Clinical trial NCT02118012
Conditions: Chronic Hepatitis C
Keywords: Chlorcyclizine HCL Direct Acting Antivirals Ribavirin Chronic Hepatitis C
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Start date: 2014-03-20; Completion date: 2016-09-20
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Hepatitis C is a liver disease caused by the hepatitis C virus. It is the most common cause of serious liver disease in the United States. Many people have few if any symptoms. It can lead to cirrhosis, which can cause liver failure and cancer. Researchers want to study how a medicine called chlorcyclizine works in patients with hepatitis C. They want to see if it can be used to treat hepatitis C alone or when used with the standard hepatitis C treatment drug ribavirin.

Objectives:

\- To see if chlorcyclizine can be used to treat hepatitis C alone or in combination with the drug ribavirin.

Eligibility:

\- Adults with chronic hepatitis C who either have never been treated for it or have relapsed after prior treatment.

Design:

* Participants will be screened with medical history, physical exam, blood and urine tests, and a questionnaire. They will also have an ultrasound of their abdomen and electrocardiogram. Some of these tests will be repeated throughout the study.
* Participants will spend 3 days as an inpatient to be monitored while starting study drug. They will be assigned randomly to a group and will begin taking the study drug. Blood will be taken frequently.
* Group I will take the study drug twice a day for 28 days.
* Group II will take the study drug twice a day and ribavirin twice a day for 28 days.
* Participants will visit the clinic every 7 days for 28 days.
* After participants stop taking the study drug, they will have 5 follow-up visits over 3 months.

Detailed description:
Up to 50 patients with chronic hepatitis C, who are treatment na(SqrRoot) ve or relapsers to any interferon/ribavirin regimen will be enrolled into this pilot study evaluating chlorcyclizine HCl with or without ribavirin (RBV) as antiviral therapy. Adult patients (greater than or equal to18 years of age) with evidence of active chronic hepatitis C infection (all genotypes) with detectable HCV RNA in serum \>10,000 IU/mL without contraindications to chlorcyclizine HCl or ribavirin or evidence/history of hepatic decompensation will be enrolled. Patients will be monitored for at least two months with regular testing for ALT and HCV RNA quantitative levels before treatment and will undergo admission to start therapy, which includes a thorough medical evaluation and timed blood sampling. Patients will be randomized to one of two treatment groups; one with chlorcyclizine HCl (75 mg twice daily) and the other with RBV+ chlorcyclizine HCl (75 mg twice daily). For all genotypes, RBV will be dosed based on weight (1000 mg daily \<75 kg and 1200 mg daily greater than or equal to 75 kg). At each clinic visit, patients will be questioned about side effects and symptoms, undergo a focused physical examination, and have blood taken for complete blood counts, HCV RNA, PT/INR and routine liver tests (ALT, AST, alkaline phosphatase, direct and total bilirubin, and albumin). At the end of 28 days of treatment, patients will undergo a repeat thorough medical evaluation inclusive of a complete physical exam, symptom scale evaluation, complete blood counts, routine liver tests, and HCV serology panels. The primary endpoint of therapy will be a decline in quantitative HCV RNA viral levels after 28 days of treatment as compared to baseline viral titers and between groups. Several secondary endpoints will be measured, including side effects of therapy, ALT levels, quantification of chlorcyclizine HCl and its metabolites in serum, and quality of life. Therapy will be stopped for intolerance to RBV and/or chlorcyclizine HCl (which will be carefully defined).

Arms: arm 1: Chlorcyclizine HCl and Ribavirin arm 2: Chlorcyclizine HCl only
Interventions: intervention 1: Chlorcyclizine HCl intervention 2: Ribavirin
Intervention descriptions: intervention 1: Chlorcyclizine HCl (75 mg twice daily) intervention 2: RBV was dosed via a weight-based regimen of 1000 mg daily\<75 kg and 1200 mg daily ≥75 kg.

Protocol documents:
Prot_SAP_000.pdf: 
Version:  08/11/14 
 
 
CLINICAL RESEARCH PROTOCOL 
 
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES 
 
DATE: August 17, 2018 
 
CLINICAL PROTOCOL NO.: 14-DK-0084 
 
 
TITLE:  Evaluation of Safety, Tolerability, and Antiviral Activity of Chlorcyclizine HCl 
Alone or in Combination with Ribavirin in Patients with Chronic Hepatitis C 
SHORT TITLE: Chlorcyclizine HCl for Chronic Hepatitis C 
 
IDENTIFYING WORDS: Chlorcyclizine HCl, Ribavirin, Direct Acting Antivirals, 
Chronic Hepatitis C 
PRINCIPAL INVESTIGATOR: Christopher Koh, M.D., MHSc, Liver Diseases 
Branch (LDB), National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) 
RESPONSIBLE INVESTIGATOR: T. Jake Liang, M.D., Chief, LDB, NIDDK  
ASSOCIATE INVESTIGATORS:   
Theo Heller, M.D., Investigator, LDB, NIDDK 
Yaron Rotman, M.D. Investigator, LDB, NIDDK 
Marc Ghany, M.D. Investigator, LDB, NIDDK 
Elenita Rivera, R.N., Research Nurse, LDB, NIDDK 
 
ESTIMATED DURATION OF STUDY: 3 Years 
NUMBER AND TYPE OF PATIENTS: 50 patients with chronic hepatitis C, ages 
above 18 years, both male and female 
SUBJECTS OF STUDY:     
Number of patients: 50     
Sex:  Male & Female       
Age Range: Above 18 years 
Volunteers: None 
PROJECT USES IONIZING RADIATION:  Yes, for medical indications only. 
PROJECT USES "DURABLE POWER OF ATTORNEY":  No 


 
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2
OFF-SITE PROJECT: No       MULTI-INSTITUTIONAL PROJECT:  No 
 
 


 
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3
Précis 
Up to 50 patients with chronic hepatitis C, who are treatment naïve or relapsers to 
any interferon/ribavirin regimen will be enrolled into this pilot study evaluating 
chlorcyclizine HCl with or without ribavirin (RBV) as antiviral therapy. Adult patients 
(≥18 years of age) with evidence of active chronic hepatitis C infection (all genotypes) 
with detectable HCV RNA in serum  >10,000 IU/mL without contraindications to  
chlorcyclizine HCl or ribavirin or evidence/history of hepatic decompensation will be 
enrolled. Patients will be monitored for at least two months with regular testing for ALT 
and HCV RNA quantitative levels before treatment and will undergo admission to start 
therapy, which includes a thorough medical evaluation and timed blood sampling.  
Patients will be randomized to one of two treatment groups; one with chlorcyclizine HCl 
(75 mg twice daily) and the other with RBV+ chlorcyclizine HCl (75 mg twice daily). 
For all genotypes, RBV will be dosed based on weight (1000 mg daily <75 kg and 1200 
mg daily ≥75 kg). At each clinic visit, patients will be questioned about side effects and 
symptoms, undergo a focused physical examination, and have blood taken for complete 
blood counts, HCV RNA, PT/INR and routine liver tests (ALT, AST, alkaline 
phosphatase, direct and total bilirubin, and albumin). At the end of 28 days of treatment, 
patients will undergo a repeat thorough medical evaluation inclusive of a complete 
physical exam, symptom scale evaluation, complete blood counts, routine liver tests, and 
HCV serology panels. The primary endpoint of therapy will be a decline in quantitative 
HCV RNA viral levels after 28 days of treatment as compared to baseline viral titers and 
between groups. Several secondary endpoints will be measured, including side effects of 
therapy, ALT levels, quantification of chlorcyclizine HCl and its metabolites in serum, 


 
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4
and quality of life. Therapy will be stopped for intolerance to RBV and/or chlorcyclizine 
HCl (which will be carefully defined). 
 
 
 


 
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5
Background 
A.  Chronic Hepatitis C and Current Therapy 
Chronic infection with hepatitis C virus (HCV) is a global health problem. The 
World Health Organization (WHO) estimates that approximately 3% of the world’s 
population is infected with HCV which amounts to an estimated 170 million to 200 
million chronic HCV infections worldwide.1,2 The prevalence varies with geographic 
region, with the highest regions being Southeast Asia and Africa.3-5 The Centers for 
Disease Control estimates that approximately 3.2 million people are chronically infected 
with HCV in the United States.6 Chronic HCV infection is a major cause of chronic liver 
disease, cirrhosis and hepatocellular carcinoma. A recent analysis suggests that the 
number of cases of cirrhosis in people who were infected in the 1970s and 80s will not 
peak until 2020.7 Without therapy, a significant proportion of these people will develop 
complications of their disease. 
Prior to 2011, the recommended therapy for chronic hepatitis C (CHC) genotype 
1 infection included a 48-week course of combination therapy with peginterferon (1.5 
µg/kg [PegIntron] or 180 µg [Pegasys] once weekly) and ribavirin (1000 to 1200 mg 
daily based upon body weight).8 In 2011, two new agents, boceprevir and telaprevir, were 
approved for use in CHC genotype 1 infection.9  Both agents are direct acting antiviral 
(DAAs) agents which inhibit the HCV NS3/NS4A protease and must be used in 
combination with peginterferon and ribavirin. When used in combination with 
peginterferon and ribavirin (triple therapy), both agents significantly improve the 
sustained virological response (SVR) rate compared to standard peginterferon and 


