Clinical trial NCT02523690
Conditions: Muscle Weakness Sepsis
Sponsor: Johns Hopkins University
Start date: 2015-12-01; Completion date: 2017-12-01
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
ICU acquired muscle weakness is a significant problem in patients recovering from critical illness. This trial will evaluate the safety and efficacy of a drug in improving muscle weakness in critically ill patients.

Detailed description:

Arms: arm 1: Lorcaserin will be administered as a single dose on day 1 and day 3 to participants in this arm. arm 2: Placebo will be administered as a single dose on day 1 and day 3 to participants in this arm.
Interventions: intervention 1: Lorcaserin intervention 2: Placebo
Intervention descriptions: intervention 1: 10 mg, oral or enteral, single dose. 30 mg, oral or enteral, single dose two days later intervention 2: Oral or enteral, single dose. Oral or enteral, single dose two days later

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
NCT02523690 
 
IRB00072940 
 
Evaluating Muscle Weakness Improvement With Lorcaserin in ICU (EMILI) 
 
Protocol Version: February 10, 2017 (Date in header of protocol, 8/1/2016 was inadvertently not updated) 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
Application Number: IRB00072940 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material in 
each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the 
top of JHM IRB eForm A. 
 
*************************************************************************************************** 
1) Abstract 
(Provide no more than a one page research abstract briefly stating the problem, the research hypothesis, and 
the importance of the research.) 
It was recently discovery that patients recovering from sepsis/critical illness have great difficulty recruiting 
motor units to generate muscle force.  Prior to this discovery, the primary etiology of muscle weakness in these 
patients was thought to be muscle disease (myopathy) and degeneration of peripheral nerve (neuropathy).  
However, since motor units are composed of a group of muscle fibers contacted by a single motor neuron arising 
from the spinal cord, these new findings suggested a problem within the spinal cord as the primary cause of 
weakness in affected patients. Consistent with these clinical findings in critically ill patients, there is a profound 
deficit in the excitability of motor neurons in the spinal cord of septic rats.  Studies characterizing the impaired 
excitability in rat motor neurons point to a specific deficit in a slowly inactivating type of sodium current (i.e., 
the persistent sodium current).  This type of sodium current has been well characterized in motor neurons; it is 
known that activation of a subtype of serotonin receptors (5-HT2C) increases this current.  In an attempt to 
normalize motor neuron firing, in prior research septic rats were treated with lorcaserin (a drug approved by 
the FDA as Belviq® for weight loss via activation of 5-HT2C receptors) and found that motor neuron excitability 
was normalized such that muscle force production improved 4-fold.  The dramatic improvement in strength in 
rats raises the possibility that lorcaserin might benefit critically ill patients with muscle weakness after sepsis.  
In this proposal, we propose the first step in translating findings these findings to patients with intensive care 
unit (ICU)-acquired weakness.  Specifically, we will examine the efficacy and safety of lorcaserin in weak critically 
ill patients recovering from sepsis.  We will assess muscle strength after two escalating doses of lorcaserin in 
these patients.   
2) Objectives  
(Include all primary and secondary objectives) 
2-1) Evaluate the safety of lorcaserin in intensive care unit (ICU) patients recovering from sepsis. 
While lorcaserin is safe for prolonged use for weight loss, it has not been used in ICU patients. 
2-2) Compare the effect of lorcaserin vs. placebo on muscle strength in ICU patients recovering from 
sepsis.   


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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3) Background  
(Briefly describe pre-clinical and clinical data, current experience with procedures, drug or device, and any other 
relevant information to justify the research) 
3-a) Severe Muscle Weakness in Critical Illness is a Frequent, Serious and Costly Health Problem 
One of the most devastating complications of critical illness is the poorly-understood, rapid and persistent 
severe weakness of skeletal muscles.  In the United States, more than 750,000 people per year have sepsis with 
380,000 requiring an intensive care unit (ICU) stay and mechanical ventilation(1).  Studies suggest that from 1/3 
to 1/2 of patients who require prolonged mechanical ventilation develop global, persistent weakness(2;3).  From 
these data we estimate that in the U.S., 100,000 to 150,000 patients per year develop profound muscle 
weakness as a result of sepsis-associated critical illness. Development of weakness has an important economic 
impact, with a 4-fold increase in average hospital cost per patient(4).  In addition, weakness results in important 
long-term impairments in physical functioning, quality of life and delayed return to work(5-7).   
3-b) Incomplete understanding and ineffective treatment 
Both a myopathy (“critical illness myopathy” - due to muscle atrophy and loss of myosin), and a neuropathy 
(“critical illness polyneuropathy” - due to death of axons) contribute to weakness(8;9).  However, as reported 
in a recent study in a rat model(10), neither myopathy nor neuropathy fully account for weakness.  A lack of 
understanding of the mechanisms causing weakness after critical illness has meant that the main therapies 
available are non-specific interventions, applied in hopes of promoting long-term recovery of neuromuscular 
function. These therapies include tight glycemic control (11) and physical therapy during critical illness(12;13), 
but these therapies have sub-optimal effect in patients with severe weakness.   
3-c) Our newly published studies identify a novel potential mechanism for central nervous system 
(CNS) dysfunction in sepsis 
 A recent prospective study of muscle weakness in ICU patients(14)  discovered that a myopathy or neuropathy 
could not fully explain the virtual paralysis exhibited by some patients who were awake and attempting to 
produce maximal voluntary contraction.  An additional factor became apparent in EMG records of motor unit 
activity, that demonstrated  poor recruitment (both low numbers of motor units recruited and low firing rates) 
consistently in patients with sepsis-induced weakness(10).  Thus, the two primary mechanisms by which the 
central nervous system regulates muscle force, i.e. recruitment and rate modulation of motor unit firing, were 
both dramatically reduced.  These findings provide a potential novel mechanism to account for CNS dysfunction 
in septic humans. 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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Another recently published study demonstrated that, in a rat model of sepsis, there is reduced intrinsic 
excitability of spinal motor neurons supplying the medial gastrocnemius muscle(10).  Excitability of individual 
motor neurons in the spinal cord in vivo was measured in terminal studies of anesthetized adult rats that were 
either healthy or made septic through the standard cecal ligation and puncture methodology.  Statistical 
comparison of motor neurons sampled from septic and healthy rats revealed a striking and consistent difference 
in repetitive firing evoked by intracellular current injection.  Repetitive firing of individual motor neurons in 
septic rats was slower and more erratic such that septic motor 
neurons fired 1/3 as many action potentials during a 5 second 
current injection(10).  None of the previously reported 
reductions in muscle and nerve excitability described with 
critical illness are this dramatic and rapid in onset.  Shown in 
Figure 1 are in vivo recordings of the action potentials and single 
motor unit force generated during 5 second stimulation of a 
motor neuron from a control rat (green) and a septic rat (red).  
The septic motor neuron is unable to sustain firing and 
generates <20% of the force generated by the control motor 
neuron.  On the right side of Figure 1 is a plot of the mean values 
of motor unit force generated in response to a 5s current 
injection for 4 control vs. 4 septic rats (p =0.03 for difference in 
force integral).  This reduced motor neuron excitability persists 
for at least 1 week following cecal ligation and puncture.  Hence, 
these studies raise the possibility that reduced motor neuron 
excitability may be the most important cause of acute weakness 
during, and in the early phase of recovery from, sepsis.   
3-d) Successful treatment of sepsis-induced weakness in 
rats 
Based on a number of experiments, there is an identified defect 
in persistent inward sodium current causing the inability of 
motor neurons in septic rats to sustain firing.  Persistent sodium 
current has been studied for years in motor neurons, and it is 
Figure 2: Increasing sodium current with 
lorcaserin normalizes motor neuron excitability 
in a septic rat. 
 
