 30-APRIL 2017 
 
 
3 
patients. 
 
for 21 days. 
response; 
6 of 8 patients had 
≥ 50% response 
>20 days off 
amitriptyline. One 
patient had no 
benefit with 
amitriptyline but 
did with 
subsequent 
gabapentin. 
 
Norris (8) 
Retrospective case 
series of 8 patients, 
consecutive 
unknown. 
 
25–100 mg 
amitriptyline, 
failures treated 
with gabapentin or 
pregabalin, 
unknown duration 
of treatment. 
 
Six of 8 improved.  
Dry mouth in 30% 
of all enrolled 
patients. 
 
Jeyakumar (5) 
Randomized 
controlled trial; 15 
patients in 
amitriptyline 
group, 14 in 
codeine group. 
Randomized by 
chart numbers 
and presence of 
nasal allergies. 
 
Amitriptyline 10 
mg daily vs. 
codeine/ 
guaifenesin 10 mL 
every 6 hours for 
10 days. 
 
Thirteen of 15 in 
amitriptyline group 
had ≥ 50% 
improvement as 
compared to 1 of 
13 in codeine/ 
guaifenesin group; 
improved QOL 
scores associated 
with amitriptyline. 
 
No mention of 
adverse effects. 
 
Stein (9) 
Retrospective chart 
review of 66 
patients. 
 
All subjects were 
prescribed 10-mg 
tablets of 
amitriptyline, with 
variable dosing.  
53% took 1 or 2 
tablets 10 or 20 
mg) at night. 42% 
took 10 mg (1 
tablet) of 
amitriptyline, also 
at night. 5% had 
dosage increased 
to 2 to 4 times a 
day as needed for 
greater control. 
The response rate 
was not correlated 
with dosage (Chi-
squared test, p = 
0.9179). 
32% complete 
response, 24% 
partial 
response, 36% no 
response, 8% 
response unknown. 
 
Sedation in 23%. 
 
 
 
Purpose/Objectives 


H-34438 Version 4.4 30-APRIL 2017 
 
 
4 
We wish to study amitriptyline, which has been previously shown to be potentially useful 
in a non-controlled study (5), in a double-blind placebo controlled trial to ascertain its 
effectiveness in treating chronic laryngeal neuropathy. Our hypothesis is that it will be 
significantly superior to placebo for this condition with respect to symptomatic relief of 
laryngopharyngeal symptoms. We believe that this is a study that presents a reasonable 
ratio of risk to benefit, since amitriptyline is the most commonly used medication for this 
condition at both BMC and elsewhere with promising results clinically, and it has a well-
established safety profile and characterized side-effects. Furthermore, in clinical 
experience here at BMC, it has been found to be well-tolerated by patients in the setting 
of chronic laryngitis, with the symptomatic relief generally outweighing the side-effects. 
However, it is critical that its effectiveness be established by comparing it to placebo. No 
trials have compared any treatment for chronic laryngitis to placebo (thus there is no 
standard to which amitriptyline could be compared), and it is unknown if currently used 
therapies are truly effective. Potential subjects will be carefully informed that they can 
get the same medication by prescription without participation in the study, and that there 
is a 50% chance that they will have their treatment delayed by 8 weeks when enrolling in 
the study. 
 
A prior pilot study H-29925 DOUBLE-BLIND PLACEBO CONTROLLED TRIAL OF 
THE TREATMENT OF CHRONIC LARYNGITIS WITH AMITRIPTYLINE confirmed the 
safety of the dosing regimens currently used at Boston Medical Center, and provided 
additional data regarding enrollment and dropout rates to help determine the sample size 
for this study.  
 
(1) Morrison M, Rammage L, Emami AJ. The irritable larynx syndrome. Journal of 
Voice. 1999;13:447- 455. 
(2) Amin, M R, and J A Koufman. "Vagal Neuropathy After Upper Respiratory 
Infection: A Viral Etiology?" American journal of otolaryngology 22, no. 4 (2001) 
(3) Koufman A. The Visible Voice Newsletter. Voice Institute of New York. ;2 
(November 2008) 
(4) Rees, Catherine J, Arthur H Henderson, and Peter C Belafsky. "Postviral Vagal 
Neuropathy." The Annals of otology, rhinology, and laryngology 118, no. 4 (2009): 247-
52. 
(5) Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough 
suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. 
Laryngoscope. 2006;116:2108-2112. 
(6) Bastian RW, Vaidya AM, Delsupehe KG. Sensory neuropathic cough: a common and 
treatable cause of chronic cough. Otolaryngol Head Neck Surg. 2006;135:17-21. 
(7) Lee, Bryant, and Peak Woo. "Chronic Cough As a Sign of Laryngeal Sensory 
Neuropathy: Diagnosis and Treatment." The Annals of otology, rhinology, and 
laryngology 114, no. 4 (2005): 253-7. 
(8) Norris BK, Schweinfurth JM. Management of recurrent laryngeal sensory neuropathic 
symptoms. Ann Otol Rhinol Laryngol 2010;119:188–191. 
(9) Stein DJ, Noordzij JP. Amitriptyline for symptomatic treatment of idiopathic chronic 
laryngeal irritability. Ann Otol Rhinol Laryngol 2013;122: 20–24. 
(10) Altman KW, Noordzij JP, Rosen CA, Cohen S, Sulica L. Neurogenic cough. 


H-34438 Version 4.4 30-APRIL 2017 
 
 
5 
Laryngoscope. 2015 Jul;125(7):1675-81. 
 
Study Design 
This study will be a randomized, double-blind, placebo-controlled trial to determine 
whether amitriptyline improves symptoms of chronic laryngeal neuropathy over an 8 
week period. 
 