 
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6
ribavirin therapy. With triple therapy in HCV genotype 1 patients, the SVR rates 
increased from 40-45% with standard combination therapy to 69-75% with triple 
combination therapy.10,11  
Currently, the two FDA approved protease inhibitors appear to have similar 
overall rates of response, but differ greatly in when and for how long they are 
administered. Telaprevir is administered during the first 12 weeks of peginterferon and 
ribavirin therapy. Thereafter, peginterferon and ribavirin is continued without the 
protease inhibitor for a total of either 24 or 48 weeks depending upon the virologic 
response during the triple combination (“response guided therapy”).9,11 In contrast, 
boceprevir is started 4 weeks into the course of peginterferon and ribavirin therapy.  It is 
then continued for either a total duration of therapy of 28 to 48 weeks based upon 
virologic response.9,10 Side effects can occur with either protease inhibitor and appear to 
worsen the known side effects of peginterferon and ribavirin. Skin rash, anemia and ano-
rectal discomfort have been dose-limiting side effects of telaprevir,11 whereas anemia and 
dysgeusia have been the major adverse events associated with boceprevir.10 Response 
rates vary greatly by virologic, host and disease characteristics, such as viral level (higher 
rates with lower baseline HCV RNA concentrations), race (lower in African Americans, 
higher in Asians), and disease severity (lower in patients with cirrhosis or advanced 
fibrosis).10,11  
For patients chronically infected with HCV genotype 2 and 3, the recommended 
therapy is a 24-week course of the combination of peginterferon and a reduced dose of 
ribavirin (800 mg daily).8 The optimal regimen for patients with genotypes 4, 5 and 6 is 
yet to be defined.8  


 
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7
Although treatment of CHC has greatly improved over the last two decades, more 
than half of patients with genotype 1 HCV infection treated with a course of 
peginterferon and ribavirin fail to achieve SVR to peginterferon and ribavirin.12-15 
Subjects who fail combination therapy are a heterogeneous group and include, persons 
who experienced virological breakthrough (detectable HCV RNA in serum during 
therapy after an initial response was achieved), virological relapse (reappearance of HCV 
RNA in serum after treatment was discontinued and an end of-treatment response was 
achieved), as well as individuals who failed to achieve an initial virological response- 
partial responders (≥ 2 log IU/mL decline in HCV RNA from baseline to treatment week 
12 but with detectable HCV RNA at week 24) and null responders (≤ 2 log IU/mL 
reduction in HCV RNA level from baseline to  treatment week 12). Boceprevir and 
telaprevir result in a two- to three-fold increase in SVR rates compared to peginterferon 
and ribavirin in previous HCV genotype 1 treatment failures.16,17 Consequently, 
boceprevir or telaprevir in combination with peginterferon and ribavirin now represents 
the new standard of care for re-treatment of HCV genotype 1 relapsers, prior partial 
responders and null responders.16,17 
Whether a subject should be re-treated now or wait for potentially better therapy 
in the future depends on many factors including the individual’s desire to be re-treated, 
the reasons underlying failure, such as inadequate drug dosing or side effect management, 
the severity of underlying liver disease, prior response to therapy and risk of disease 
progression over the next three to five years. Currently, more effective therapies with 
fewer side effects that do not include interferon are under investigation and likely 
represent the future of HCV therapy.  


 
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8
B.  Ribavirin therapy in HCV infection 
Ribavirin is a nucleoside analogue with broad activity against both RNA and 
DNA viruses in vitro. Ribavirin has been used in several viral diseases and is approved 
for use in respiratory syncytial virus disease. In hepatitis C, ribavirin was found to lower 
serum alanine aminotransferase (ALT) levels and to improve liver histology, but it had 
little effect on HCV RNA levels in blood or liver. Addition of ribavirin to interferon 
therapy greatly increased the response rate. Multiple studies using both standard and 
pegylated interferon have shown that ribavirin increases SVR rates by two to three-fold.14  
Ribavirin affects SVR rates in two ways: first, a higher proportion of patients become 
HCV RNA negative on therapy (usually ~10% more than with peginterferon 
monotherapy) and, second and more importantly, ribavirin appears to markedly decrease 
the relapse rate (from ~50% after standard interferon or peginterferon monotherapy to 10-
15% after combination therapy).14 The mechanisms of action of ribavirin in mediating 
these effects are not well-defined.  
For patients with genotype 1 HCV infection, the dose of ribavirin is based on 
body weight, being 1000 mg daily for individuals ≤75 kg and 1200 mg daily for those 
>75 kg. For patients with genotypes 2 and 3 HCV infection, a lower fixed dose of 800 mg 
daily is adequate to achieve high response rates and low relapse rates.18 Higher doses of 
ribavirin have been evaluated indirectly in several large-scale studies19 and directly in 
small pilot studies from Sweden and by the Liver Diseases Branch of the NIDDK.20 
Ribavirin is currently being tested as combination therapy with various DAAs either as 
interferon-containing or -free regimens.21-26 These studies indicated that ribavirin appears 
to be an important component of the combination therapy to achieve optimal response. 


 
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9
C.  The Future of HCV Therapy 
As the future of HCV therapy is headed towards interferon-free regimens, various 
clinical trials are ongoing with oral combination antiviral therapy. Many of these DAA 
studies still utilize ribavirin as a component of the oral combination therapy. A recent 
phase 2a study exploring two DAAs plus ribavirin for 12 weeks has shown promise in 
treatment naive HCV genotype 1 patients with extended rapid virological response rates 
ranging from 79-89% and sustained virological response rates 12 weeks after the end of 
therapy from 93-95%.27 Another study has evaluated an interferon-free oral combination 
DAA therapy utilizing the nucleotide polymerase inhibitor sofosbuvir plus ribavirin 
achieved a sustained virological response rate of 100% at 24 weeks after therapy.23 
However, in a phase 3 non-inferiority study evaluating HCV genotype 2 or 3 infection 
comparing sofosbuvir plus ribavirin or peginterferon plus ribavirin for 12 weeks, the 
response rates were nearly identical at 67%.26 Thus, while the notion of an interferon-free 
DAA oral combination regimen appears achievable, the search for the ideal pan-
genotypic oral combination regimen continues. 
D. Chlorcyclizine HCl (CCZ) 
 
Chlorcyclizine HCl is a first generation antihistamine of the phenylpiperazine 
class. Specifically, it functions as a competitive antagonist of histamine (H1 and H2) 
receptors. Chlorcyclizine HCl was originally granted marketing authorization by FDA 
under NDA 6-938 Di-Paralene Tablets marketed by Abbott Laboratories and NDA 6-947 
Perazil Tablets marketed by Burroughs Wellcome Co. Clinical experience with 
chlorcyclizine HCl dates back to its initial introduction in 1949 as Di-Paralene and 


 
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10
Perazil.  Di-Paralene was prescribed at an initial dose of 50 mg three times daily (150 mg 
per day) whereas Perazil was prescribed at a dose of 50 mg once or twice daily (50 or 100 
mg per day).28  
Chlorcyclizine HCl is currently marketed as a nonprescription drug product. 
Chlorcyclizine HCl is listed in 21 CFR 341.12 as being generally recognized as safe and 
effective for the use as an antihistamine. Chlorcyclizine HCl is currently available in 
various combination over-the-counter (OTC) formulations (e.g. NDC 58407-025-30) as 
an antihistamine drug for the indication of allergy symptoms. It is primarily used to treat 
allergy symptoms such as rhinitis, urticarial and pruritus, and may be used as an 
antiemetic. The Federal Drug Administration (FDA) listed the chlorcyclizine HCl final 
monograph in the Federal Register Notice (Volume 52, No. 163), dated August 24, 1987, 
as an antihistamine drug product for OTC human use.29 
E. Chlorcyclizine HCl and HCV 
Based on a cell-based HCV infection system, a high-throughput screen of 
chemical libraries with a collection of known pharmacological drugs (NPC Library) was 
performed. This screen identified a group of drugs in the class of anti-histamines that has 
potent anti-HCV activities in vitro. Further validation, characterization and structure-
activity relation (SAR) analysis demonstrated that chlorcyclizine HCl has the most potent 
anti-HCV activities in various HCV assays. Further preclinical evaluation has identified 
the following: 
1. Chlorcyclizine HCl Inhibits HCV Infection in a Dose-Dependent Manner 


 
Version:  08-17-2018 
11
HCV harboring a luciferase reporter gene (HCV-Luc) was used to infect Huh7.5.1 
cells in the presence of increasing concentrations of compounds. Viral infection and 
replication was measured by luciferase signal 48 hours after treatment. Cytotoxicity was 
evaluated in parallel with the ATP-based cell viability assay (ATPlite). Racemic, (R)- and 
(S)-chlorcyclizine HCl showed comparable potent EC50 values, low cytotoxicity and high 
selective indices (SI). (Figure 1 and Table below). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ID 
Chemical 
Structure 
HCV-Luc 
EC50 (μM) 
ATPlite 
TC50 (μM) 
Selective 
Index  
Racemic  
Chlorcyclizine 
HCl 
 
0.049 
25.1 
512 
(R)- 
Chlorcyclizine 
HCl 
 
0.031 
29.9 
965 
(S)- 
Chlorcyclizine 
HCl 
 
0.054 
27.1 
502 
Cyclosporin A 
- 
0.080 
- 
- 
Doxorubicin 
- 
- 
0.520 
- 
Figure 
1. 
Chlorcyclizine 
HCl 
inhibits HCV infection in a dose-
dependent manner, and exhibits 
low cell toxicity. The results shown 
are the means of three independent 
experiments ± SE. 


 
V ersi o n:  0 8 -1 7 -2 0 1 8  
1 2  
2.  C hl orcyclizi ne H Cl Dr a m atic all y Re d uces H C V R N A Level i n Cell C ult ure -derive d  
H C V Ass ay  
Cell c ult ure -d eri ve d H C V ( H C Vcc) was use d t o i nfe ct H u h 7. 5. 1 cells wit h or 
wit h o ut t he treat me nt of race mic, ( R )- a n d ( S )-c hl orc yclizi ne H Cl  at 1 0 μ M. 4 8 h o urs  
later, i ntra cell ular a n d e xtra cell ular viral R N A le v els were e val u ate d b y q ua ntit ati v e real-
ti me P C R. T his H C Vcc s yste m pr o vi des dir ect e vi de nce of a nti-H C V acti vit y of t he 
c o m p o u n ds. As s h o w n i n Fi g ure 2  ( bel o w), t h e e xtr a cell ular a n d i ntrac ell ular vir al R N A 
le vels were dr a maticall y re d u ce d wit h t he tr eat me nt of race mic, ( R )- a n d (S )-
c hl orc yclizi ne H Cl .  
 