Shown are three response to a 5s current 
injection in a single motor neuron from a septic 
rat before and at two times after injection of 3 
mg/kg lorcaserin.  Before lorcaserin, the motor 
neuron fires action potentials only infrequently 
during the 5s current injection.  15 minutes after 
lorcaserin, the motor neuron fires the whole 5s, 
but 
firing 
is 
still 
slow 
and 
somewhat 
inconsistent.  1 hour after injection of lorcaserin, 
the motor neuron fires normally for the whole 5 
s. 
Figure 1- Inability to sustain motor neuron firing causes acute weakness during sepsis in rats 
 
Shown are the motor neuron action potentials and force records from motor units in a control and septic rat during 
continuous current injection into the motor neuron in the spinal cord in vivo.  The control motor neuron fires throughout 
the 5s current injection to generate stable muscle force for 5s.  The motor neuron from the septic rat fires erratically, 
such that muscle force is low and irregular.  On the right, the mean values of motor unit force generated in response to 
a 5s current injection is plotted for 4 control vs. 4 septic rats (p =0.03 for difference in force integral). 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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known that activation of serotonin receptors (5-HT2C) in the spinal cord increases persistent inward sodium 
current to allow motor neurons to fire repetitively(15-18).  Based on this knowledge, rats that had been septic 
for 1 day were treated with 3 mg/kg of the selective 5-HT2C agonist lorcaserin.  lorcaserin (trade name Belviq) 
has an excellent safety profile and is FDA-approved for weight loss(19).  Using glass microelectrode 
impalements of single motor neurons for up to 2 hours, the firing pattern before and after intraperitoneal 
injection of lorcaserin in 4 different rats were recorded (one motor neuron studied per rat; Figure 2).  Prior to 
injection of lorcaserin, motor neurons were unable to sustain steady firing (top trace Fig 2).  Fifteen minutes 
after lorcaserin, motor neuron firing was improved, but still not normal (middle trace Fig 2).  One hour after 
injection of lorcaserin, motor neurons fired normally throughout the 5 second current injection (lower trace Fig 
2).  There was similar normalization of firing in all 4 motor neurons that recorded before and after lorcaserin 
injection. 
3-e) Drug dosing   
The lorcaserin dose that normalizes motor neuron firing in rats is 3 mg/kg delivered via intraperitoneal injection.  
The human dose for weight loss is 10 mg PO twice daily, but doses up to 60 mg were tolerated in clinical trials.  
Based on rat-to-human allometric scaling of both pharmacokinetic parameters and 5-HT2c receptor sensitivity 
(EC50), the 3 mg/kg dose in a rat that fully restored motor unit function is 0.26 mg/kg or 18 mg in a 70 kg 
adult.  Based on doses of lorcaserin that were given to patients prior to FDA approval and rat to human 
allometric scaling, it appears that treatment of patients with effective doses of lorcaserin is feasible.  
3-f) Study Design Rationale 
Below, we propose a sequential 2-level dose escalation study of the safety, pharmacokinetics (drug 
concentration over time) and pharmacodynamics (i.e., muscle strength response) of lorcaserin in critically ill 
patients with muscle weakness. We selected two different one-time doses of the study drug to provide dose-
response data over a range of doses deemed safe for the ICU setting. As described above, these doses are 
anticipated to bracket (i.e., fall above and below) the anticipated effective dose based on preclinical studies 
and established differences between species. Observations for drug effect on muscle weakness, adverse 
events, and drug concentration will be made at specified intervals after each dose (as outlined below). The 
time between doses, 48 hours, was selected to provide time for the anticipated drug concentrations and 
muscle strength effects to return to baseline before the second, higher dose 
4) Study Procedures 
4-a) Study design, including the sequence and timing of study procedures (distinguish research 
procedures from those that are part of routine care). 
Potentially eligible participants will be identified through screening of the Johns Hopkins Hospital’s medical and 
surgical ICU census (see section 5 for specific eligibility criteria) and IRB approved medical floors under a HIPAA 
waiver. We will be engaging the CCDA to develop and provide us a daily report of patients on our IRB approved 
floors who were screened by a treating provider for sepsis and the results of this sepsis screen. Daily reports 
would be sent to the SAFE virtual desktop. Members of research team who are on this protocol will then review 
the charts of these patients who had a positive sepsis screen to determine if they meet other inclusion criteria 
and do not meet exclusion criteria. Potential eligibility will be confirmed by the research team with the patient’s 
attending physician. A treating provider will obtain permission from the patient or surrogate to approach them 
for a discussion about possible participation in the study.  
 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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4-a-1) Informed Consent   
Informed consent will be sought for completion of the study eligibility screening and for participation in the 
study via oral and written consent respectively. Some patients may be incapable of providing informed consent.  
In such cases, informed consent will be obtained from their surrogate decision-maker.  Surrogate decision-
makers will be identified as the individual who is making decisions on behalf of the patient for clinical care in 
the ICU.  Consent will be obtained in two steps. First, oral consent will be obtained to perform a brief (< 5 minute) 
in–bed assessment of muscle strength using a standardized protocol to determine eligibility. Only those patients 
who are weak, defined either by (a) composite muscle strength sum-score, using Medical Research Council 
(MRC) scale, <48/60, or (b) a handgrip strength of <11 kg in men and <7 kg in women(2), will be offered written 
informed consent (since demonstrated muscle weakness is an entry criteria).  During the written informed 
consent process details on the intent of the proposed study, its design, the type of information collected, and 
potential risks and benefits of participation will be discussed.  If surrogates were consented because of the 
patient’s incapability, we will monitor the patient for return of capability and once they are capable, acquire 
consent from them for continuation in the study.   
4-a-2) Planned flow of participants through the study 
After consent is obtained, a chart review will be performed to ensure patient still meets eligibility and safety 
criteria (sections 5 and 4-f, respectively). 
4-a-3) Randomization 
After informed consent is obtained, eligible patients will be randomly assigned in a 2:1 ratio to the intervention 
(lorcaserin) or control group (placebo) respectively. (Please see Table 3 and section 4-a-6 for detailed study 
events.) Group assignment will be masked for patients, clinical and research staff administering the 
lorcaserin/placebo, and assessing outcomes (muscle strength, safety outcomes, or serum sample collection), as 
discussed under section 4-c. 
4-a-4) Measurement of Exposures and Potential Confounders: 
Patient exposures and potential confounders will be collected at study enrollment and are outlined in Table 1. 
Table 2 summarizes ICU-related exposures and possible confounders that will be collected during the study. 
Table 1:  Patient-related exposures and potential confounders – Baseline status 
Patient Risk Factors  
Method for data collection 
Measurement Scale 
Age/sex/race/ethnicity 
Weight/Height 
Chart review 
Chart review 
Continuous/Binary/Categorica
l 
Continuous 
Comorbidities: Charlson* & Functional 
Indices** 
Chart review 
Ordinal 
Severity of illness: APACHE II*** 
Leg/Hand dominance 
Past Psychiatric History*** 
Chart review 
Patient/Proxy interview 
Chart review 
Continuous 
Binary 
Categorical 
*Charlson Comorbidity index: a score derived from 19 categories of comorbidities, with an increased score reflecting an increased 
likelihood of one-year mortality(20). 
**Functional Comorbidity Index: An 18 item list of diagnoses which uses physical function as the outcome of interest, with increased 
score indicative of decreased function(21). 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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***Acute Physiology and Chronic Health Evaluation (APACHE II):  An index of disease severity that takes into account age, pre-existing 
medical conditions, and 12 acute physiologic variables that are assessed during the first 24 hours of ICU admission.  Scored on a scale 
from 0-71, with higher scores indicating more severe disease and increased mortality risk(22). 
Table 2:  Potential confounders – ICU status 
ICU exposure risk factors 
Method of Data Collection 
Measurement Scale 
Sequential Organ Failure Assessment (SOFA) 
Score**   
Chart review 
Continuous 
ICU admission diagnosis details 
Chart review 
Categorical 
** SOFA: A composite score that takes into account 6 organ systems used to assess the severity of organ dysfunction in ICU(23), 
collected on Days 1 and 3. 
4-a-5) Sequence and Timing of Study Events  
On Day 1, intervention and control group participants receive 10 mg of lorcaserin or placebo, respectively. Both 
groups also will undergo assessments before and after administration of lorcaserin/placebo (for assessment 
details and times, see table 3 and section 4-a-6) 
On Day 2, the intervention and control group participants will not receive any lorcaserin/placebo, but will 
undergo repeat assessments (for assessment details and times, see table 3 and section 4-a-6) 
On Day 3, the intervention and control group participants receive 30 mg of lorcaserin or placebo, respectively. 
Both groups also will undergo assessments before and after administration of lorcaserin/placebo (identical to 
Day 1). 
On Day 4, the intervention and control group participants will not receive any lorcaserin/placebo, but will 
undergo assessments (identical to Day 2).  
4-a-6) Measurements 
Participants will be monitored to ensure safety of lorcaserin/placebo administration. This monitoring will 
include a daily review of interim history (via chart review), medications, and laboratory values (details below), 
as well as assessment for changes in mental status and monitoring for serotonin syndrome (see table  3).  
We also will obtain a battery of outcome measures to test the efficacy in improving muscle strength and assess 
the safety of lorcaserin, as described in tables 3.   
All monitoring will be done by assessors blinded to group allocation.   
Table 3: Safety and Efficacy Measures (numbers indicate the number of times within each study day that 
each measurement is performed) 
Measurement 
Number of assessments 
 