The target of our study is to have 100 subjects complete the study, excluding prior pilot 
study data.  We will run a blinded interim analysis on the primary endpoint when 25 
subjects in each arm have completed treatment and follow-up, and a conditional power 
for detecting a significant treatment effect by the planned end of the study (100 subjects) 
will be determined.  If this conditional power is between 50 and 80%, the sample size 
will be recalculated to achieve 80% conditional power following the algorithm of Chen 
and DeMets (2004).  Otherwise, the study will continue until 100 patients have 
completed treatment.  
 
Based on prior pilot study data, we anticipate the study dropout rate to be approximately 
30%, from time of initial enrollment to completion of the post-treatment survey. During 
the prior pilot study, the dropout rate was 50% initially, and dropped to 30% during the 
last 8 months of enrollment, until the study was closed. Dropout rate was the same in 
each arm, with 5 subjects in each arm dropping out after starting treatment. Only three 
subjects cited adverse events (AEs) as a reason for drop out; two subjects on placebo 
complained of headache and dry mouth, respectively, and one subject on amitriptyline 
complained of sedation.  
 
Thus, we anticipate a dropout rate during treatment of 30%, and anticipate having to 
enroll at least 75 subjects in order for 25 patients in each arm to complete the study by the 
interim analysis.  
 
The physician may elect to discontinue study drug due to serious adverse events (SAEs) 
or unintended pregnancy. If a subject withdraws from treatment due to adverse events, 
we will ask that they continue coming in for follow-up visits and finish the remaining 
parts of the visits off the study drug. 
 
The primary endpoint of the trial will be the total modified RSI at 8 weeks.  The Reflux 
Symptom Index (RSI) has been validated by Belfasky et. al. [Belafsky PC, Postma GN, 
Koufman JA. Validity and reliability of the reflux symptom index (RSI). Journal of 
Voice. 2002;16:274-277]. The RSI is a questionnaire consisting of 9 statements to be 
ranked 0-5. We have added two additional symptoms to be assessed with the RSI, "throat 
pain or burning" and "pain with swallowing", which we believe are also relevant to 
chronic laryngeal neuropathy.   
 
The total modified RSI score at 8 weeks will be averaged for each group (amitriptyline 
vs. placebo) and differences compared between the treatment and placebo arms using 
analysis of covariance adjusting for baseline severity scale at an overall two-sided 0.05 
level of significance across the interim and final analysis (a two-sided significance level 


H-34438 Version 4.4 30-APRIL 2017 
 
 
6 
of 0.00306 at the interim and 0.049 at the final analysis). A Wilcoxon Rank Sum test will 
be used in the case that the data is found to have a non-normal distribution. 
 
A secondary outcome will be improvement in overall symptoms (yes/no), as subjectively 
assessed by patients. The post treatment survey will ask both the patient and the principal 
investigator whether they thought the subject was on amitriptyline or placebo. 
 
Additional secondary outcomes will be whether there are changes in scores from baseline 
on the Voice Handicap Index-10 after treatment [Rosen et. al. Development and 
Validation of the Voice Handicap Index-10. The Laryngoscope. 2004; 114: 1549-1556] 
and change in score from baseline on the Cough Severity Index (CSI).[ Shembel AC et 
al.. Development and validation of the cough severity index: a severity index for chronic 
cough related to the upper airway. Laryngoscope. 2013;123(8):1931-6.] The VHI-10 is a 
10-question scale that addresses effects on quality of life from voice disorders while the 
CSI is a 10-item likert scale that assesses cough symptoms. Furthermore, we will 
determine whether the severity of each symptom within the modified RSI has improved 
after treatment. This will account for questions that may be less relevant to laryngitis 
overall (and more specific to reflux). 
 
Frequencies of AEs for both groups of patients and the rate of discontinuing treatment 
will be recorded. 
 
The study will be stopped if any patient is permanently disabled, seriously injured, or dies 
in a manner that could be consistent with the drug usage. The study will be continued if 
said patient(s) were taking the placebo or the event is demonstrably unrelated to the 
subject's participation in the trial. 
 
An independent monitor within the otolaryngology department who is not associated with 
study recruitment or data analysis will also review adverse events for all subjects. The 
independent monitor will submit a report to the PI, who will then review these events and 
submit a report to the IRB. Also, if there is a concerning event or group of events, the PI 
will bring these to the attention of the independent monitor as they occur.  
 
A report will be submitted to the IRB and the PI by the independent monitor at the 
intervals described in safety monitoring section (see section on Safety monitoring/ 
reporting for more detail).  
 
 
Analysis (efficacy and safety) 
 
We will be using the 8 week post-treatment 11-point modified RSI score as our primary 
outcome.   Treatments will be compared using analysis of covariance adjusting for the 
baseline value using a two-sided 0.05 level of significance. 
 
We thus used the RSI to calculate our sample size.  The average starting RSI for subjects 
with a similar type of laryngitis to what we are studying is 20.9. After treatment, the 
average was 12.8 (Belfasky et. al. 2002). We estimated a 20% improvement for the 


H-34438 Version 4.4 30-APRIL 2017 
 
 
7 
placebo group, using the estimate for continuous indicators from Hróbjartsson et. al. 
meta-analysis of placebo effects. Thus, we predicted the final mean RSI for the placebo 
patients to be 16.72. The difference between the means is thus assumed to be 3.92.  
Dividing this mean difference by the anticipated standard deviation (10.0, using the value 
from Belfasky et. al. for the final RSI value post-treatment) gives an anticipated 
standardized effect size of 0.392. Using this for the calculation for a-priori sample size 
calculations (using two-sided p <0.05 and a desired power level of 0.8) gives a needed 
sample size of 208.  
 
In prior pilot study data, mean difference in RSI scores was +13 (increase in score post 
treatment) for the amitriptyline group and +16.4 in the placebo group, with standard 
deviations of 7.8 and 12.1, respectively. The p-value used to determine significance was 
0.5 for a two-tailed unpaired t-test.  
 