 
 
 
 
 
 
 
 
 
 
3.  T he A ntivir al Eff ect of C hl orc yclizi ne H Cl is Hi g hly Sy ner gistic wit h C u rre nt A nti-
H C V Dr u gs  
As pre vi o usl y disc usse d, t he c o m bi nati o n of pe gi nterfer o n , ri ba viri n a n d a D A A  
(tela pr e vir or b oce pr e vir) is t h e ne w sta n dar d of care treat me nt f or H C V ge n ot y p e 1 
i nfecti o n. H o we ver, ne xt ge n erati o n D A As (s uc h as daclast a vir a n d s of os b u vir) are 
D M S O
R a c e m ic  C C Z
(R )-C C Z
(S )-C C Z
C y c lo s p o rin  A
0. 0 × 1 0 + 0 0
2. 0 × 1 0 0 4
4. 0 × 1 0 0 4
6. 0 × 1 0 0 4
* * 
* * 
* * 
* * 
E xtr a c ell ul ar
H C V  R N A  C o p ie s /m l
D M S O
R a c e m ic  C C Z
(R )-C C Z
(S )-C C Z
C y c lo s p o rin  A
0. 0 × 1 0 + 0 0
2. 0 × 1 0 0 5
2. 0 × 1 0 0 5
2. 0 × 1 0 0 8
4. 0 × 1 0 0 8
* *
* *
* *
I ntr a c ell ul ar
* *
H C V  R N A  C o p ie s /m g  R N A
Fi g ure 2. C hl orc ycli zi ne H Cl  ( C C Z) re d uces H C V R N A 
le vel dr a m atic all y i n H C Vcc ass a y. T he res ults s h o w n are 
t he mea ns of t hree i n de pe n de nt e x peri me nts ± S E. Asteris ks 
( * *P  < 0. 0 0 0 1) i n dicate statisticall y si g nifica nt re d uces of 
c o m p o u n d -treate d res ults fr o m t he D M S O-treate d res ults b y 
St u de nt’s t test. C ycl os p ori n A was  us e d as p ositi ve c o ntr ol.  


 
Version:  08-17-2018 
13
currently being investigated as potential therapies ± peginterferon and/or ribavirin in all 
HCV genotypic infections. Here we investigated the combination of (S)-chlorcyclizine 
HCl with different classes of anti-HCV drugs. HCV-Luc assay in parallel with the 
ATPlite assay (as described above) was performed in the presence of various 
concentrations of (S)-chlorcyclizine HCl in combination with various concentrations of 
each drug. As shown in the left panel of Figure 3 (below), the combination of (S)-
chlorcyclizine HCl and each drug led to an greater HCV inhibitory effect than either of 
them alone in a dose-dependent manner without toxic effect on cell viability. In the right 
panel of Figure 3, three-dimensional surface plots were generated according to the Bliss 
independence model by using MacSynergy II program.30 The surface represents 
theoretical additive plane, while peaks above the plane demonstrate synergy at the 
corresponding concentration combination and depressions below the plane shows 
antagonism. The antiviral effect of (S)-chlorcyclizine HCl is highly synergistic with 
ribavirin, interferon- (IFN-), telaprevir (NS3/4A inhibitor), daclatasvir (NS5A 
inhibitor), cyclosporin A, and 2’-C-methylcytidine (NS5B inhibitor), without significant 
cytotoxicity, supporting its use in combination therapy with these drugs. 
The observed synergistic effects suggest that (S)-chlorcyclizine HCl inhibits HCV 
infection through a different mechanism from any one of these drugs. The mechanism of 
action of ribavirin and interferon-α is mediated through host antiviral response. 
Telaprevir is NS3/4A protease inhibitor and declatasvir inhibits HCV NS5A.31,32 
Cyclosporin A targets virus RNA replication and 2-C’-methylcytidine is a NS5B 
polymerase inhibitor.32,33 The synergistic effect of (S)-chlorcyclizine HCl with these 
reagents suggests that its mechanism of action is novel and unique. This makes 


 
Version:  08-17-2018 
14
chlorcyclizine HCl a more attractive agent for development with a possibly unique 
mechanism and lower probability of selecting resistant virus strains during treatment. 
 


 
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15
 
Figure 3. The antiviral effect of chlorcyclizine HCl (CCZ) is highly synergistic with (A) ribavirin, (B) 
IFN-α, (C) telaprevir, (D) daclatasvir, (E) cyclosporin A, and (F) 2’-C-methylcytidine. Left panel, 
normalized viral inhibition and cytotoxicity after treatment with various concentration of (S)- chlorcyclizine 
HCl in combination with various concentration of each drug. The results shown are the means of three 
independent experiments ± SE. Right panel, differential surface plots at the 95% confidence interval 
(generated by MacSynergy II). The three dimensional plots illustrate the differences between the observed 
effects and the theoretical additive effects at various concentrations of the two compounds. The colors 
indicate level of synergy or antagonism. 


 
V ersi o n:  0 8 -1 7 -2 0 1 8  
1 6  
4. C hl orcyclizi ne H Cl I n hi bits H C V Ge n oty p e 1 b a n d 2 a I nfecti o n I n Viv o  
(S )-C hl orc yclizi n e H Cl  was teste d i n Al b-U P A/ S CI D c hi meri c m o use m o d el  
i nfect e d wit h H C V ge n ot y pe 1 b a n d 2a res pecti vel y.3 4 ,3 5 As s h o w n i n Fi g ure 4  ( bel o w), 
t he d oses of 5 0 m g/ k g a n d 1 0 m g/ k g dail y l e d t o ti m e-de pe n de nt re d ucti o n of H C V viral 
titer fr o m pretr eat m e nt baseli ne i n mi ce wit h g e n ot y pe 1 b a n d 2a i nf ecti o n ( 2-l o g a n d 1. 5-
l o g, res pecti vel y). D oses as l o w as 2 m g/ k g dail y als o ca use d si g nifi ca nt d ec reases of 
ge n ot y pe 1 b vir al  titer (a p pr o xi matel y 1 -l o g). A re b o u n d of viral titer after st o p pi n g of 
treat me nt was o bser ve d i n b ot h ge n ot y p e i nfe cti o ns. H o we ver, H C V viral tit ers c o nti n ue d 
t o decli ne d uri n g t he tr eat m e nt peri o d wit h o ut r e b o u n d, s u g gesti n g abse nce of e mer ge n ce 
of dr u g -resista nt vir us. T his a nti viral pr ofile is si milar t o t hat of mic e treate d wit h 
i nterfer o n-.3 6  
 
 
0
2
4
6
8
1 0 6
1 0 7
1 0 8
H u m a n  S e ru m  
A lb u m in
(n g /m l)
P re tre a tm e n t
W e e k s  a fte r tre a tm e n t
- 3
- 2
- 1
0
1
D H C V  R N A
(lo g  c o p y /m l)
5 0  m g /k g  d a ily
1 0  m g /k g  d a ily
2  m g /k g  d a ily
   
(S )-C C Z  
- 3
- 2
- 1
0
1
 (S ) - C C Z   
0
2
4
6
8
1 0
1 0 6
1 0 7
1 0 8
P re tre a tm e n t
W e e k s  a fte r tre a tm e n t
G e n o ty p e  1 b
G e n o ty p e  2 a
Fi g  Fi g ure 4 . C hl orc yclizi ne H Cl ( C C Z) i n hi bits H C V ge n ot y pe 1 b a n d 2 a i nf ecti o n i n viv o. Al b -
U P A/ S CI D mice were e n grafte d wit h pri mar y h u ma n he pat oc ytes a n d t he n i nfecte d wit h H C V s er u m 
s a m ples of ge n ot y pe 1 b or 2a. T he mice were m o nit ore d f or s er u m H C V R N A a n d h u ma n  al b u mi n f or 4 -
6 wee ks bef ore treat me nt. T he s er u m H C V R N A le vels were sta ble wit h little  fl uct uati o ns d uri n g t he 
wee ks bef ore i nfecti o n, a n d t he pretreat me nt H C V R N A val ues were deter mi ne d  b y a vera gi n g H C V R N A 
le vels of wee k -2, -1 a n d 0 bef ore i nitiati o n of treat me nt. Left pa nel: c ha n ges  i n t he ge n ot y pe 1 b H C V 
titers fr o m pretreat me nt bas eli ne o ver a peri o d of 8 wee ks wit h 4-wee k  (S )-c hl orc yclizi ne H Cl treat me nt 
a n d 4-wee k of f oll o w -u p wit h o ut treat me nt ( o nl y i n t he gr o u p r ecei ve d  5 0 m g/ k g d os e) i n H C V -i nfecte d 
c hi meric mice; Ri g ht pa nel: c ha n ges i n t he ge n ot y pe 2a H C V titers  fr o m pretreat me nt bas eli ne o ver a 
peri o d of 1 0 wee ks wit h 6 -wee k ( S )-c hl orc yclizi ne H Cl treat me nt a n d 4 -wee k of f oll o w -u p wit h o u t 
treat me nt (i n b ot h gr o u ps) i n H C V-i nfecte d c hi meric mice. 


 
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F. Summary 
In both in vitro and animal in vivo studies, we have identified that chlorcyclizine 
HCl is effective against HCV for both genotype 1 and 2. In addition, chlorcyclizine HCl 
has shown to provide a synergistic effect in combination with ribavirin in in vitro 
experiments. We propose that chlorcyclizine HCl can be utilized as antiviral therapy in 
persons with chronic HCV infection and will result in a decrease in serum quantitative 
HCV RNA viral titers. The primary focus of this protocol is to evaluate the utility of 
chlorcyclizine HCl as a potential therapeutic modality and to assess the safety profile in 
patients chronically infected with HCV. We propose to treat patients with chlorcyclizine 
HCl with and without ribavirin for 28 days to evaluate for decline in quantitative HCV 
RNA during therapy. We will also evaluate safety, tolerability and viral kinetic responses 
during treatment. 
 
 


 
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Hypothesis and Aims 
Hypothesis: 
Therapy with chlorcyclizine HCl (CCZ) leads to a decrease in hepatitis C virus levels in 
serum and is safe in chronic hepatitis C patients. 
Primary Endpoints: 
1) Decline in serum HCV RNA viral titer during therapy as compared to baseline 
measured by PCR (qPCR). 
2) The ability to tolerate the drug at the prescribed dose for the duration of therapy. 
Secondary Endpoints: 
1. A significant change in alanine aminotransferase (ALT) levels compared to 
baseline. 
2. Quantification of chlorcyclizine HCl and its metabolites in serum during therapy. 
3. Changes in symptom scale measurements during and after therapy. 
 