Day 1* 
Day 2† 
Day 3**‡ 
Day 4† 
Safety Measures 
Chart Review 
1 
1 
1 
1 
Laboratory Tests (details below) 
1 
1 
1 
1 
EKG 
2 
1 
1 
1 
RASS sedation score 
2*** 
1 
2*** 
1 
CAM-ICU delirium screen 
2*** 
1 
2*** 
1 
Neuro Psychiatric Screen 
2 
1 
1 
1 
Hunter Serotonin Toxicity Criteria 
1 
1 
1 
1 


Date: 1 August 2016 
Principal Investigator:  Dale Needham, MD PhD 
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Efficacy Measures 
Handgrip Strength (Primary Outcome) 
2*** 
1 
2*** 
1 
Arm & leg strength (MMT using MRC Scale) 
2*** 
1 
2*** 
1 
Quadriceps Strength using handheld 
dynamometry 
2*** 
1 
2*** 
1 
Lorcaserin serum drug levels₴ 
1 
1 
1 
1 
Electromyography & Nerve Conduction Study  
once only to assess for any peripheral 
neuromyopathy**** 
MMT: Manual muscle strength testing; MRC: Medical Research Council; HHD: Hand-Held Dynamometry; EKG: Electrocardiogram; 
RASS: Richmond Agitation Sedation Scale; NPI-C: Neuropsychiatric Inventory - Clinician Rating Scale; CAM-ICU: Confusion 
Assessment Method for the ICU; Hunter Criteria: will be used to evaluate patients for serotonin syndrome (24) 
* 10 mg of lorcaserin or placebo administered  
** 30 mg of lorcaserin or placebo administered 
*** measures are performed as close to the time as drug or placebo administration as possible (within 4 hours) 
and as soon as possible (between 2 - 6 hours) after drug or placebo administration, on Days 1 and 3 only 
**** EMG & NCS will be performed at any time point after the patient is randomized into study, and will be 
used to help interpret the results of strength tests  
₴ Peak concentration serum samples will be collected 2 hours ± 15 minutes or 3 hours ± 15 minutes after drug 
administration (see section 4-a-6.11 for details) and trough concentration serum samples will be collected 24 
hour ± 30 minutes after drug administration (see section 4-a-6.11 for details) 
† Days 2 and 4 are consecutive to days 1 and 3 respectively. 
‡ Day 3 may or may not be consecutive to day 2 depending on assessor availability. 
 