Currently, funding is available for 100 subjects to complete this study, not including 
subjects who completed treatment in the prior pilot study. With a dropout rate of 30%, we 
expect to enroll 130 subjects in order for 100 to complete treatment. With a standard 
deviation of 10 as per prior assumptions, we would be able to detect a mean difference of 
6 by one-tailed ANOVA analysis. 
 
When 25 subjects in each arm (placebo and amitriptyline) have completed the study and 
follow-up (i.e. at least 50 subjects total), a blinded interim analysis will be performed, 
and conditional power for detecting a significant treatment effect by the planned end of 
the study (100 subjects) will be determined.  If this conditional power is between 50 and 
80%, the sample size will be recalculated to achieve 80% conditional power following 
the algorithm of Chen and DeMets (2004).  Otherwise, the study will continue until 50 
subjects in each arm have completed treatment. 
 
For data analysis, we will be performing both per-protocol and multiple imputation 
approach analyses. Multiple imputation using the linear regression approach will be used 
to impute missing data, for subjects who do not complete treatment. Intention-to-treat 
analysis is not possible, since our outcomes are determined by the 8 week post-treatment 
survey, and there are no intermediate data points with regards to treatment efficacy 
outcomes (ie, subjects who drop out will not have any outcomes recorded).  
 
The primary outcome measure will be the pre- and post- treatment difference in scores on 
the Reflux Symptom Index (RSI), with two additional questions added to assess for 
symptoms that may be more specific to chronic laryngeal neuropathy. 
 
The RSI is a validated questionnaire consisting of 9 statements to be ranked 0-5. We have 
added two additional symptoms to be assessed to the RSI, "throat pain or burning" and 
"pain with swallowing", which we believe may also be relevant to chronic laryngeal 
neuropathy.    
 
The modified RSI score will be averaged for each group (amitriptyline vs. placebo), and 
since it is a nearly continuous variable (with an expected normal distribution) and we will 


H-34438 Version 4.4 30-APRIL 2017 
 
 
8 
be comparing the mean of the change rather than categorizing the treatment into 
responder and non-responders, we will also analyze it using an Analysis of Covariance or 
Wilcoxon Rank Sum test if determined to have a non-normal distribution. 
 
For the modified RSI, we will also conduct a secondary analysis looking at change in 
severity of each symptom individually. This will account for questions that may be less 
relevant to laryngitis overall (and more specific to reflux). 
 
Secondary outcome measures will be 1) subjective percent improvement from baseline to 
after 8 weeks of treatment, 2) subjective report of whether symptoms are better, worse, or 
same after treatment, and 3) the pre- and post- treatment mean difference in scores on the 
Voice Handicap Index-10 (VHI-10).  4) the pre- and post- treatment mean difference in 
scores on the Cough Severity Index. 
 
The VHI-10 is a 10-question scale that addresses effects on quality of life from voice 
disorders. By asking respondents to score symptoms on the VHQ-10 scale, we expect to 
gain additional data on the effects of amitriptyline on improvement in voice-related 
issues.  
 
The Cough Severity Index is a 10-item likert scale. which is a validated questionnaire 
used to quantify a patient’s symptoms associated with upper airway chronic cough, and 
will allow us to better understand the effect of the amitriptyline intervention for chronic 
cough.  
 
Subjects  
 
Inclusion Criteria: 
1. Age 18 or older and able to consent for themselves 
2. Structural pathology such as tumor previously ruled out using flexible 
laryngoscopy 
3. Able to speak and read the English language 
4. Failed a 2 month or longer trial of a proton pump inhibitor for the treatment of 
gastro-esophageal reflux 
5. Women under 55 years of age who may become pregnant must have a negative 
pregnancy test and agree to barrier or hormonal methods of contraception during 
the study 
 
Exclusion Criteria: 
1. Active, untreated environmental allergies.   
2. Smoking within past 5 years 
3. Current upper respiratory infections 
4. Use of narcotics (e.g. oxycodone, methadone) within the past week  
5. History of amitriptyline use or other tricyclic antidepressants, pregabalin, 
gabapentin, baclofen, or other GABA analogues or inhibitors, for any medical 
conditions (not limited to chronic laryngitis) with in the past 6 months 
6. Use of any other monoamine oxidase inhibitors (MAOIs) other than amitriptyline 


H-34438 Version 4.4 30-APRIL 2017 
 
 
9 
within the past 4 weeks (selegiline, phenelzine, tranylcypromine, isocarboxazid, 
rasagiline, phenelzine sulfate, selegiline hydrochloride, rasagiline mesylate, 
tranylcypromine sulfate)  
7. History of urinary retention 
8. History of an acute episode of a major depressive disorder within the past 12 
months 
9. For women 18-55 years of age without history of menopause: currently nursing or 
pregnant, plans to become pregnant, or unwillingness to utilize contraception 
(barrier or hormonal methods) 
10. Currently participating in another clinical trial. 
11. Active, untreated gastro-esophageal disease 
 
Study Procedures 
Patients who present to the Otolaryngology-Head & Neck Surgery clinic at Boston 
Medical Center with the symptoms of chronic laryngitis will first be evaluated according 
to the standard clinical procedure. Standard practice includes the following procedures: 
firstly, the patient’s laryngeal symptoms will be documented, as well as related symptoms 
and past medical history. Consistent with the current standard of care, all other possible 
etiologies (e.g. untreated laryngopharyngeal reflux, untreated allergies, cancer) will have 
been ruled out prior to consideration of treatment using neuromodulating medications for 
chronic laryngitis secondary to presumed neuropathy. For example, subjects will have 
had a minimum 2 month course of a proton-pump inhibitor to rule out gastroesophageal 
reflux prior to discussion of study enrollment and had structural lesions (e.g. cancer) 
ruled out by flexible laryngoscopy. After the physician explains to the subject the 
possibility that his/her laryngitis may be caused by a neuropathic disorder, the patient will 
then be asked if he/she wishes to consider treatment for this disorder. 
 