Summary Of Investigational Agent 
Chlorcyclizine HCl 
 
For the purposes of this study, AHIST (chlorcyclizine hydrochloride) 25 mg 
tablets (Magna Pharmaceuticals, Inc, Louisville, KY) will be purchased for distribution 
by the NIH Clinical Center pharmacy. 
Safety Pharmacology of Chlorcyclizine HCl 


 
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Chlorcyclizine HCl is a sedating antihistamine with clinical experience dating 
from its introduction in 1949.37 In vitro pharmacology experiments have demonstrated it 
to be a low nanomolar antagonist of the histamine receptor.38 The piperazine class of 
antihistamines including chlorcyclizine HCl also share anticholinergic, antiemetic, local 
anesthetic, and mild sedative properties presumably deriving from activity at muscarinic 
receptors and other targets.39,40 Despite its polypharmacology, chlorcyclizine HCl retains 
a favorable side-effect profile: 
A mildly sedative antihistaminic agent with prolonged action and low incidence 
of toxic side effects. Chlorcyclizine HCl has slight anticholinergic and 
antispasmodic actions and enhances action of the epinephrine. It also has some 
local anesthetic action.41 
Other antihistamine agents astemizole and terfenadine have been associated with 
rare reports of ventricular arrhythmias, but this is not believed to be a class effect.42 The 
action of chlorcyclizine HCl on the QT interval or potassium channels in cardiac tissues 
has not been examined. In one preclinical study of cardiac repolarization with isolated, 
perfused, feline heart, chlorcyclizine HCl was the least potent of the antihistamines 
tested.43 No reports of torsade de pointes have been associated with chlorcyclizine HCl.44  
The absorption, distribution, metabolism and excretion of chlorcyclizine HCl in 
humans have not been characterized in detail. Chlorcyclizine HCl is metabolized in 
humans and other preclinical models primarily to norchlorcyclizine through oxidative N-
demethylation and also a minor amount to chlorcyclizine N-oxide through N-oxidation 
which has been detected in urine in humans.45,46 Both metabolic products lack 


 
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antihistamine activity.45,46 It is expected that this is mediated by cytochrome P450 
metabolism of chlorcyclizine HCl, though the specific metabolizing enzyme has not been 
identified to date. Chlorcyclizine HCl might therefore affect or be affected by 
concomitant administration of other cytochrome P450-interacting agents. Chlorcyclizine 
HCl may also have some potential to induce cytochrome P450 enzyme expression in 
studies in both rat47 and dog45 which may limit exposure to chlorcyclizine HCl. 
Furthermore, although described in an underpowered study, patients with chronic 
hepatitis C infections may have lower endogenous CYP3A4 and CYP2D6 activities than 
healthy volunteers which may increase exposure in this patient population if 
chlorcyclizine HCl metabolism is mediated by CYP3A4 or CYP2D6.48 Thus, 
chlorcyclizine HCl exposure in the intended patient population might be greater or lower 
than the seasonal and perennial allergic rhinitis patient population.  
The pharmacokinetics of oral chlorcyclizine HCl dosing is not known. The 
primary metabolite norchlorcyclizine preferentially distributes in preclinical models from 
plasma into certain tissues, especially to liver and spleen.45 Norchlorcyclizine has a half-
life of approximately 6 days in man with some amount detectable 20 days after the 
termination of dosing possibly reflecting this extensive tissue distribution.49 
Human Experience with Chlorcyclizine HCl 
Chlorcyclizine HCl is a sedating antihistamine37 with clinical experience dating 
from its introduction in 1949 in two different products, Di-Paralene and Perazil. Di-
Paralene prescribed initial dosing of 50 mg three times daily (150 mg per day) whereas 
Perazil labeling prescribed oral dosing of 50 mg tablets once or twice daily (50 or 100 mg 


 
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21
per day).28  The OTC monograph for chlorcyclizine HCl 25 mg directs “1 tablet by mouth 
every 6-8 hours, not to exceed 3 tablets in 24 hours, or as directed by a doctor” (75 mg 
per day or as directed by a doctor).29 
The effects of acute doses of chlorcyclizine HCl have been observed in humans, 
and are similar to other first-generation piperazine antihistamines. In general, adults have 
survived single doses of 2.5-5.0 grams of first generation antihistamines.50 There is a case 
report of a 16 month old boy who consumed 900 mg; he experienced a prolonged 
convulsive state but eventually made a full recovery.51 One patient suffering from an 
allergic reaction to penicillin was treated with 600 mg chlorcyclizine HCl over 12 hours 
and cumulatively 1300 mg over 3 days without side effect.52  
The clinical profile of chlorcyclizine HCl seems consistent with other first 
generation antihistamines (excerpt taken from Pyrilamine, a first generation 
antihistamine): 
In acute poisoning with H1 antagonists, their central excitatory effects constitute 
the greatest danger. The syndrome includes hallucinations, excitement, ataxia, 
incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed 
face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend 
the syndrome a remarkable similarity to that of atropine poisoning. Terminally, 
there is deepening coma with cardiorespiratory collapse and death, usually within 
2 to 18 hours.53  
Single oral doses of 400 mg chlorcyclizine HCl have been administered without 
toxic effects to three patients.52 One patient suffering from an allergic reaction to 
penicillin was treated with 600 mg chlorcyclizine HCl over 12 hours and cumulatively 


 
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22
1300 mg over 3 days without any side effects.52 In other studies with single oral doses of 
100 mg, drowsiness was the most common side effect, reported in 17 of 63 doses (this 
fact is further clarified in Brown 1950). Other mild side effects were reported in 21 of 63 
doses (dryness of mouth, nausea, headache, light headedness, nervousness, difficulty in 
walking, vomiting, vertigo, palpitation, inability to concentrate, stimulation, and tingling 
of fingers).54 By limiting single doses to 50 mg, patients are able to obtain allergy relief at 
cumulative doses equal to or greater than 100 mg per day without side effects, including 
50 mg b.i.d. 54,55, 50 mg t.i.d.49,54, 50 mg q.i.d.54,55, though some drowsiness was also 
noticed at 50 mg q.i.d. in one study.55 
The FDA has evaluated the safety of chlorcyclizine HCl in two ways, during the 
initial NDA process (NDA 6-947 Perazil Tablets marketed by Burroughs Wellcome Co. 
and NDA 6-938 Di-Paralene Tablets marketed by Abbott Laboratories) and in context of 
risk-benefit analysis through the DESI review process56 for seasonal and perennial 
allergic rhinitis. This rhinitis patient population would be expected to a broad, 
heterogeneous patient population, and a wide safety margin would be expected for the 
use of this drug in any general population. 
Chronic 4-week dosing of chlorcyclizine HCl has not been studied in a controlled 
clinical setting. The product is indicated for perennial allergic rhinitis and some chronic 
use is anticipated. In an early clinical study, a few patients took daily 50 mg doses for one 
month without significant side effects.52 Moreover, patients experiencing side effects 
quickly recover after discontinuing treatment or reducing dosage. The OTC product label 
indicates “Uses: temporarily relieves these symptoms due to hay fever or other upper 
respiratory allergies.” It is assumed that “temporarily” in the indication refers to the 


 
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23
pharmacokinetics of the product and not to its potential chronic use. Cetirizine OTC 
products have very similar labels. Neither chlorcyclizine HCl nor cetirizine labels include 
any warning to stop use after an extended period, unlike Sudafed which has the warning 
“stop use and ask a doctor if … symptoms do not improve within 7 days or occur with a 
fever”. Warnings in the chlorcyclizine HCl OTC product labeling include: “Do not take 
this product unless directed by a doctor. If you have; a breathing problem such as 
emphysema or chronic bronchitis, glaucoma, difficulty in urination due to enlargement of 
the prostate gland, ask a doctor before use or if you are taking sedatives or tranquilizers. 
If pregnant or breast-feeding, ask a health professional before use.” 
Toxicology of Chlorcyclizine HCl 
The LD50 in mice is 137 mg/kg.54 Kuntzman reported that the administration of a 
single 50 mg/kg oral dose of chlorcyclizine to a dog caused tremors and convulsions – 
the fate of that animal is not known, but data obtained for the 14 days following that 
single dose indicated recovery; other dogs were chronically dosed for up to 125 days with 
oral doses of at least 10 mg/kg without significant findings.45,57 
Based on a detailed scientific review of preclinical and clinical data surrounding 
possible teratogenic effects of chlorcyclizine HCl and related compounds, the FDA found 
that the data does not support any special restriction on the use of chlorcyclizine HCl or a 
pregnancy warning29 beyond the general precautionary labeling required on OTC 
products by § 201.57(f)(6). Chronic administration of chlorcyclizine HCl at high doses in 
rodents induces lipidosis and at similar 75 mg/kg doses also cause abortions in rat.58,59 50 
mg/kg dosage during pregnancy in rats induced lipodosis in the fetus as well.59 60 mg/kg 
and 90 mg/kg doses during sensitive periods for palate development induced cleft-palate 


 
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24
and other malformations of rat fetal development.60 Developmental toxicity has been 
noted with chlorcyclizine HCl and other antihistamines in rodents.61,62 
Concomitant Use with Ribavirin 
As discussed above, ribavirin appears to be an important component of 
combination therapy with various DAAs in HCV therapy and synergizes with 
chlorcyclizine HCl in anti-HCV in vitro assays. We therefore decided to use ribavirin in 
combination with chlorcyclizine HCl as an interferon-free combination therapy to 
compare with chlorcyclizine HCl monotherapy in this study. Because this is the first 
study utilizing the combination of the ribavirin and chlorcyclizine HCl for the therapy of 
chronic HCV infection, the side effects of combining the two drugs are not known. 
Results of in vitro studies of ribavirin using both human and rat liver microsome 
preparations indicated little or no cytochrome P450 enzyme-mediated metabolism, with 
minimal potential for P450 enzyme-based drug interactions63 and its indicated drug 
interactions list only nucleoside analogues and azathioprine64, and so the risk of an 
interaction with concomitant administration of chlorcyclizine is expected to be low. 
Protocol 
We propose to treat 50 patients with chronic hepatitis C infection (all genotypes) 
who are treatment naïve or relapsers to previous forms of interferon and ribavirin therapy 
with chlorcyclizine HCl with or without ribavirin for twenty-eight days monitoring HCV 
RNA levels as well as routine safety measures and liver function tests.  
Study Population 
Inclusion Criteria 