Safety Measures 
4-a-6.1) Chart Review: A daily review of participants’ medical records for interim medical history and 
medications will be performed to monitor for any safety issues and ensure that participants continue to meet 
eligibility and safety criteria (see sections 5 and 4-f respectively). 
4-a-6.2) Laboratory Tests: As indicated in table 3 above, participants will undergo daily blood draws for the 
following standard laboratory tests: Heme 8 and CMP. In particular, laboratory tests will be obtained prior to 
every dose of lorcaserin or placebo to ensure that patients meet eligibility and safety criteria (see sections 5 and 
4-f respectively).  If the relevant tests have already been done for clinical purposes, they will NOT be repeated 
for research purposes.  As these labs are typically measured, at least daily, in the ICU setting, they may not need 
to be drawn for research purposes and the pre-existing values will be reviewed for research purposes.   
4-a-6.3) EKG: Daily EKGs will be obtained to determine if participants develop bradycardia, new-onset QT 
prolongation (as defined in Section 4.f.3.4 below) or new 2nd or 3rd degree AV block. In particular, this test will 
be obtained prior to every dose of lorcaserin or placebo to ensure that patients meet eligibility and safety criteria 
(see sections 5 and 4-f respectively).  If this test has already been done for clinical purposes, it will NOT be 
repeated for research purposes.  As this test is commonly done, at least daily, in the ICU setting, it may not need 
to be done for research purposes and the pre-existing test will be reviewed for research purposes.   


Date: 1 August 2016 
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4-a-6.4) Richmond Agitation Sedation Scale (RASS)(25): is a validated instrument to measure agitation and 
sedation status in ICU patients. Participants will be screened for their sedation status daily as well as pre- and 
post-drug or placebo administration as indicated in table 3 above.  
4-a-6.5) Confusion Assessment Method for the Intensive Care Unit (CAM-ICU): The CAM-ICU is a validated 
delirium screening test for ICU patients. Participants will be screened for their delirium status daily as well as 
pre- and post- drug or placebo administration as indicated in table 3above.  
4-a-6.6) Neuropsychiatric Screening adapted from NPI-C (Neuropsychiatric Inventory-Clinician Rating Scale): NPI-
C is a validated instrument used to screen for the presence and severity of symptoms in a number of psychiatric 
domains, in non-verbal patients, and includes clinician-rating methodology in addition to patient and caregiver 
inputs(26). Subscales of NPI-C will be adapted to perform daily screening for any hallucinations, delusions, 
euphoria and agitation in study participants.  
4-a-6.7) Hunter Serotonin Toxicity Criteria: Daily physical examinations for serotonin toxicity criteria will be 
performed using this pre-existing criteria(24) as indicated in table 3 above.   
Efficacy Measures 
4-a-6.8) Dynamometry of Handgrip Strength (Primary Outcome): Bilateral handgrip strength will be measured 
pre- and post-drug or placebo administration  at time points listed in table 3 above, using a Jamar Plus digital 
dynamometer in sitting position(27;28)  
4-a-6.9) Manual Muscle Strength Testing: Standardized manual muscle testing (MMT) of patients’ arm and leg 
strength using the Medical Research Council (MRC) scale will be measured pre- and post-drug or placebo 
administration in table 3 above, via physical examination. 
4-a-6.10) Dynamometry of Quadriceps Strength: Bilateral quadriceps muscles strength will be measured using a 
Micro FET Dynamometer in supine position(27;28) pre- and post-drug or placebo administration as indicated in 
table 3 above. If the patient cannot or will not perform the test for an individual muscle group, the reason for 
this will be recorded. 
4-a-6.11) Serum Drug Levels: Daily blood samples will be collected to determine lorcaserin serum levels by a LC-
MS/MS assay and pharmacokinetics. The serum drug samples will be collected and run in at least 2 batches, 
with the first batch run on specimens after randomization of at least the first 3 patients to lorcaserin (will be 
done without unblinding the research team regarding the study ID of these subjects). The peak plasma 
concentration after oral dosing is 1.5 to 2 hours. However, feeding can increase the peak plasma time by 1 hour. 
Thus, peak concentration samples will be collected at 2hours ± 15 minutes for NPO patients and at 3 hours ± 15 
minutes for fed patients. Lorcaserin has a plasma half-life of about 11 hours, and trough concentration samples 
will be collected at approximately two half-lives, or 24 hours ± 30 minutes. 
4-a-6.12) Electromyography (EMG) and Nerve Conduction Studies (NCS): 
 
Nerve conduction will be assessed via the following screening nerve conductions studies in participants after 
enrolment, to detect potential peripheral neuropathy. NCS results will help us interpret the results of strength 
tests. 
 Motor NCS of bilateral peroneal nerves 
 Motor NCS of unilateral ulnar nerve. If ulnar neuropathy at the elbow is diagnosed (slowing of ulnar 
conduction velocity across the elbow to below 35 m/s or a drop in ulnar motor amplitude of >50% with 
stimulation above the elbow), Motor NCS of the ulnar nerve of the other extremity will be performed 
as well. 


Date: 1 August 2016 
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 Sensory NCS of unilateral ulnar and sural nerves 
 
Motor unit recruitment rate will be assessed via the following EMG studies as well 
 EMG of unilateral vastus lateralis muscle 
 EMG of unilateral deltoid muscle 
If EMG and NCS studies have already been done for clinical purposes, they will NOT be repeated for research 
purposes, and the pre-existing results will be used for research purposes. 
4-b) Study duration and number of study visits required of research participants. 
Each participant regardless of group, will be in the study for two 2-day blocks. The detailed timeline of events 
are detailed in Table 3. 
4-c) Blinding, including justification for blinding or not blinding the trial, if applicable. 
All participants, clinical staff, and research staff (including those performing outcomes assessments and 
administering the drug/placebo) will be blinded to the randomization allocation. The investigational pharmacy 
(which will not be blinded) will prepare the lorcaserin/placebo for administration in similar forms and packaging 
to prevent unblinding.  
 
If any unexpected, adverse event occurs that may be directly related to the study protocol, unblinding of 
treatment allocation for that specific participant will occur, as needed, for the principal investigator and IRB (the 
outcomes assessor(s) would still remain blinded if the patient continued in the trial).  Time points and the 
number of ‘unblinding’ episodes will be recorded.  
4-d) Justification of why participants will not receive routine care or will have current therapy 
stopped. 
All participants, regardless of study group, will continue to receive routine medical care in the ICU.  For safety 
reasons, in consultation with a panel of experts (Drs. Dale Needham – Critical Care; Craig Hendrix – Clinical 
Pharmacology; Karin Neufeld – Psychiatry, Annette Rowden – MICU Pharmacist), the following procedures were 
developed and will be followed in the event a participant is scheduled to receive pharmacologic therapies that 
may potentially interact with the study drug (see Appendices A and B for list of drugs ) to minimize the risk of 
serotonin syndrome or other potential adverse drug effect from CYP2D6 effect on drug metabolism. 
 