If the patient wishes to pursue treatment, he/she will be explained that there are four 
medications commonly used to treat this disorder: amitriptyline, nortriptyline, gabapentin 
and pregabalin. The patient will be presented with the option of receiving one of the 
standard medical treatments in accordance with standard of care here at BMC, most 
commonly amitriptyline.  
 
If the patient expresses interest in trying amitriptyline, the physician will first offer to 
write a prescription for amitriptyline. Based on eligibility for treatment with 
amitriptyline, the physician will also explain to the patient that he/she is potentially 
eligible to participate in a study testing the efficacy of this medication.  The physician 
will also clearly explain that the patient is under no obligation to join the trial, and that 
declining to participate will not in any way change the care provided. It will be explained 
that since the trial is a placebo-controlled double-blind trial, there is an equal chance that 
the subject will receive either amitriptyline or a placebo, and that neither the physician 
nor the subject will know which treatment the subject will be receiving until after 
completion of the study, which may be years from the initial enrollment date. The 
physician will further clarify that there is a 50% chance that as a subject, the patient 
would be delayed in getting treatment for two months. Since the patient will not know 
which treatment they have received until the study is completed, they will have the option 


H-34438 Version 4.4 30-APRIL 2017 
 
 
10
of starting amitriptyline, or other neuropathic agents such as pregabalin or gabapentin, at 
the discretion of the principal investigator, at the end of the 8 week study treatment 
period. In addition, the physician will clarify that even if the subject agrees to participate 
in the study, it is possible that he/she will not meet all of the inclusion/exclusion criteria 
and hence may not be eligible to enroll. In that case, the subject would be offered a 
prescription per standard of care.  
 
The subject will be informed that participating in the study will require additional 
paperwork and time, but will not add any costs for the subject or his insurer. Subjects will 
also be informed that they will be contacted every week by telephone by study personnel 
after receiving their study drug, in order to document dosage and side effects, and address 
any questions or concerns.  
 
The subject will then be asked to choose whether to enter the trial, receive one of the 
standard medications outside of the study, or not to receive any medication. Subjects who 
choose not to receive any medication may elect to participate in the study subsequently 
provided they are still eligible; those who receive a standard treatment outside the study 
are ineligible to join the study once they begin treatment.   
 
For women who could potentially be pregnant (55 or younger and have not gone through 
menopause as determined by a medical provider), the physician will also explain that the 
effects of amitriptyline on the fetus during pregnancy are unknown, and that the patient 
cannot take the medication if she is pregnant or is nursing, plans to become pregnant, or 
is unwilling to use reliable contraception such as barrier or hormonal methods, if sexually 
active. Subjects known to be pregnant are not eligible to participate (and those who 
become pregnant will have to discontinue the medication), and all patients under the age 
of 55 who have not undergone menopause, as verified by a medical provider, will be 
required to undergo pregnancy testing at the Boston Medical Center patient laboratory 
before being eligible to receive medication.  
 
If the patient chooses to join the trial, the physician will then discuss in detail all of the 
requirements of the trial, its potential benefits/risks, and its purpose. If the subject agrees 
to participate, he/she will be asked to sign and date the consent form. They will also be 
assigned a subject number. The consent will be signed during a regular clinic visit. 
Alternatively, patients may take the consent home and mail it back once they have 
decided to participate.  The principle investigator will sign the consent when the subject 
returns it. 
 
The subject will be informed that he/she will be started on either amitriptyline or placebo 
tablets taken at bedtime. The subject will then be randomized to amitriptyline or placebo 
in a 1:1 manner.  Randomization of subjects will be managed by Boston Medical Center 
Investigational Pharmacy Services (IPS).  
 
The starting dose will be 12.5mg nightly at bedtime. The dose may subsequently be 
increased by an additional 12.5mg tablet nightly every week if symptoms have not 
completely resolved, until either further increase is limited by side effects or a maximum 


H-34438 Version 4.4 30-APRIL 2017 
 
 
11
of 50mg nightly is reached. If the dose is increased and results in side effects such as 
intolerable dry mouth or fatigue, the patient will be counseled to decrease the dose to the 
most recent one that was well tolerated. Each patient will be given a “diary” that will 
specify both the recommended dose escalation schedule and space for the patient to 
record on a daily basis the dose that was actually taken. All patients will be asked to bring 
back all remaining capsules at the end of the 8 week treatment period, or return remaining 
capsules via a prepaid mailer, to further corroborate the dosing diary. At the conclusion 
of the 8 weeks of treatment, the patients may discontinue the medication without any 
additional tapering. However, if they choose to start a new prescription of amitriptyline 
before conclusion of the entire study period, they will be counseled that they will need to 
re-titrate gradually increase the dosage as needed, at the prescribing clinician’s discretion.  
 
At the first study visit, if they meet eligibility criteria, he/she will be asked to complete a 
pre-treatment questionnaire, which will include the Voice Handicap Index-10 (VHI-10), 
Cough Severity Index, and a modified Reflux Symptom Index (RSI) scales to assess the 
baseline severity of symptoms. The RSI will be modified to assess two additional 
symptoms which are commonly seen with chronic laryngitis, "throat pain or burning" and 
"pain with swallowing". After these forms have been collected, coded data will be added 
to a secure database, and the original forms will be kept in a secure locked location. All 
information in the database will be input under the subject's assigned study number. A 
separate secure database will be kept correlating the subject’s assigned study number to 
personal identifying information, such as contact information, which will be accessed 
only as needed to assess for trial safety and to contact subjects. Randomization data will 
be kept separately, accessible only to BMC Investigational Pharmacy Services (IPS) until 
study completion, except in case of emergency. 
 
If the subject meets all inclusion criteria they will be assigned a randomization number 
and receive the assigned study drug according to the Treatment Assignment Table 
prepared by BMC IPS.  The drug may be given to the subject in person or mailed to the 
subject’s address. 
 