 
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(1) Adults, ages 18 and above; 
(2) Chronic hepatitis C (HCV RNA in serum for more than 6 months); 
(3) HCV RNA in serum at or above 10,000 IU/mL; 
(4) Treatment naïve patients defined as individuals whom have never undergone any 
form of interferon and ribavirin therapy for chronic HCV infection or relapsers 
defined as reappearance of HCV RNA in serum after treatment (with any form of 
interferon and ribavirin therapy) was discontinued and an end-of-treatment 
response was achieved; 
(5) No major contraindications to agents being used (chlorcyclizine HCl and 
ribavirin); 
(6) Females of childbearing potential must have a negative serum or urine pregnancy 
test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours before the first dose of study drug; 
(7) Women of childbearing potential and men, participants and partners, must use 
highly effective methods of birth control to minimize the risk of pregnancy and 
must follow instructions for birth control for the entire duration of the study 
including a minimum of 24 weeks after the last dose of ribavirin.  Two forms of 
birth control are required from the time of screening throughout the duration of 
the on-treatment study period and for at least 24 weeks after the last dose of 
ribavirin.  Examples of effective birth control include: condom with spermicide; 
diaphragm with spermicide; cervical cap with spermicide; female condom; 
intrauterine devices (IUDs); vasectomy in men;   
Exclusion Criteria  


 
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(1) Liver or any other organ transplant (including hematopoietic stem cell transplants) 
other than cornea and hair; 
(2) Current or known history of cancer (except in situ carcinoma of the cervix or 
adequately treated basal or squamous cell carcinoma of the skin) within 5 years 
prior to enrollment; 
(3) Documented or suspected HCC, as evidenced by previously obtained imaging 
studies or liver biopsy (or on a screening imaging study/liver biopsy if this was 
performed); 
(4) Evidence of decompensated liver disease including, but not limited to, bilirubin 
>4 mg/dL, albumin <3.0 gm/dL, prothrombin time >2 sec prolonged or a history 
or presence of ascites, bleeding varices, or hepatic encephalopathy.  Patients with 
ALT levels >500 U/L will not be enrolled but may be followed until three 
determinations are below this level; 
(5) Evidence of a medical condition contributing to chronic liver disease other than 
chronic HCV infection (such as, but not limited to: acute hepatitis C infection, 
hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver 
disease, toxin exposures); 
(6) History of chronic hepatitis B virus (HBV) as documented by HBV serologies 
(eg, HBsAg-seropositive). Subjects with resolved HBV infection may participate 
(eg, HBsAb-seropositive with concurrent HBsAg-seronegative); 
(7) Any prior exposure to direct-acting antiviral therapies for chronic HCV infection; 
(8) History of HIV infection; 


 
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(9) History of hemoglobinopathies (eg. thalassemia major or sickle cell anemia), 
diagnoses associated with an increased baseline risk for anemia (eg, 
spherocytosis), hemolytic anemia, or diseases in which anemia would be 
medically problematic, or hemophilia; 
(10) Confirmed, uncontrolled hypertension (any screening systolic blood pressure ≥ 160 
mmHg or diastolic blood pressure ≥ 100 mmHg should be excluded unless 
discussed with the central medical monitor); 
(11) Any other medical and/or social reason, including active substance abuse as defined 
by DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse, which in the opinion 
of the investigator would make the candidate inappropriate for participation in this 
study; 
(12) Significant systemic or major illnesses other than liver disease, including, but not 
limited to, clinically significant emphysema or chronic bronchitis, symptomatic 
benign prostatic hypertrophy, glaucoma, gastrointestinal motility related illnesses, 
congestive heart failure, renal failure (eGFR <50 mL/min), and active coronary 
artery disease; 
(13) Significant prior history suggestive of cardiovascular instability, including but not 
limited to evidence of significant myocardial ischemia, unstable re-entry 
phenomena, other significant dysarrhythmias and/or uncontrolled hypertension; 
(14) Inability to tolerate oral medication; 
(15) For relapsers: exposure to interferon based therapy with ribavirin within 12 weeks 
prior to screening; 
(16) Allergy or hypersensitivity to chlorcyclizine HCl or ribavirin; 


 
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(17) Any known contraindication to ribavirin, not otherwise specified; 
(18) Inability to refrain from operating heavy machinery while on therapy; 
(19) Breastfeeding women; 
(20) Inability to understand or sign informed consent; 
(21) Active use of chlorcyclizine HCl or another piperazine class antihistamine within 
6 months of enrollment; 
(22) Inability to abstain from piperazine class antihistamines during enrollment in the 
clinical trial period. 
Initial Evaluation 
Pre-treatment Phase: (screening visits) 
Patients will be seen by the Liver Diseases Branch of NIDDK in the outpatient 
clinic of the Clinical Center, NIH, where they will initially undergo evaluation under the 
omnibus protocol 91-DK-0214 “Evaluation of Patients with Liver Disease.” During this 
evaluation, patients will also undergo evaluation for assessment of eligibility: 
(1) History and physical examination; 
(2) Concomitant medication query (including dose and indication for each); 
(3) A standard symptom questionnaire [which focuses on fatigue and abdominal 
pain], which provides information on categorical presence of symptoms as well as 
their severity, pattern and frequency (Appendix 1); 
(4) Blood tests.  These include complete blood count (CBC with differential and 
platelet count), prothrombin time (PT), partial thromboplastin time (PTT), 
sedimentation rate (ESR), reticulocyte count, plasma haptoglobin level, alanine 


 
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29
aminotransferase (ALT), aspartate aminotransferase (AST), direct and total serum 
bilirubin, albumin, total protein, lactate dehydrogenase (LDH), creatine 
phosphokinase (CK), sodium, chloride, bicarbonate, potassium, blood urea 
nitrogen, creatinine, glucose, magnesium, uric acid, calcium, phosphorus, 
cholesterol, triglycerides, iron and iron-binding capacity (transferrin), ferritin, 
immunoglobulin levels, thyroid stimulating hormone (TSH), antinuclear antibody 
(ANA), alpha fetoprotein (AFP), rheumatoid factor, cryoglobulins, hepatitis B 
surface antigen (HBsAg), antibody to HBsAg (Anti-HBs), antibody to hepatitis B 
core antigen (anti-HBc), hepatitis B e antigen (HBeAg), antibody to HBeAg (anti-
HBe), hepatitis B virus DNA (HBV DNA), antibody to hepatitis d antigen (anti 
HDV), anti-HCV, hepatitis C virus RNA (HCV RNA), HCV genotype testing and 
anti-HAV.  HBV DNA and HCV RNA will be tested by polymerase chain 
reaction.  An additional 10 mL of whole blood will be collected and stored at -80 
°C.  Women of childbearing potential will have a pregnancy test; 
(5) A routine urinalysis will be performed; 
(6) An abdominal ultrasound will be performed; 
(7) An electrocardiogram (EKG) in digital format will be performed.  
Treatment 
 
The treatment design of this study entails randomization of patients into one of 
two dosing groups (I and II) (Figure 1). Group I patients will receive chlorcyclizine HCl 
at a dose of 75 mg BID. Group II patients will receive chlorcyclizine HCl (75 mg BID) 
with ribavirin. For all genotypes, ribavirin will be dosed via a weight-based regimen of 
1000 mg daily <75 kg and 1200 mg daily ≥75 kg.  For patients receiving 1000 mg daily, 


 
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patients will take 2 (200 mg each) tablets in the AM and 3 (200 mg each) tablets in the 
PM.  For patients receiving 1200 mg daily, patients will take 3 (200 mg each) tablets in 
the AM and 3 (200 mg each) tablets in the PM. 
After the pre-treatment evaluation, patients will be admitted to the NIH Clinical 
Center for 48 hours, for induction of therapy, observation of side effects, administration 
of medication, and timed blood draws to facilitate analysis of virological response 
kinetics. Upon initiation of therapy, all patients will be administered a one-time dose of 
150 mg (about 2mg/kg) of chlorcyclizine at time 0.  From day 2 through 28, patients will 
take 75 mg of chlorcyclizine twice daily as prescribed. Approximately 10 patients 
receiving chlorcyclizine monotherapy will undergo a detailed pharmacokinetic (PK) 
study (measurement of chlorcyclizine and its metabolites in the blood). In patients 
undergoing PK analysis, sampling will begin upon initiation of therapy (Time= 0, 30 
min, 1 h, 2 h, 4 h, 8 h, 12 h, 18 h, 24 h and 48 h), while on therapy (days 7, 14, 21 and 28) 
and after the completion of therapy (post-therapy week 1 and 2). For viral kinetic 
analysis, all patients will have blood sampled at Time=0, 4h, 12h, 18h, 24h, 36h and 48h 
as outlined in Table 1.  
It is possible that ribavirin co-administration may alter the pharmacokinetic 
parameters of chlorcyclizine, but there is no evidence in the literature that these two 
drugs interfere with each other’s absorption and metabolism. We will be obtaining blood 
samples on all patients and therefore can measure the blood chlorcyclizine levels at 
certain time points after therapy to compare those receiving chlorcyclizine only and those 
receiving chlrocyclizine plus ribavirin. 