1. First, a non-interacting substitute will be sought in consultation with the primary clinical team. 
 
2. In the event that no safe and effective substitute is available, and the interacting agent is classified in 
a. Appendix A, participants will be excluded or withdrawn from the study.  
b. Appendix B participants will not receive more than one other serotonergic agent during the trial, 
with consideration of the following strategies when/if feasible 
i. In consultation with the participant’s clinical team, a decision will be made regarding the 
safety of temporarily discontinuing a non-essential drug therapy before the start of the 
4-day protocol, and restarting the drug at least 2 days (i.e., 4 half-lives of lorcaserin) after 
the last administration of lorcaserin/placebo.  
ii. If the dosage of any interacting agent (e.g.,  analgesic) is routinely titrated for desired 
clinical effect, the clinical team will be informed and cautioned to ensure titration occurs 
with the consideration for potentiation or decrease in the interacting agent’s effect.   
iii. If neither substitution, temporary discontinuation or titration of a potential interacting 
agent is possible, the patient will be excluded / withdrawn from the study. 


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4-e) Justification for inclusion of a placebo or non-treatment group. 
In our proposed study, patients will be randomized to receive either lorcaserin or Placebo.  The FDA-approved 
drug under study in this trial, lorcaserin, does not have any published data supporting efficacy for muscle 
weakness in the ICU.  Hence, no therapy known to be effective is being withheld from the placebo group.  Given 
that our primary and secondary outcomes are based on semi-objective assessments of muscle strength or 
subjective assessments of cognitive/psychological symptoms, a control group (with blinded outcomes 
assessments) is required to reduce bias in patients’ outcome assessment.  Patients in the control group will 
continue with routine therapy as deemed appropriate by the clinical team. 
4-f) Definition of treatment failure or participant removal criteria. 
1. Participants will be removed from this study if the surrogate decision-maker, the patient (when capable 
of medical decision-making) or the patients’ medical team makes a request for removal from the study. 
 
2. As stated in Section 4-d, in the event a participant is scheduled to receive pharmacologic therapies that 
may potentially interact with the study drug (see appendix A), and substitution, gradual titration or 
discontinuation of interacting agent is not safe or feasible, within the decision rules outlined in Section 
4-d, the participant will be withdrawn from the study.  
 
3. The study drug or placebo will be discontinued for the following physiologic changes. Data collection will 
continue in these participants.  
1. An increase AST > 8 times the upper limit of normal (ULN)  
2. An increase in ALT > 8 times ULN,  
3. A decrease in creatinine clearance <30 mL/min,  
4. New-onset Q-T prolongation, defined as 
 QTc>500 msec 
 A >60 msec increase in QTc from baseline 
5. New-onset 2nd or 3rd degree heart block without a permanent pacemaker, 
6. Persistent heart rate <60 bpm   
7. New-onset priapism 
8. Serotonin Toxicity (as determined by Hunter Criteria, as previously described) 
9. New-onset psychosis 
10.  Onset of new symptoms of hallucinations or euphoria (as determined by NPI-C assessment as 
described above) 
4. If the patient is given a sedative medication during this brief period between baseline and follow-up 
testing, with a change in mental status that prohibits the ability to perform muscle strength testing, no 
further testing or administration of lorcaserin/placebo will be done in that patient and a new patient 
would be recruited and consented in place of this patient. 
4-g) Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
Those who end their participation in this study prematurely will not be given any further lorcaserin/placebo 
doses.  Similarly, lorcaserin/Placebo administration will cease upon the end of the study. Cessation of lorcaserin 
will not be harmful to the patient.  There are no known adverse effects associated with withdrawal of lorcaserin 
and there is no need for tapering.  Thus its absence or cessation will not directly cause any adverse outcomes. 
Patient care will continue without change after cessation of lorcaserin/placebo. 


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5) Inclusion/Exclusion Criteria 
5-a) Inclusion Criteria: 
1. Age ≥18 years old 
2. Sepsis [ ≥2 Systemic Inflammatory Response Syndrome (SIRS) Criteria  AND known or suspected infection] 
3. Muscle weakness [Medical Research Council sum score <48/60 or handgrip strength <11 kg in men and <7 
kg in women ] 
4. Obey Commands [Score for DeJonghe Awakening Score of ≥3/5] 
5-b) Exclusion Criteria (based on medical record review and discussion with patient/surrogate) 
1. Severe renal insufficiency [Creatinine Clearance <30 mL/min – or receiving dialysis]  
2. Acute infectious or auto-immune hepatitis, acute liver failure, or a history of cirrhosis without liver 
transplant 
3. History of psychosis 
4. Bradycardia, or 2nd or 3rd degree AV block without pacemaker 
5. History of valvular heart disease without valve replacement 
6. History of priapism 
7. Receiving drugs with serotonergic effects and/or CYP2D6 substrates which cannot be substituted stopped 
or titrated (as described in section 4d). 
8. Receiving Sulfonylurea medication at the time of the study 
9. Prior neuromuscular or central nervous system disease, including pre-existing neuropathy 
10. Inability to perform study’s muscle strength assessments based on patient’s baseline status prior to 
hospital admission 
11. Unable to receive, or unlikely to absorb, study drug (e.g. bowel obstruction, ischemia, or infarction; short 
gut syndrome) 
12. Body mass index >40 
13. Patient not expected to survive >4 days 
14. Pregnancy (based on urine or blood test results based on standard practice in the subject’s ICU) or 
lactation 
15. Allergy to lorcaserin or lorcaserin taken in the prior 7 days  
16. Enrolled in another interventional drug or physical rehabilitation trial 
17. Physician declines for patient to be enrolled 
18. Patient or proxy declines consent 
19. Unable to reach proxy for consent 
20. Non-English speaking 
6) Drugs/ Substances/ Devices 
6-a) The rationale for choosing the drug and dose or for choosing the device to be used. 
It is known that activation of serotonin receptors (5-HT2C) in the spinal cord increases persistent inward 
sodium current to allow motor neurons to fire repetitively, and lorcaserin, as a selective 5-HT2C agonist was 
used successfully in rat models (see Background, section 3-d)  
The lorcaserin dose that normalizes motor neuron firing in rats is 3 mg/kg. The human dose for weight loss is 
10 mg PO twice daily, but doses up to 60 mg were tolerated in clinical trials.  Based on rat-to-human allometric 
scaling of both pharmacokinetic parameters and 5-HT2c receptor sensitivity (EC50), the 3 mg/kg dose in a rat is 


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0.26 mg/kg or 18 mg in a 70 kg adult.  Based on doses of lorcaserin that were given to patients prior to FDA 
approval and rat to human allometric scaling, it appears that treatment of patients with effective doses of 
lorcaserin is feasible (See Background, section 3-e) 
 
6-b) Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are changed. 
See attached IND Exemption document 
6-c) Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
Not Applicable 
 