The treatment assignment will not be available to the clinical staff that will administer the 
study questionnaires and analyze resulting data while subjects are receiving the study 
drug or placebo, except in case of severe adverse side effect or other emergency requiring 
urgent unblinding. If emergency unblinding is required as noted by the PI or study staff, 
they will contact the IPS on-call personnel who will have access to the randomization 
table.  
 
On Days 7, 14, 21, 28, 35, 42, 49, and 56 of the study the subject will be contacted by 
phone by a blinded study coordinator. The subject will be asked about side-effects and 
concerns, and confirm the dose they are taking that week. The study coordinator will 
relay any medical concerns to the primary investigator for consideration and follow-up, 
or to the nearest emergency department if the issue is too urgent to wait. The study staff 
will instruct the subject to remain at the same dose, increase the dose by 1 capsule or 
discontinue the study drug in accordance with the protocol.  The subject will also be 
encouraged to contact the study coordinator both before and after the scheduled phone 


H-34438 Version 4.4 30-APRIL 2017 
 
 
12
calls and initial visits if they experience any adverse events or have additional concerns. 
 
The subject will be instructed to discontinue taking all capsules after 8 weeks, regardless 
of the number of capsules remaining or any improvement experienced on the capsules. 
No tapering is required prior to stopping treatment. 
 
At the time of enrollment, at the initial study visit, the subject will also be scheduled for 
an in-office follow-up 8 weeks after starting the capsules (as is standard of care for the 
treatment of chronic laryngitis). At this visit the subject will be asked to fill out a post-
treatment questionnaire including a repeat modified RSI, CSI, VHI-10, and reported 
overall subjective percentage improvement from baseline. The latter will serve as a 
separate independent variable, given that neither the RSI, CSI, nor VHI-10 were 
specifically designed to evaluate chronic laryngeal neuropathy. Any questions the subject 
might have regarding the questionnaires are answered by the PI. 
 
The subject will be given the option to receive a prescription for amitriptyline post-study 
(if clinically appropriate).  For subjects who do not wish to take amitriptyline, the 
physician will discuss the other options for treatment according to the standard of care for 
chronic laryngitis, and other prescriptions may be provided if the subject wishes to 
continue pursuing treatment with the physician.  
 
Overall, study participation will be 10 weeks for each subject.  After completion of the 8 
week course of treatment, weekly phone calls will continue for 2 additional weeks to 
ensure no adverse effects are being experienced after cessation of treatment, although this 
is not expected. Any recurrence of symptoms after prior improvement on treatment will 
also be documented. Alternatively, if the patient desires to start amitriptyline treatment, 
the weekly phone calls will also serve to document any change in symptoms or side 
effects after starting new regimen. If an adverse event is noted, it will be followed up 
until its resolution. For most patients no further follow up will be needed after 10 weeks, 
since any possible side effects should be noted within the first 4 weeks of starting the 
initial study treatment, and if the patient is starting treatment after conclusion of the 
study, further follow up will be arranged accordingly outside of the study. If there is 
concern for amitriptyline exposure during pregnancy, the patient will be followed up until 
delivery. 
 
The initial office visit, including flexible fiberoptic laryngoscopy, will be billed to the 
subject's health insurance provider, not to the study, since it is an evaluation visit part of 
the standard of care for individuals being treated for presumed neuropathic laryngitis 
using medications such as amitriptyline.  
 
During the 8 week treatment period, previously unplanned office visits due to medication 
side effects or procedures done strictly for the purpose of the study will not be billed to 
the insurer, while other tests/procedures related/unrelated to the treatment for chronic 
laryngitis will be billed to the insurance. If a pregnancy test is ordered to determine 
eligibility for the study, this will not be billed to the patient’s insurance.  
 


H-34438 Version 4.4 30-APRIL 2017 
 
 
13
The final study visit, after 8 weeks of treatment, will be conducted at no charge to the 
insurer, and will consist of the post-study paperwork and the discussion of post-study 
therapy. All visits after the final study visit at 8 weeks after initiating treatment or 
placebo will be billed to the insurance, unless the visit is to follow up a study related 
adverse event. 
 
All post-study contact regarding clinical treatment outside of the 10-week study period 
will be conducted according to standard of care by the clinical office staff and the 
physician. Given the low dose of amitriptyline prescribed in this study, compared to the 
usual on-label doses used, no significant adverse effects are anticipated with treatment 
discontinuation, other than return of symptoms. The usual clinical scheduling staff will 
handle all scheduling. If the subject needs to come in for study purposes only, the subject 
will be contacted by phone/email/mail, depending on his/her preference, and asked to 
come in or provide the information over the phone if possible. They will not be 
compensated for this additional visit. There will be no financial compensation for 
subjects. 
 
Personal identifying information collected for the study will not be disclosed to any non-
study personnel. Any study personnel found to be using such data in an inappropriate 
manner will be removed from the study. Subjects' names, medical record numbers, and 
assigned study subject numbers will be stored on a master Excel spreadsheet and kept on 
a secured server with access limited to study coordinators and the principal investigator. 
This will be kept separate from each subject’s randomization number and assigned 
treatment arm, which will be managed by IPS. Only the PI and previously approved 
clinical investigators will have access to outcomes data. No patient names or medical 
record numbers will be released or published. The data will be kept for 5 years after the 
publishing of the results or 10 years after beginning of data collection, whichever comes 
sooner and then deleted from a secured hospital server. All information will be recorded 
using subject number, and only the master file will link the study subject number to the 
subject identifiers. 
 
Safety monitoring/reporting  
The study is IND exempt based on prior communications with the Boston Medical Center 
Institutional Review Board.  
 
The PI of the study will have overall responsibility for the monitoring plan.  Blinded 
study coordinators will contact each subject by phone once per week during the study 
period to monitor for adverse events. Adverse events will be documented and reported to 
the PI on a weekly basis and classified as per “adverse event definitions” outlined in the 
supplement section below. Any event that is severe and/or serious will be reported to the 
PI immediately.  If the event is determined to meet the criteria for Unanticipated Problem 
(UP) it will be reported to the IRB within 2 business days. 
 