 
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After induction of therapy, patients will be treated as outpatients and followed on 
a regular basis in the outpatient clinic at the NIH (See below and Table 1). Drug therapy 
compliance will be monitored through patient diaries. Therapy will be stopped for 
intolerance to chlorcyclizine HCl or ribavirin (which will be carefully defined). Patients 
will also be reminded to refrain from operating heavy machinery while on therapy. 
At the 28-day point, patients will undergo a repeat outpatient evaluation.  This 
evaluation will include all of the elements listed above under (Pre-treatment phase) which 
will include multiple blood tests, urine tests, symptom questionnaires, and virological 
testing. 
After 28 days of therapy, patients will be monitored and followed off therapy for 
HCV without treatment at various intervals (Table 1) for the next 3 months. Patients may 
be offered standard therapies for disease flares that lead to clinically significant 
deterioration during the 3-month post-treatment monitoring period.  Thereafter, patients 
will be followed in the usual fashion by the Liver Diseases Branch. If eligible, patients 
will be offered enrollment in other HCV studies offered by the Liver Diseases Branch.  
 
 


 
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Figure 1: Study Design 
• 2 dosing groups: 
o I=Chlorcyclizine HCl 
 
 
 
o II=Chlorcyclizine HCl + ribavirin 
 
 
• 1 mo Rx / 3 mo off drug  
 
 
              
 
 
 
  1 mo Rx    
3 mo off drug 
 
Randomization 
After initial evaluation and determination of eligibility, patients will be asked to 
provide written informed consent. All patients who consent will then be randomized by a 
set of random numbers held in the Pharmaceutical Development Service (PDS) into 
either group I or group II. The randomized code will be blocked into groups of 5 so that 
equal numbers of patients will be randomized to each group of 25 patients have been 
enrolled. Randomization will be stratified by HCV genotype (HCV genotype 1 and non-
HCV genotype 1). 
Monitoring During Therapy 
Patients will be seen, interviewed and have blood tests taken at regular intervals 
before, during and after therapy (Table 1). Patients will be seen and have blood drawn at 
least 3 times during the 6 months before treatment. An electrocardiogram will be 
performed prior to starting therapy and during therapy as described in Table 1. Patients 
will be admitted and have frequent blood samples during the first 48 hours of therapy 
(baseline, 4, 12, 18, 24, 36 and 48 hours), to assess the initial viral kinetics in response to 
I 
 
II 
 


 
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33
therapy. For patients undergoing intensive PK analysis, an additional tube of blood 
sampling will be obtained as previously described above. 48 hours after starting therapy, 
patients will be discharged and seen in the outpatient clinic for blood testing at 7, 14, 21 
and 28 days. At each time point, an acceptable deviation would include +/-3 day. After 
stopping therapy, patients will be seen for blood testing at 1, 2, 4, 8, 16 and 24 weeks. At 
each time point, an acceptable deviation would include +/- 1 day. The timing of blood 
specimens, physical examination and other evaluations is provided in Table 1. Routine 
blood tests will include complete blood count and differential, serum chem-20 (ALT, 
AST, alkaline phosphatase, LDH, CPK, direct and total bilirubin, albumin, total protein, 
electrolytes, calcium phosphate, glucose, blood urea nitrogen, magnesium, creatinine and 
uric acid) and HCV RNA. Extended blood tests will also include prothrombin time, TSH 
and a pregnancy test. Serum to evaluate of chlorcyclizine HCl and its metabolites will 
also be drawn as shown in Table 1. When appropriate, blood will be drawn in pediatric 
tubes and the amount of blood that will be drawn from adult patients (i.e.: those persons 
18 years of age or older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller over any eight week period. At specified outpatient visits during 
therapy (Table 1), patients will be asked about their symptoms, fill out a symptom 
questionnaire and will undergo assessment of vital signs and medication diaries.  
Potential neurological, cardiac, gastrointestinal, and psychiatric side effects associated 
with antihistamines will be carefully monitored at each visit (table 2). At extended 
outpatient visits, patients will undergo a brief history and physical examination. 
HCV RNA will be tested at the NIH Clinical Center utilizing real time PCR 
(sensitivity ~15 IU per mL), COBAS Ampliprep/COBAS Taqman HCV Testing 


 
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Methodology which is an FDA approved assay intended for the use as an aid in the 
management of chronic HCV infection.  Samples will be collected at baseline (at least 3 
times) and at each sampling time point to enable resistance monitoring and analysis and 
viral kinetics.  The latter will include determination of baseline determination of baseline 
isolate sequence analysis to enable identification and monitoring changes in viral genome 
sequences as a function of treatment duration.  Analysis of both chlorcyclizine HCl and 
chlorcyclizine HCl + ribavirin will enable an assessment of background genomic 
variability. Any clinical evidence of breakthrough or rebound (defined as a greater than 1 
log increase above an observed viral load nadir) will prompt a more in-depth viral 
genomic analysis. Because other unanticipated mechanisms of resistance could 
theoretically be operative; however, we would anticipate performing full genome 
sequencing to enable maximally unbiased assessment for candidate resistance mutations. 
We will also have the ability to engineer any identified candidate resistance mutation 
back into an HCV vector competent for in vitro replication, in order to confirm that the 
mutation is indeed causative of any suspected decreased sensitivity to chlorcyclizine HCl 
(CCZ) and/or ribavirin (RBV). 
 
 
 


 
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Table 1: Design of Study 
 
Time 
Therapy 
Routine 
Visit 
Extende
d Visit 
Pharmacokine
tic, 
Chlorcyclizine 
HCl  and 
Metabolite 
Testing 
HCV 
RNA 
Testing 
Comments 
-8 wk. 
None 
* 
 
 
* 
 
-4 wk. 
None 
* 
 
 
* 
 
Day 0-2 
(Inpatie
nt Stay) 
Start 
Therapy 
with CCZ 
or 
CCZ+RBV
with 150 
mg CCZ, 
with days 
2-28 with 
75 mg 
BID. 
* 
* 
* 
* 
Consent 
signed at or 
before Day 0, 
Symptom 
Questionnaire 
at Baseline, 
Baseline & 48 
hr EKG. 
Perform PK 
studies.  
Day 7 
CCZ or 
CCZ+RBV 
* 
 
* 
* 
EKG, 
Symptom 
Questionnaire 
Day 14 
CCZ or 
CCZ+RBV 
* 
* 
* 
* 
EKG, 
Symptom 
Questionnaire 
Day 21 
CCZ or 
CCZ+RBV 
* 
 
* 
* 
EKG, 
Symptom 
Questionnaire 
Day 28 
Stop 
Therapy 
* 
* 
* 
* 
Symptom 
Questionnaire, 
EKG 
Post-Therapy Follow-up 
Week 1 
None 
* 
 
* 
* 
EKG, 
Symptom 


 
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36
Questionnaire 
Week 2 
None 
* 
 
* 
* 
 
Week 4 
None 
* 
 
 
* 
 
Week 8 
None 
* 
 
 
* 
 
Week 12 None 
* 
* 
* 
* 
Symptom 
Questionnaire 
 
Routine Visit: Review of diary, vital signs, review of symptoms, interim medical history, 
urinalysis, and routine blood tests for ALT, AST, alkaline phosphatase, direct and total 
bilirubin, albumin, total protein, BUN, creatinine, hematocrit, white blood cell count and 
differential, platelet count. 
Extended Visit: Prothrombin time, TSH and physical examination. Women of 
childbearing age will have a pregnancy test. 
Pharmacokinetic, Chlorcyclizine HCl and Metabolites Testing: 8 cc of blood will be 
collected in a red-top tube for PK testing at the designated time points. 10 cc of blood 
will be collected in a red-top SST tube to be tested for chlorcyclizine HCl and its 
metabolites. 
HCV RNA Testing: Real-time quantitative polymerase chain reaction assay (qPCR) for 
viral titer with a sensitivity of 15 IU per mL. 
Symptom Questionnaire: Will be administered on several occasions. Before and after 
28 days of therapy and at the 6 month off-treatment follow-up visit. 
Start Therapy: Includes blood drawn immediately before and then at 4, 12, 18, 24, 36 
and 48 hours after the first dose of chlorcyclizine HCl or chlorcyclizine HCl+ribavirin for 
measurement of HCV RNA. 
Assessment of Response 


 
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The primary therapeutic endpoint will be a decrease of HCV RNA viral titer as 
compared to baseline measurements in serum, as measured by quantitative PCR (qPCR).  
A secondary therapeutic endpoint will include a change in ALT levels compared to 
baseline measurements. 
 
The primary safety endpoint will be ability to tolerate the drug at the prescribed 
dose for the full 4-week duration.  Discontinuation of the medication will be considered 
failure to tolerate. 
 
Secondary safety endpoints will include changes in specific values in symptom 
scales, in the safety questionnaire or worsening of liver disease and quantification of 
metabolites of chlorcyclizine HCl during therapy. Chlorcyclizine HCl has undergone 
various phase II, III & IV studies and has been used as an allergy medication with good 
safety and tolerability. Although we cannot be certain, we do not expect to have differing 
safety and tolerability issues in comparison to these studies. 
Design of Trial/Statistical Considerations 
This study is designed as a phase 1b proof-of-concept treatment trial to determine 
the ability of chlorcyclizine HCl to suppress HCV at tolerable doses. The effective dose 
is not known. This trial should show if HCV suppression is possible with chlorcyclizine 
HCl and also help in suggesting the optimal dose and duration for viral suppression and 
how well it is tolerated. Therefore assessment of virologic response and tolerance in each 
open label group will be the primary analysis. Secondarily the magnitudes of viral 
declines will be compared between the two groups with standard statistical methods to 
assess the combined effect of chlorcyclizine HCl and ribavirin. Normal fluctuation of 