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7) Study Statistics 
7-a) Primary outcome variable.  
The primary analysis will compare the mean change in hand grip strength from baseline to post-drug testing 
across the 30 mg intervention dose vs. control group using a two-sample t-test.   
7-b) Secondary outcome variables. 
Secondary analyses will include the following:  
1) replication of the primary analysis for the 10 mg intervention dose vs. control group,  
2) replication of the primary analysis excluding any patients with neuropathy based on nerve conduction 
studies (29)within the intervention group, 
3) comparison of the change from baseline to post-drug testing across the 10 mg versus 30 mg conditions 
using a paired t-test 
4)  a PK-PD analysis for all concentration-strength measures for all observations (across the 4 days) using 
a traditional Emax model pooling all subjects and all time points.  
7-c) Statistical plan including sample size justification and interim data analysis. 
The sample size (N=10 for lorcaserin and N=5 for placebo) is a convenience sample to establish preliminary 
data for a potential larger future study.  With alpha = 0.05, power = 80%, and a mean (standard deviation) 
baseline value of 9 (9) kg for the primary outcome of grip strength, under a 30 mg dose of lorcaserin we could 
detect a difference of >9 kg for the change in strength from baseline to post-drug testing (on the same day) for 
the invention group versus no change for the placebo group.  This difference represents a 100% increase in 
strength versus a 400% increase detected with an equivalent dose in the rat model.  This calculation assumes 
that the baseline and post-drug testing measures would be highly correlated (r = 0.8).  Under a worst case 
scenario (i.e., no correlation between baseline and post-drug testing), we could detect at least a 220% 
increase in strength which is adequate given the large increase expected based on rat models. 
7-d) Early stopping rules 
There are no early stopping rules for this pilot trial. 
8) Risks 
8-a). Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
1) Side effects of Drug / Placebo:  
Participants will be closely monitored for any side effects related to administration of the study drug or 
placebo.  
 
The placebo has no known side effects.  
 


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The study drug, lorcaserin, has been extensively studied, has an excellent safety profile and is FDA approved 
for chronic use for purposes of weight loss(19). The major potential side-effects are listed below. A full list of 
side effects is available in Appendix C, the FDA prescribing information.  
a) Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS) like Reactions: Although lorcaserin has 
not been associated with any known cases of either serotonin syndrome or NMS, the safety of co-
administration of lorcaserin with other serotonergic or anti-dopaminergic agents has not been established.  
b) Cardiac valvular and conduction abnormalities: Asymptomatic aortic or mitral regurgitations were seen in 
patients who were in a randomized control trial of lorcaserin vs placebo for a one-year period, likely due to 
long-term activation of serotonin receptors on cardiac interstitial cells. In a similar year-long trial of lorcaserin 
vs placebo, some patients experienced a decrease in their heart rate over time.  
c) Cognitive Impairment and Depression or suicidal thoughts:  in trials of at least 1 year duration, lorcaserin 
administration was associated with difficulty with concentration and attention, difficulty with memory and 
confusion, and some mood problems such as depression.  
d) Psychiatric Disorders (including euphoria and dissociation):  have been associated with short-term studies 
of lorcaserin at supratherapeutic dosages.  
e) Hypoglycemia was observed in some participants with Type 2 Diabetes on lorcaserin while concomitantly 
on a sulfonylurea.  
f) Priapism:  Although lorcaserin has not been associated with cases of priapism, serotonergic drugs like 
lorcaserin have been associated with priapism.  
2) Risk of stopping/adjusting other medications: There may be risks associated with the temporary stopping 
of other medications 
3) EMG and Nerve Conduction Studies: Participants may experience some discomfort. There might also be 
some bruising in the area where the wire is inserted. Most subjects will not experience any bleeding with the 
needle studies; even for patients receiving therapeutic anticoagulation, the reported risk of clinically silent 
hematoma formation is less than 2% (30). If bleeding occurs, no more than a few drops is expected. The risk of 
infection is extremely small. 
4) Blood sampling: Participants may experience discomfort, bruising or bleeding at the site of blood draws. All 
patients will have blood drawn for research purposes either through indwelling catheters or percutaneously 
by either a licensed clinical staff or trained research personnel. Risks of percutaneous blood draws are 
uncommon and include bleeding, discomfort and bruising.   
5) Chart Abstraction: There is a risk of loss of privacy, since we will be collected data on participants.  
6) Strength testing: Participants may feel some tiredness or discomfort in the arm and leg muscles  
7) Questions:  There is a small chance that a participant could become uncomfortable, bored or fatigued in 
answering our questions. 
8-b) Steps taken to minimize the risks. 
1) Side effects of drug/placebo 


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a) Serotonin Syndrome and NMS-like reactions:  
Although this syndrome is rare, the theoretical risk of serotonin syndrome and NMS-like reactions will be 
mitigated by  
i. 
Monitoring participants for liver and renal failure, which may affect drug levels  
ii. 
Reviewing medication lists to exclude patients on drugs that may cause serotonin syndrome when 
administered along with lorcaserin (see Appendix A and section 4-d above).  
iii. 
Allowing participants to be on no more than 1 serotonergic agent (plus lorcaserin/placebo) during 
the trial. 
iv. 
Closely monitoring patients, for toxicity using the NPI-C for mental status changes and Hunter 
Criteria for Serotonin toxicity.    
b) Cardiac valvular and conduction abnormalities:  
Patients with a history of valvular heart disease, bradycardia, and 2nd or 3rd degree AV block without 
pacemaker will be excluded. Participants are unlikely to develop new onset valvular defects given that they 
will only receive two doses in this trial. Participants will be closely monitored via EKG for bradycardia and new 
onset 2nd or 3rd degree AV block. 
c) Cognitive impairment, Psychiatric Disorders (including euphoria and dissociation) and Depression:  
Patients with pre-existing cognitive impairment and psychosis will be excluded. During the trial, patients will 
be closely monitored using the RASS, CAM-ICU and NPS (Neuropsychiatric screening) instruments. 
d) Hypoglycemia: Patients will be excluded if they are receiving a sulfonylurea medication at the time of the 
study 
e) Priapism: this is a theoretical risk will be mitigated by excluding patients with a prior history of priapism, 
and monitoring during the trial via any noted side effect. 
2) Risks of stopping/adjusting other medications: These risks will be assessed on a case-by-case basis, in 
consultation with the participants’ medical team.  
3) EMG and Nerve Conduction Studies:  This is an abbreviated version of a clinical test routinely done, 
including in the critical care setting. The discomfort to participants is very brief and will not persist beyond the 
end of this short screening test. The risks of bleeding and infection will be minimized even further by using 
single-use, small needles, cleaning the area of insertion, and avoiding needle insertion in areas of untreated 
infection. 
4) Blood sampling: Person(s) collecting blood samples will be trained to minimize avoidable discomfort, 
bruising and bleeding. Most blood will be drawn through indwelling catheters and most of the routine lab 
work required for this study will already be drawn as part of routine care with little, if any, additional lab work 
required for this study.  
5) Protection of Privacy:   
All patient data will be confidential and secure due to physical and electronic data security measures, including 
locked offices and locked filing cabinets for records and computers, and password protection for computers 
and electronic data storage.  All electronic data will be routinely backed up.  Only study staff that are directly 
involved in data entry, management, or processing, will know the linkage between the unique identifier and 
participant-identifying information.  We will keep all patient information confidential in accordance with 
Public Health Services Act (42 USC 299a-1(c)).  