The study will be stopped if any patient is permanently disabled, seriously injured, or dies 
in a manner that could be consistent with the drug usage. The study will be continued if 
said patient(s) were taking the placebo or the event is demonstrably unrelated to the 


H-34438 Version 4.4 30-APRIL 2017 
 
 
14
subject's participation in the trial. 
 
An independent monitor within the otolaryngology department who is not associated with 
study recruitment or data analysis will also review adverse events (see appendix for 
definitions) for all subjects after every 10th subject has completed 8 weeks of treatment. 
Dr. Michael Platt has agreed to act as this independent monitor. He is not directly 
supervised by the PI, Dr. J. Pieter Noordzij. His salary is not determined or affected by 
Dr. Noordzij. The independent monitor will submit a report to the PI, who will then 
review these events and submit a report to the IRB. Also, if there is a concerning event or 
group of events, the PI will bring these to the attention of the independent monitor as they 
occur, within 2 business days, regardless of whether they are thought to be related to 
treatment or not.   
 
Additionally, reporting to the IRB will be expedited (within 2 business days) for any 
event that is unexpected, possibly related to treatment and causes risk to subjects or 
others, or is serious.   
 
We will assess and document all adverse events and will report any adverse event that 
meets the definition of unanticipated problem, as defined in the Boston Medical Center 
Data Safety and Monitoring Plan (DSMP). 
  
A report will be submitted to the IRB and the PI by the independent monitor at the above 
intervals.  
 
 
Upon enrollment, subjects will be provided with an emergency contact card with a short 
description of the study drug used and contact information for Investigational Pharmacy 
services, in case of emergency. 
 
Funding 
The study is investigator-initiated and funded by the American Laryngological 
Association (ALA) ALA - ALVRE RESEARCH GRANT. 
 
There are no other sponsors or industry affiliations. 
 
Patients will receive medication or placebo during the 8-week course and participate in a 
follow up visit free of charge. Any additional visits during the 8 weeks of treatment due 
to side effects will also be free of charge. There will be no other compensation provided. 
 
Supplements 
 
Sample screening logs 
Enrollment data will be kept in the format below.  
 
Noordzij H-34438 
Chronic Laryngitis - Amitriptyline Study  
Screening Log 
Study ID # 
Subject 
Date 
Eligible for 


H-34438 Version 4.4 30-APRIL 2017 
 
 
15
Initials 
Consented 
study? (if 
excluded, list 
reasons why) 
S-040 
 
 
 
S-041 
 
 
 
S-042 
 
 
 
S-043 
 
 
 
S-044 
 
 
 
S-045 
 
 
 
S-046 
 
 
 
S-047 
 
 
 
 
 
 
 
 
 
Adverse Event Definitions 
The following definitions have been adapted from:  
• FDA Guidance for Industry and Investigators Safety Reporting Requirements for 
INDs and BA/BE Studies  
(http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf) 
• FDA Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance 
(http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf, Sections 1.2, 
1.50, 1.60) 
 
A. Adverse Event  
Adverse event means any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. An adverse event (also referred to as 
an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, 
and does not imply any judgment about causality. An adverse event can arise with any 
use of the drug (e.g., off-label use, use in combination with another drug) and with any 
route of administration, formulation, or dose, including an overdose. 
 
B. Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of this study, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between 
the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by 
a drug. 


H-34438 Version 4.4 30-APRIL 2017 
 
 
16
The following examples are types of evidence that would suggest a causal relationship 
between the drug and the adverse event: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture) 
• An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or 
other events that commonly occur in the study population independent of drug 
therapy) that indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
C. Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event. 
 
D. Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. This means that events not listed for the particular 
drug under investigation in the study application are considered “unexpected” and those 
listed are considered “expected.”  
 
E. Serious  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: Death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 
F. Life-Threatening  
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
 


H-34438 Version 4.4 30-APRIL 2017 
 
 
17
Drug Profile and Side Effects 
 
Trade Drug Name: 
Not applicable 
Generic Drug Name: 
Amitriptyline  
Investigational Drug Name: 
  
Identify the name of the 
manufacturer or source of 
investigational drug/biologic: 
  
Is the drug supplied at no cost? 
Yes   
Is the Drug FDA Approved: 
Yes   
Is this a new drug or a new use 
of an already approved drug 
Yes   
Is an IND necessary 
No   
IND Number 
  
Who holds the IND: 
N/A   
IND details: 
  
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption: 
The drug being used will be amitriptyline capsules compounded 
by the Investigational Drug Service at BMC. We believe our use 
meets the requirements for an IND exemption as per 21 CFR 
312.2.  
 
As previously mentioned in part D, we believe that the risks of 
amitriptyline are well-characterized, and not out of proportion to 
the benefits for patients. Furthermore, this is one of the standard 
medications used at BMC by otolaryngologists to treat chronic 
laryngitis felt to be possibly resulting from neuropathy, and has 
been used successfully for hundreds of patients for this purpose. 
In a recent analysis of over 50 patients given amitriptyline for 
this purpose at BMC, over half had significant improvement, and 
less than 10% had to discontinue use because of side-effects.  
 
In addition, this study is not intended to change the indication or 
marketing for amitriptyline in any way. Nor will the study involve 
any marketing or commercial activity.  
 
Lastly, the study will follow the guidelines set forth in part 50 
and 56, as outlined in the applicable sections of this proposal.  
  