 
Version:  08-17-2018 
38
HCV RNA in serum over a short-term period (< 3 months) has been described to be 
approximately 0.5 log10.65 In a prior study performed by our group, 28 days of ribavirin 
monotherapy resulted in a mean decrease of 0.55 log10 without significant difference 
between genotype 1 and non-genotype 1 infection.66 Therefore, accounting for normal 
short-term fluctuation of HCV RNA in serum, and the effect of ribavirin therapy, to show 
at least a 0.5 log improvement while on therapy (comparing baseline with either 
chlorcyclizine HCl or chlorcyclizine HCl+ribavirin or comparing between groups) with 
an alpha of .05 and a power of .8, and accounting for a 10% dropout rate, the total needed 
for each group is 25 patients and a total for the study of 50 patients. 
Hazards and Discomforts 
The hazards associated with this study are the following. 
(1) The risks and discomforts of frequent phlebotomy. To document stable levels of 
biochemical and serologic markers of chronic hepatitis and to monitor the effects 
and toxicities of the therapy, frequent blood sampling will be required. Patients 
will have between 15-20 venipunctures during their course of therapy. Each 
venipuncture will be for 15 to 70 mL of blood. The amount of blood that will be 
drawn from adult patients (i.e., those persons 18 years of age or older) for 
research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, 
over any eight week period. 
(2) The risks and hazards of chlorcyclizine HCl therapy. Chlorcyclizine HCl is a 
sedating antihistamine37 with reported mild side effects including dryness of 
mouth, nausea, headache, light headedness, nervousness, difficulty in walking, 


 
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39
vomiting, vertigo, palpitation, inability to concentrate, stimulation, and tingling of 
fingers.54 The extensive summary of chlorcyclizine HCl including risks and 
hazards of therapy are described earlier in this protocol in the section entitled 
“Summary of Investigational Agent” starting on page 17. 
(3) The hazards and discomforts of ancillary evaluations. Patients with risk factors 
for coronary artery disease will undergo thallium stress testing. If one has been 
performed within one year prior to study enrollment, a repeat test will not be 
necessary. Exercise stress testing requires that the patient undergo treadmill 
exercise testing while being monitored for vital signs and EKG changes. The 
exercise itself takes 3 to 15 minutes and consists of graded exercise on a 
mechanical treadmill. The patient will have an intravenous line in place and EKG 
monitors. This is a standard means of evaluation of patients at high risk for 
coronary artery disease and is not a research procedure per se. Exercise stress 
testing has a small risk; deaths due to cardiac arrhythmias have been reported to 
occur once in every 10,000 patients studied. The cardiology service at the NIH 
Clinical Center is proficient in this methodology and perform it frequently as a 
part of evaluation of patients for both routine and research medical procedures. 
(4) The risks and hazards of ribavirin therapy. Treatment with ribavirin has been 
associated with few severe adverse side effects.67-70 The following discussion of 
side effects is based largely upon our own experience in several pilots studies (90-
DK-49, 91-DK-11 and 93-DK-140) and our randomized, double-blind controlled 
trials of ribavirin (91-DK-178 and 98-DK-003).71-73 
a. Hemolytic anemia. Ribavirin results in dose dependent hemolysis of 


 
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40
varying degree in most patients.73 In patients without hemolysis or bone 
marrow suppression, clinically significant anemia is not common. In large 
clinical trials of combination therapy using ribavirin, between 8-10% of 
patients required ribavirin dose modification because of 
anemia67,6867,6867,6867,6866,6765,6665,6665,6664,65.63,64 In all cases, the hematocrit 
rose to pretreatment levels within a month of stopping therapy. Anemia 
can result in symptoms of fatigue, palpitations, dyspnea on exertion, 
headaches and general weakness. In the current study, patients will be 
monitored closely with blood counts every two to eight weeks. The initial 
dose of ribavirin will be 1000 to 1200 mg per day. Growth factors (epoetin 
alfa, darbopoeitin alfa) will not be started in this trial. Patients with pre-
existing hemolysis or bone marrow compromise are more sensitive to the 
hemolysis induced by ribavirin. 
b. Lymphopenia. Analysis of our controlled trial of ribavirin indicated that 
there was a 10% to 15% decrease in lymphocyte counts among the 
patients treated with ribavirin72. The lymphopenia has not been severe or 
associated with an increase in opportunistic infections. Lymphocyte 
counts return to pretreatment values when ribavirin is stopped.   
c. Gout. Ribavirin is a purine analogue and is metabolized to uric acid. In 
some patients, uric acids increase during ribavirin therapy and these 
increased levels may trigger an acute attack of gout. Acute gout has been 
described in patients with a history of gout who receive ribavirin, and can 
be managed with typical therapy without stopping ribavirin, unless the 


 
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41
attack is severe and prolonged or does not respond to standard therapy. 
d. Cholelithiasis. Both chronic hemolysis and chronic liver disease are 
associated with an increased risk of pigment gallstones. It is therefore 
possible that ribavirin could increase the risk of having gallstones, 
particularly in patients with pre-existing liver disease. Development of 
gallstones has been described in small numbers of patients receiving 
ribavirin for up to 48 weeks. Patients in this study undergo routine 
ultrasound of the abdomen before therapy and at the end of follow up. 
e. Pruritus. Itching occurs in approximately 20% of patients receiving 
ribavirin for 24 weeks or more and is the reason for stopping therapy in 
some patients. The pruritus is usually mild, but can be severe in some 
patients, interfering with sleep. This side effect typically appears after 
several months of treatment and is improved by decreasing the dose. This 
side effect suggests that ribavirin has histamine-like effects. 
f. Nasal stuffiness, sinusitis and upper respiratory infections.  
Respiratory symptoms are common among patients receiving ribavirin, 
being reported in as many as 20% of patients. These can include repeated 
upper respiratory infections, chronic cough, wheezing, sinusitis and ear 
ache. These side effects, like pruritus, tend to arise after several months of 
therapy and both may be related to histamine-like effects of ribavirin. 
g. Hepatic iron accumulation. Studies of liver biopsies from before and 
after therapy with ribavirin have demonstrated an accumulation of iron 
with therapy. This is probably due to the chronic hemolysis induced by 


 
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42
ribavirin causing accumulation of macrophagic iron as well as increases in 
iron absorption caused by anemia. In most cases, the amount of iron 
appeared slight. In our controlled trial of combination therapy, 
quantitation of hepatic iron performed on liver tissue from before and after 
48 weeks of therapy, the hepatic iron concentrations increased from a 
mean of 826 to 1857 g per gram of dry weight.71 This degree of iron 
accumulation is not clinically significant. In other studies, we have 
performed follow up liver biopsies on four patients who developed 
stainable hepatic iron with ribavirin therapy and all four showed 
disappearance of iron staining; neither had been treated with phlebotomy. 
Thus, the increase in iron with therapy may gradually resolve 
spontaneously. In this study, quantitative analysis of iron concentration 
will be performed on liver biopsies done at the start of therapy. Patients 
with elevated levels of iron will undergo phlebotomy as would be 
recommended in standard practice. 
h. Fetal and reproductive effects. The risks of ribavirin therapy to the fetus 
during pregnancy are not known.74 Studies in animals indicate that 
ribavirin can cause fetal wasting and fetal abnormalities in all animal 
species studied. This effect is probably due to induction of severe and fatal 
hemolysis in the fetus. At doses equivalent to what is used in humans, 
ribavirin did not have teratogenic effects in rabbits and rats. Nevertheless, 
female patients of childbearing age will be strongly cautioned about the 
possible risk in pregnancy and will be counseled about practicing adequate 


 
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43
contraception for the duration of treatment and the subsequent six months. 
A pregnancy test will be done at the start of therapy in these individuals 
and repeated at each visit during treatment and for the next 6 months. 
Patients who are pregnant will not be entered into this study, and the drug 
will be discontinued immediately if pregnancy occurs. Ribavirin will also 
be discontinued in male patients should their partners become pregnant, as 
advised in the package insert for the medication. Male patients will also be 
cautioned and the potential for decrease in spermatogenesis will be 
discussed.  
i. Carcinogenesis. In vitro assays have suggested that ribavirin has 
carcinogenic and mutagenic potential. However, in recent oncology 
studies in the mouse and rat, there was no evidence of carcinogenicity in 
either species. Nevertheless, the potential of carcinogenesis will be 
discussed in the consent form. 
j. Non-specific Symptoms. Some patients in placebo-controlled trials of 
ribavirin complained of anxiety, irritability, fatigue and myalgias. These 
symptoms could not be clearly related to ribavirin and also occurred in 
some placebo recipients. The reasons for these complaints are not clear.  
However, many medications can cause such non-specific complaints and 
these will be mentioned in the consent form. 
k. Retinal Changes. In rats given ribavirin for 12 to 24 months, retinal 
atrophy and degeneration were noted on ophthalmologic examination as 
well as microscopically. These findings led to a routine use of 


 
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44
ophthalmologic examinations at the beginning and end of therapy and in 
follow up in the U.S. multicenter trial of ribavirin for chronic hepatitis C. 
In that study there was no increase in retinal changes or cataracts in the 
treated patients compared to controls. 
l. Photosensitivity. Ribavirin increases skin sensitivity to sunlight. This can 
lead to a range of problems from mild irritation with redness and pruritus 
to severe blistering sunburn. This risk extends to indirect sunlight, such as 
through a windshield or window. Patients are advised to use sunscreen and 
to cover up sun-exposed areas during treatment. This is of particular 
concern in fair-skinned individuals. 
(5) The risks of the combination of ribavirin and chlorcyclidine HCl. As this the first 
study utilizing the combination of chlorcyclidine HCl and ribavirin for the therapy 
of chronic HCV infection, the side effects of combining the two drugs are not 
known. However, chlorcyclizine HCl is an FDA approved antihistamine therapy 
approved for temporary relief of allergy symptoms, and is also an over-the-
counter drug. To the best of our knowledge, no reports have been described of 
significant side-effects with the combination of ribavirin and chlorcyclizine. Thus, 
we do not anticipate significant side effects aside from each drug’s individual side 
effect profile mentioned above. 
Adverse Events and Modifications of Dose of Chlorcyclizine HCl and Ribavirin 
 
Patients will be monitored side effects. Discontinuation of chlorcyclizine HCl or 
ribavirin will be based upon the scoring of adverse events shown in table 2. The scoring 
of toxicity will be performed from the CTCAE Version 3.0 with modifications for 


 
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45
leukocytes, hemoglobin, hematocrit, platelets, prothrombin time, partial thromboplastin 
time, ALT, AST and bilirubin. These variables have been modified because the original 
version was designed by the National Cancer Institute (NCI) with use for cancer trials 
and not for clinical trials in liver disease. The modified version to be utilized for this 
clinical trial accounts for accepted variations of liver tests used in various other liver 
disease clinical trials by the Liver Diseases Branch. Factor that will lead to 
discontinuation of chlorcyclizine HCl with or without ribavirin include pregnancy, any 
grade 3 (except leukocyte and platelet categories) or any grade 4 adverse events or any 
adverse event, which, in the opinion of the investigator, places the patient at increased 
risk. Drug discontinuation may also be based on individual clinical presentations of each 
subject. For example, AST and ALT values will be evaluated in the context of each 
individual’s baseline values. Rather than utilizing specific cutoff values, which may not 
be in the best interest of each subject, if the investigator identified a significant elevation 
in liver related laboratory tests which may jeopardize the patient’s safety, the drug may 
be discontinued. If the female becomes pregnant, the patient’s obstetrician will be 
provided with the standard of care guidelines to prevent HCV transmission. 
Chlorcyclizine HCl with or without ribavirin will not be restarted unless another cause 
for the abnormality or symptom is found. 
Table 2.  Scoring of toxicity for dose modifications. Scoring of toxicity from the 
CTCAE Version 3.0, with modifications for leukocytes, hemoglobin, hematocrit, 
platelets, prothrombin time, partial thromboplastin time, ALT, AST and bilirubin. 
Normal ranges for values at the NIH Clinical Center are used. 
 