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6) Muscle Strength Testing: We will minimize discomfort of strength testing by monitoring patients and 
assuring that pre-existing pain is treated before study procedures, by positioning carefully, and by allowing the 
option to cancel or postpone any assessment, either by subject request or clinical condition. 
7) Recruitment and Informed Consent 
An informed consent process, consistent with the IRB policies and procedures, will be used to enroll each 
patient for this proposed investigation.  It will be emphasized that participation is entirely voluntary and may 
be discontinued at any time without any impact on the care received during his/her hospital stay.  Consent will 
be documented in writing on an IRB-approved consent form and entered into the medical record, to ensure all 
ICU providers and nursing staff are aware of the patient’s participation. 
8-c) Plan for reporting unanticipated problems or study deviations. 
The primary investigator (Dr Needham) is a board-certificated critical care physician practicing in the intensive 
care unit at Johns Hopkins.  He will be involved in the daily conduct of the clinical trial and closely supervise 
the daily screening for patient eligibility, informed consent, and study procedures such outcomes assessments 
and safety monitoring during the trial.  Consequently, immediate knowledge of any unanticipated problem or 
study deviation that may arise will be available to the P.I. (Dr. Needham) on a timely basis for immediate 
action and reporting to the IRB as necessary.  If Dr. Needham is unavailable, the study will maintain a list of 
clinicians associated with the study and Dr. Needham’s research group who can provide medical guidance.   
Administration of lorcaserin/Placebo will be done by licensed clinical staff in coordination with the research 
pharmacy. 
Examples of events that are anticipated in this population of critically ill patients include:  transient hypoxemia 
and hypotension, agitation, delirium, skin breakdown, nosocomial infections, glucose dysregulation, deep 
venous thrombosis/pulmonary embolus, tube feeding intolerance, cardiovascular compromise, end organ 
compromise or failure (e.g. renal failure) and death.  These events and other similar events, which are often 
the focus of prevention efforts as part of routine ICU care, will not be considered reportable adverse events 
unless they are considered by Dr. Needham to be associated with the study protocol.  Serious adverse events 
are defined any untoward clinical events that are: 
o Fatal or immediately life threatening 
o Permanently disabling or severely incapacitating 
o Requires prolonged inpatient hospitalization 
o Important medical events that may not result in death, be life threatening, or require prolonged 
hospitalization may be considered serious adverse events when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
serious outcomes listed above. 
If clinically important, unanticipated adverse problems or clinically important study-related, serious adverse 
events occur, they will be recorded on a designated case report form.  All events that are serious and 
unanticipated, or study-related and adverse will be reported to Institutional Review Board within the required 
reporting timeline.   
8-c) Legal risks such as the risks that would be associated with breach of confidentiality. 
All patient data will be confidential and secure due to physical and electronic data security measures, including 
locked offices and locked filing cabinets for records and computers, and password protection for computers 


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and electronic data storage.  All participant-identifying information will be removed from the dataset before 
analysis.  Only study staff who are required to, will know the linkage between the unique identifier and 
participant-identifying information.  We will keep all patient information confidential in accordance with 
Public Health Services Act (42 USC 299a-1(c)).  There is low risk of a breach of confidentiality.   
8-d) Financial risks to the participants. 
There are no expected financial risks to the participants 
9) Benefits 
9-a) Description of the probable benefits for the participant and for society. 
There is no direct benefit to participants in this study.  
If this trial yields encouraging preliminary data, this would encourage further prospective assessments of 
lorcaserin using repeat dosing, to establish repeat dosing safety in the ICU and efficacy ( i.e., improvement in 
muscle strength) in critically ill patients with sepsis.  
Demonstration of lorcaserin efficacy could result in the first specific drug therapy treating muscle weakness in 
critically ill ICU patients.  Expediting the physical recovery of these patients early in their ICU course has the 
potential to improve rehabilitation after critical illness.  Possible patient benefits could include reduced 
hospital stays and improved functional outcome. Since lorcaserin is already FDA-approved and on the market 
with an excellent safety profile (29), success in identifying a biological effect of lorcaserin to improve motor 
unit function in ICU patients may make translation of these findings into ICU practice more feasible.  
10) Payment and Remuneration 
10-a) Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
Participants will not be paid for participating in this study.   
11) Costs 
11-a) Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who 
will pay for them. 
There will not be any additional costs to participants beyond routine financial obligations for their 
hospitalization.   
 
 


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12) Appendices 
12-A) Appendix A – List of drugs that if currently administered, will result in exclusion of the 
participant (details in Section 4-d of eFormA).(31-34). Basis of the exclusion (i.e., either serotonin 
interaction or CYP2D6 interaction) is indicated.  
GENERIC NAME 
COMMON 
NAME 
CLASS/GROUP 
USE 
Serotonin 
Interaction 
CYP2D6 
Interaction 
NOTES 
5-hydroxytryptophan 
Oxitriptan / 5-HTP 
OTC supplement of a  naturally 
occurring amino acid 
Sleep aid - anti depression 
Yes 
  
OTC. The interaction reports 
apply to the OTC supplement 
form. 
Amitriptyline  
(> 50 mg/day) 
  
TCA 
  
Yes 
Yes 
  
Amphetamine 
  
Stimulant 
ADHD - narcolepsy 
Yes 
  
  
Aripiprazole 
  
Atypical antipsychotic 
Psychosis 
  
Yes 
  
Atomoxetine 
Strattera 
Norepinephrine reuptake 
inhibitor 
ADHD 
  
Yes 
  
Brompheniramine 
  
Antihistamine 
Common cold and allergic 
rhinitis 
Yes 
  
OTC 
Bupropion 
Wellbutrin 
Aminoketone 
Antidepressant 
Yes 
Yes 
 
Carvedilol 
  
Beta blocker 
CHF-HTN 
  
Yes 
  
Clomipramine 
Anafranil, clofranil 
TCA 
  
Yes 
Yes 
  
Clorgiline 
  
Irreversible MAO-A inhibitor 
Scientific research 
Yes 
  
  
Cyclobenzaprine 
Amrix, Flexeril,  
Fexmid 
  
Muscle relaxer 
Yes 
  
  
Desipramine 
Desmethylimiprami
ne 
TCA 
  
Yes 
Yes 
  
Dextromethorphan 
  
Morphinan 
Cough suppressant 
Yes 
Yes 
Ingredient in many OTCs 
Doxepin 
Deptran, sinequan 
TCA 
  