Are you currently using this IND 
in another research project? 
No   
If yes, list the IRB Number(s): 
  
Dose Range: 
 0-50 mg 
Frequency: 
qhs   
Route of administration: 
PO   
Will the investigational pharmacy 
be dispensing? 
Yes   
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
  


H-34438 Version 4.4 30-APRIL 2017 
 
 
18
stability and sterility of the 
investigational drug/biologic: 
Identify who will be preparing 
the investigational drug/biologic 
for administration and describe 
in detail how it will be prepared: 
Amitriptyline 12.5mg and matching placebo capsules will be 
compounded by IPS at BMC using Avicel as the placebo and inert 
filler. 
Indication(s) under 
Investigation: 
Chronic laryngitis   
Where will the drug be stored 
IPS at BMC.   
Drug Storage Restrictions 
(including temperature, etc.): 
 Controlled Room Temperature (15⁰-30⁰C) 
Administration Instructions: 
The medication will be given in 12.5mg capsules. Patients will 
take one capsule before bed for one week. The patient may 
increase dosage by one 12.5mg tablet each week if no 
improvement and no adverse side effects are noted, up to four 
12.5mg capsules every night at bedtime for a maximum dose of 
50mg daily. If any adverse side effects are noted, the patient 
may decrease the dosage to the last well-tolerated dose. Patients 
are counseled not to completely discontinue treatment without 
consulting the PI first.   
Possible Untoward Effects, Their 
Symptoms & Treatment: 
The most common side effects of amitriptyline are: 
1) Feeling lightheaded, sleepy, having blurred vision, or a 
change in thinking clearly.  
2) Feeling dizzy 
3) Constipation 
4) Dry mouth 
5) Change in color of urine to blue or green. 
 
All potential side effects include: 
Cardiovascular: Orthostatic hypotension, tachycardia, ECG 
changes (nonspecific), AV conduction changes, cardiomyopathy 
(rare), MI, stroke, heart block, arrhythmia, syncope, 
hypertension, palpitation 
 
Central nervous system: Restlessness, dizziness, insomnia, 
sedation, fatigue, anxiety, cognitive function impaired, seizure, 
extrapyramidal symptoms, coma, hallucinations, confusion, 
disorientation, coordination impaired, ataxia, headache, 
nightmares, hyperpyrexia 
 
Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia 
 
Endocrine & metabolic: Syndrome of inappropriate ADH secretion 
 
Gastrointestinal: Weight gain, xerostomia, constipation, paralytic 
ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, 
diarrhea, black tongue 
 
Genitourinary: Urinary retention Hematologic: Bone marrow 
depression, purpura, eosinophilia 
 
Neuromuscular & skeletal: Numbness, paresthesia, peripheral 
neuropathy, tremor, weakness 
 
Ocular: Blurred vision, mydriasis, ocular pressure increased 
 
Otic: Tinnitus   


H-34438 Version 4.4 30-APRIL 2017 
 
 
19
Potential or Actual Antidotes for 
Excessive or Adverse Drug 
Effect: 
Sodium bicarbonate can be used in cases of overdose with 
cardiac effects.   
Contraindications and 
Interactions, If Known: 
Contraindications: Hypersensitivity to amitriptyline or any 
component of the formulation (cross-sensitivity with other 
tricyclics may occur); use of MAO inhibitors within past 14 days; 
acute recovery phase following myocardial infarction; concurrent 
use of cisapride 
 
Interactions:  
Acetylcholinesterase Inhibitors (Central): Anticholinergics may 
diminish the therapeutic effect of Acetylcholinesterase Inhibitors 
(Central). Acetylcholinesterase Inhibitors (Central) may diminish 
the therapeutic effect of Anticholinergics. If the anticholinergic 
action is a side effect of the agent, the result may be beneficial. 
Risk 
 C: Monitor therapy 
 
Alcohol (Ethyl): CNS Depressants may enhance the CNS 
depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy 
 
Alfuzosin: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk C: Monitor therapy 
 
Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants 
may enhance the vasopressor effect of Alpha-/Beta-Agonists 
(Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy 
modification 
 
Alpha1-Agonists: Tricyclic Antidepressants may enhance the 
vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy 
modification 
 
Alpha2-Agonists: Tricyclic Antidepressants may diminish the 
antihypertensive effect of Alpha2-Agonists. Exceptions: 
Apraclonidine; Brimonidine. Risk D: Consider therapy 
modification 
 
Altretamine: May enhance the orthostatic hypotensive effect of 
Tricyclic Antidepressants. Risk C: Monitor therapy 
 
Amphetamines: Tricyclic Antidepressants may enhance the 
stimulatory effect of Amphetamines. Tricyclic Antidepressants 
may also potentiate the cardiovascular effects of Amphetamines. 
Risk C: Monitor therapy 
 
Anticholinergics: May enhance the adverse/toxic effect of other 
Anticholinergics. Exceptions: Levocabastine (Nasal); 
Levocabastine (Ophthalmic); Paliperidone. Risk C: Monitor 
therapy 
 
Artemether: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk X: Avoid combination 
 
Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance 
the antiplatelet effect of Aspirin. Risk C: Monitor therapy 
 
Barbiturates: May increase the metabolism of Tricyclic 
Antidepressants. Risk D: Consider therapy modification 
 
Beta2-Agonists: Tricyclic Antidepressants may enhance the 


H-34438 Version 4.4 30-APRIL 2017 
 
 
20
adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy 
BuPROPion: May decrease the metabolism of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
CarBAMazepine: May increase the metabolism of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Chloroquine: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk C: Monitor therapy 
 
Cimetidine: May decrease the metabolism of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Cinacalcet: May increase the serum concentration of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk C: Monitor therapy 
 
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect 
of QTc-Prolonging Agents. Risk C: Monitor therapy 
 
Cisapride: Amitriptyline may enhance the arrhythmogenic effect 
of Cisapride. Risk X: Avoid combination 
 
CNS Depressants: May enhance the adverse/toxic effect of other 
CNS Depressants. Exceptions: Epinastine; Levocabastine 
(Nasal); Levocabastine (Ophthalmic); Olopatadine; Olopatadine 
(Ophthalmic). Risk C: Monitor therapy 
 
Conivaptan: May increase the serum concentration of CYP3A4 
Substrates. Management: Upon completion/discontinuation of 
conivaptan, allow at least 7 days before initiating therapy with 
drugs that are CYP3A4 substrates. Risk D: Consider therapy 
modification 
 