Yes 
Yes 
  
Flecainide 
Tambocor 
Class Ic antiarrhythmic 
Tachyarrhythmia 
  
Yes 
  
Fluoxetine 
  
SSRI 
  
Yes 
Yes 
  
Furazolidone 
  
Antibacterial 
  
Yes 
  
  
Ginseng 
  
Plant 
Energy drinks - herbal teas 
Yes 
  
  
Hypericum 
perforatum  
St. John’s wort 
Plant 
Herbal treatment for 
depression 
Yes 
  
  
Imipramine 
  
TCA 
  
Yes 
Yes 
  
Isocarboxazid 
  
Irreversible MAO inhibitor 
Mood disorders 
Yes 
  
  
Linezolid 
Zyvox 
Antibiotic 
  
Yes 
  
  
Lofepramine 
  
TCA 
Antidepressant 
Yes 
  
  
L-tryptophan 
Dietary supplement 
One of the 22 standard AA 
essential AA in  human diet 
Dietary supplement 
Yes 
  
OTC. The interaction reports 
apply to the OTC supplement 
form. 
Methadone 
  
Opioid 
Analgesic - maintenance anti-
addictive 
Yes 
  
  
Metoclopramide 
  
Dopamine-receptor antagonists 
Treat nausea and vomiting 
Yes 
  
  
Mexiletine 
Mexitil 
Class Ib anti-arrhythmic 
  
  
Yes 
  
Moclobemide 
  
Reversible MAO-I 
  
Yes 
  
Not USA approved yet 
Nortriptyline 
  
TCA 
Depression - nocturnal 
enuresis - chronic pain 
Yes 
  
  


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Paroxetine 
  
SSRI 
  
Yes 
Yes 
  
Peganum harmala 
Esfand, Syrian rue, 
harmel 
Plant 
  
Yes 
  
  
Pentazocine 
  
Mixed agonist–antagonist 
narcotic 
Analgesic 
Yes 
  
  
Phenelzine 
  
MAO-I 
Antidepressant 
Yes 
  
  
Procarbazine 
  
Antineoplastic chemotherapy 
drug 
Hodgkin's lymphoma 
Yes 
  
  
Propoxyphene 
  
Opioid 
Analgesic 
Yes 
  
  
Ritonavir 
Norvir 
Protease inhibitor 
HIV/Aids 
Yes 
  
  
Selegiline 
  
Irreversible MAO-I 
Parkinson/depression/dement
ia 
Yes 
  
  
S-metoprolol 
  
Beta blocker 
  
  
Yes 
  
Tamoxifen 
  
Agonist-antagonist estrogen  
Cancer 
  
Yes 
  
Thioridazine 
  
Typical antipsychotic 
  
  
Yes 
 
Timolol 
  
Beta-adrenergic receptor 
antagonist 
Glaucoma - HTN - Migraine 
  
Yes 
  
Tramadol 
Ultram 
Opioid 
Pain 
Yes 
Yes 
  
Tranylcypromine 
Parnate 
Irreversible MAO-I 
Depression - anxiety 
Yes 
  
  
12-B) Appendix B – List of drugs that if currently administered, will require physician approval 
for participant to be included in the study (details in Section 4-d of eFormA).(31-34)  
GENERIC NAME 
COMMON 
NAME 
CLASS/GROUP 
USE 
Serotonin 
Interaction 
CYP2D6 
Interaction 
NOTES 
Codeine 
3-methylmorphine 
Opiate 
Analgesic 
  
Yes 
  
Duloxetine 
Cymbalta 
SNRI 
MDD - GAD 
Yes 
Yes 
  
Haloperidol 
Haldol 
Typical antipsychotic 
  
  
Yes 
  
Risperidone 
  
Atypical antipsychotic 
  
  
Yes 
  
Venlafaxine 
Effexor 
SNRI 
  
Yes 
Yes 
  
Amitriptyline (≤ 50 
mg/Day) 
  
TCA 
  
Yes 
Yes 
  
Bromocriptine 
Parlodel, Cycloset 
Ergoline Derivative - Dopamine 
agonist 
Pituitary tumors - Parkinson’s - 
Hyperprolactinemia - NMS  
Yes 
  
  
Buspirone 
Buspar 
Azapirone 
 anxiolytic 
Yes 
  
  
Carbamazepine 
  
  
Anticonvulsant 
Yes 
  
  
Chlorphenamine 
Chlorpheniramine,  
piriton  
Antihistamine 
Allergies 
Yes 
  
  
Citalopram 
Celexa, cipramil 
SSRI 
  
Yes 
  
  
Dextropropoxyphene 
  
Opioid 
Analgesic 
Yes 
  
  
Escitalopram 
Lexapro, cipralex 
SSRI 
  
Yes 
  
  
Fentanyl 
Fentanil 
Opioid 
Analgesic 
Yes 
  
Including the patch 
(Duragesic) 
Fluvoxamine 
  
SSRI 
  
Yes 
  
  
Granisetron 
Kytril 
Antiemetic 
After chemo 
Yes 
  
  
Lithium 
  
Element 
Bipolar disorder 
Yes 
  
  
Meperidine 
Pethidine 
Opioid 
Analgesic 
Yes 
  
  


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Milnacipran 
Ixel, savella,  
dalcipran, 
toledomin 
SNRI 
Fibromyalgia 
Yes 
  
  
Mirtazapine 
  
NaSSA 
Antidepressant 
Yes 
  
  
Nefazodone 
Dutonin, nefadar,  
serzone 
SNDRI 
Antidepressant 
Yes 
  
  
Sertraline 
  
SSRI 
  
Yes 
  
  
Tapentadol 
Nucynta 
Opioid  
Analgesic 
Yes 
  
  
Toloxatone 
Humoryl 
Antidepressant 
  
Yes 
  
  
Trazodone 
  
Serotonin antagonist and 
reuptake inhibitor 
Antidepressent 
Yes 
  
  
Triptans 
(controversial) 
Sumatriptan, 
rizatriptan, 
naratriptan, 
eletriptan, 
almotriptan, 
frovatriptan, 
avitriptan, 
zolmitriptan 
  
  
Yes 
  
  
Valproate 
Valproic acid 
Anticonvulsant 
Anticonvulsant/mood 
stabilizer 
Yes 
  
  
Ondansetron 
Zofran 
Serotonin 5-HTa receptor 
antagonist 
Antiemetic 
Yes 
Yes (minor) 
  
Oxycodone 
  
Opioid 
Analgesic 
  
Yes (minor) 
  
Propafenone 
  
Anti-arrhythmic medication 
  
  
Yes (minor) 
  
 
 
 


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Reference List 
 
 
(1)  Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis 
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