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of 
CYP2D6 Substrates. Risk C: Monitor therapy 
 
CYP2D6 Inhibitors (Strong): May decrease the metabolism of 
CYP2D6 Substrates. Risk D: Consider therapy modification 
 
Desmopressin: Tricyclic Antidepressants may enhance the 
adverse/toxic effect of Desmopressin. Risk C: Monitor therapy 
 
Dexmethylphenidate: May enhance the adverse/toxic effect of 
Tricyclic Antidepressants. Dexmethylphenidate may increase the 
serum concentration of Tricyclic Antidepressants. Risk C: Monitor 
therapy 
 
Divalproex: May increase the serum concentration of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Dronedarone: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of Dronedarone. Risk X: Avoid combination 
 
DULoxetine: May decrease the metabolism of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Gadobutrol: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk D: Consider therapy modification 
 


H-34438 Version 4.4 30-APRIL 2017 
 
 
21
Iobenguane I 123: Tricyclic Antidepressants may diminish the 
therapeutic effect of Iobenguane I 123. Risk X: Avoid 
combination Lithium: May enhance the neurotoxic effect of 
Tricyclic Antidepressants. Risk C: Monitor therapy 
 
Lumefantrine: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk X: Avoid combination 
 
MAO Inhibitors: May enhance the serotonergic effect of Tricyclic 
Antidepressants. This may cause serotonin syndrome. Risk X: 
Avoid combination 
 
MAO Inhibitors: May enhance the orthostatic hypotensive effect 
of Orthostatic Hypotension Producing Agents. Risk C: Monitor 
therapy 
 
Methylphenidate: May enhance the adverse/toxic effect of 
Tricyclic Antidepressants. Methylphenidate may increase the 
serum concentration of Tricyclic Antidepressants. Risk C: Monitor 
therapy 
 
Metoclopramide: May enhance the adverse/toxic effect of 
Tricyclic Antidepressants. Management: Seek alternatives to this 
combination when possible. Monitor patients receiving 
metoclopramide with tricyclic antidepressants for signs of 
extrapyramidal symptoms, neuroleptic malignant syndrome, and 
serotonin syndrome. Risk D: Consider therapy modification 
 
Nilotinib: May enhance the QTc-prolonging effect of QTc-
Prolonging Agents. Risk X: Avoid combination 
 
NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary 
Amine) may enhance the antiplatelet effect of NSAID (COX-2 
Inhibitor). Risk C: Monitor therapy 
 
NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary 
Amine) may enhance the antiplatelet effect of NSAID 
(Nonselective). Risk C: Monitor therapy 
 
Peginterferon Alfa-2b: May decrease the serum concentration of 
CYP2D6 Substrates. Risk C: Monitor therapy 
 
Pimozide: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of Pimozide. Risk X: Avoid combination 
 
Pramlintide: May enhance the anticholinergic effect of 
Anticholinergics. These effects are specific to the GI tract. Risk 
D: Consider therapy modification 
 
Propoxyphene: May enhance the CNS depressant effect of 
Tricyclic Antidepressants. Risk C: Monitor therapy 
 
Protease Inhibitors: May increase the serum concentration of 
Tricyclic Antidepressants. Risk C: Monitor therapy 
 
QTc-Prolonging Agents: May enhance the adverse/toxic effect of 
other QTc-Prolonging Agents. Their effects can be additive, 
causing life-threatening ventricular arrhythmias. Risk D: 
Consider therapy modification 
 
QuiNIDine: Tricyclic Antidepressants may enhance the QTc-
prolonging effect of QuiNIDine. QuiNIDine may increase the 


H-34438 Version 4.4 30-APRIL 2017 
 
 
22
serum concentration of Tricyclic Antidepressants. Risk D: 
Consider therapy modification 
 
QuiNINE: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of QuiNINE. QuiNINE may enhance the QTc- 
prolonging effect of QTc-Prolonging Agents. Risk X: Avoid 
combination 
 
Selective Serotonin Reuptake Inhibitors: May decrease the 
metabolism of Tricyclic Antidepressants. Risk D: Consider 
therapy modification 
 
Serotonin Modulators: May enhance the adverse/toxic effect of 
other Serotonin Modulators. The development of serotonin 
syndrome may occur. Risk D: Consider therapy modification 
 
Sibutramine: May enhance the serotonergic effect of Serotonin 
Modulators. This may cause serotonin syndrome. Risk X: Avoid 
combination 
 
St Johns Wort: May increase the metabolism of Tricyclic 
Antidepressants. The risk of serotonin syndrome may 
theoretically be increased. Risk D: Consider therapy modification 
 
Sulfonylureas: Cyclic Antidepressants may enhance the 
hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy 
 
Terbinafine: May decrease the metabolism of Tricyclic 
Antidepressants. Risk D: Consider therapy modification 
 
Terbinafine (Systemic): May decrease the metabolism of Tricyclic 
Antidepressants. Risk D: Consider therapy modification 
 
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of Tetrabenazine. Risk X: Avoid combination 
 
Thioridazine: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of Thioridazine. Risk X: Avoid combination 
 
TraMADol: Tricyclic Antidepressants may enhance the 
neuroexcitatory and/or seizure-potentiating effect of TraMADol. 
Risk C: Monitor therapy 
 
Valproic Acid: May increase the serum concentration of Tricyclic 
Antidepressants. Risk C: Monitor therapy 
 
Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants 
may enhance the anticoagulant effect of Vitamin K Antagonists. 
Risk C: Monitor therapy 
 
Yohimbine: Tricyclic Antidepressants may increase the serum 
concentration of Yohimbine. Risk C: Monitor therapy 
 
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-
prolonging effect of Ziprasidone. The risk of a severe arrhythmia 
may be increased. Risk X: Avoid combination   
Investigators Authorized to 
Prescribe: 
Dr. Noordzij