Scoring of toxicity for dose modification 


 
Version:  08-17-2018 
46
 
Grade 
Adverse 
Event 
Name 
1 
2 
3 
4 
5 
Allergic 
reaction/ 
hypersensitivi
ty (Including 
drug fever) 
Allergic 
Reaction 
Transient 
flushing 
or rash; 
drug fever 
<38 C 
(<100.4 F) 
Rash; 
flushing; 
urticarial; 
dyspnea; 
drug fever 
>38 C 
(>100.4F F) 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
medications(s) 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
Anorexia 
Anorexia 
Loss of 
appetite 
without 
alteration 
in eating 
habits 
Oral intake 
altered 
without 
significant 
weight loss 
or 
malnutrition; 
oral 
nutritional 
supplements 
indicated 
Associated with 
significant weight 
loss or malnutrition 
(e.g., inadequate 
oral caloric and/or 
fluid intake); IV 
fluids, tube 
feedings or TPN 
indicated 
Life 
threatening 
consequences 
Death 
Anxiety 
Anxiety 
Mild 
symptoms
; 
interventio
n not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe symptoms; 
limiting self care 
ADL; 
hospitalization not 
indicated 
Life-
threatening; 
hospitalizatio
n indicated 
Death 
Nausea 
Nausea 
Loss of 
appetite 
without 
alteration 
in eating 
habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration 
or 
malnutrition; 
IV fluids 
indicated 
<24 hrs. 
Inadequate oral 
caloric or fluid 
intake; IV fluids, 
tube feedings, or 
TPN indicated >24 
hrs. 
Life 
threatening 
consequences 
Death 
Agitation 
Agitation 
Mild 
mood 
alteration 
Moderate 
mood 
alteration 
Severe agitation; 
hospitalization not 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 


 
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47
Fatigue 
(asthenia, 
lethargy, 
malaise) 
Fatigue 
Mild 
fatigue 
over 
baseline 
Moderate or 
causing 
difficulty 
performing 
some ADL 
Severe fatigue 
interfering with 
ADL 
Disability 
_____ 
Depressed 
level of 
consciousness 
Depressed 
level of 
consciousne
ss 
Decreased 
level of 
alertness 
Sedation; 
slow 
response to 
stimuli; 
limiting 
instrumental 
ADL 
Difficult to arouse 
Life-
threatening 
consequences 
Death 
Somnolence 
(excessive 
sleepiness and 
drowsiness) 
Somnolence 
Mild but 
more than 
usual 
drowsines
s or 
sleepiness 
Moderate 
sedation; 
limiting 
instrumental 
ADL 
Obtundation or 
stupor 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Tremor 
(uncontrolled 
shaking 
movement of 
the whole 
body or 
individual 
parts) 
Tremor 
Mild 
symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe symptoms, 
limiting self care 
ADL 
_______ 
_______ 
Dry Mouth  
Dry Mouth 
Symptoma
tic without 
significant 
alteration 
(e.g., dry 
or thick 
saliva) 
Moderate 
symptoms; 
oral intake 
alterations 
(e.g., copious 
water, other 
lubricants, 
diet limited 
to purees 
and/or soft, 
moist foods) 
Inability to 
adequately aliment 
orally; tube feeding 
or TPN indicated 
_______ 
_______ 
Akathisia 
(uncomfortabl
e feeling of 
inner 
restlessness 
and inability 
to stay still) 
Akathisia 
Mild 
restlessnes
s or 
increased 
motor 
activity 
Moderate 
restlessness 
or increased 
motor 
activity; 
limiting 
instrumental 
ADL 
Severe restlessness 
or increased motor 
activity; limiting 
self care ADL 
_______ 
_______ 
Concentration 
Concentrati
Mild 
Moderate 
Severe impairment 
_______ 
_______ 


 
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48
Impairment 
on 
impairment 
inattention 
or 
decreased 
level of 
concentrat
ion 
impairment 
in attention 
or decreased 
level of 
concentration
; limiting 
instrumental 
ADL 
in attention or 
decreased level of 
concentration; 
limiting self care 
ADL 
Dysesthesia 
(distortion of 
sensory 
perception, 
resulting in an 
abnormal & 
unpleasant 
sensation) 
Dysesthesia 
Mild 
sensory 
alteration 
Moderate 
sensory 
alteration; 
limiting 
instrumental 
ADL 
Severe sensory 
alteration; limiting 
self care ADL 
_______ 
_______ 
Dizziness 
(lightheadedn
ess, 
unsteadiness, 
giddiness, 
spinning or 
rocking) 
Dizziness 
Mild 
unsteadine
ss or 
sensation 
of 
movement 
Moderate 
unsteadiness 
or sensation 
of 
movement; 
limiting 
instrumental 
ADL 
Severe unsteadiness 
or sensation of 
movement; limiting 
self care ADL 
_______ 
_______ 
Paresthesia 
(tingling, 
numbness, 
pressure, cold, 
warmth in the 
absence of 
stimulus) 
Paresthesia 
Mild 
symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe symptoms; 
limiting self care 
ADL 
_______ 
_______ 
Urinary 
retention 
Urinary 
retention 
Urinary, 
suprapubi
c or 
intermitte
nt catheter 
placement 
not 
indicated; 
able to 
void with 
some 
residual 
Placement of 
urinary, 
suprapubic or 
intermittent 
catheter 
placement 
indicated; 
medication 
indicated 
Elective operative 
or radiologic 
intervention 
indicated; 
substantial loss or 
affected kidney 
function or mass to 
urinate 
Life-
threatening 
consequences; 
organ failure; 
urgent 
operative 
intervention 
indicated 
Death 
 
Diarrhea 
Diarrhea 
Increase 
of <4 
stools per 
Increase of 
4-6 stools per 
day over 
Increase of >6 
stools per day over 
baseline; 
Life 
threatening 
consequences 
Death 


 
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49
day over 
baseline; 
mild 
increase in 
ostomy 
output 
compared 
to baseline 
baseline; IV 
fluids 
indicated 
<24 hrs.; 
moderate 
increase in 
ostomy 
output 
compared to 
baseline; not 
interfering 
with ADL 
incontinence; IV 
fluids >24 hrs.; 
hospitalization; 
severe increase in 
ostomy output 
compared to 
baseline; interfering 
with ADL 
(e.g. 
hemodynamic 
collapse) 
Distention/blo
ating, 
Abdominal 
Distention 
Asympto
matic 
Symptomatic 
but not 
interfering 
with GI 
function 
Symptomatic 
interfering with GI 
function 
______ 
______ 
Vomiting 
Vomiting 
1 episode 
in 24 hrs. 
2-5 episodes 
in 24 hrs.; IV 
fluids 
indicated 
<24 hrs. 
>5 episodes in 24 
hrs.; IV fluids, or 
TPN indicated >24 
hrs. 
Life 
threatening 
consequences 
Death 
Cardiac 
Conduction 
Disorder 
(pathological 
irregularities 
in the cardiac 
conduction 
system) 
Cardiac 
conduction 
disorder 
Mild 
symptoms
; 
interventio
n not 
indicated 
Moderate 
symptoms 
Severe symptoms; 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Creatinine 
Creatinine 
>ULN-
1.5X ULN 
>1.5-2.0X 
ULN 
>2.0-6.0X ULN 
>4.0X ULN 
Death 
Glomerular 
Filtration Rate 
GFR 
<75-60% 
LLN 
<60-40% 
LLN 
<40% LLN, chronic 
dialysis not 
indicated 
Chronic 
dialysis or 
renal 
transplantatio
n indicated 
Death 
Glucose, 
serum-low 
(hypoglycemi
a) 
Hypoglyce
mia 
<LLN-55 
mg/dL 
<LLN-3.0 
mmol/L 
<55-40 
mg/dL <3.0-
2.2 mmol/L 
<40-30 mg/dL 
<2.2-1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Triglyceride, 
serum-high 
(hypertriglyce
ridemia) 
Hypertrigly
ceridemia 
>ULN-
2.5X ULN 
>2.5-5.0X 
ULN 
>5.0-10X ULN 
>10X ULN 
Death 
Pain-
Pain-
Mild pain 
Moderate 
Severe pain; pain or Disabling 
_____ 


 
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50
Headache 
Headache 
not 
interfering 
with 
function 
pain; pain or 
analgesics 
interfering 
with 
function, but 
not 
interfering 
with ADL 
analgesics severely 
interfering with 
ADL 
Pain-
Abdominal 
Pain-
Abdominal 
Mild pain 
not 
interfering 
with 
function 
Moderate 
pain; pain or 
analgesics 
interfering 
with 
function, but 
not 
interfering 
with ADL 
Severe pain; pain or 
analgesics severely 
interfering with 
ADL 
Disabling 
______ 
Infection-
Upper Airway 
NOS 
Infection-
Upper 
Airway 
NOS 
Mild 
Moderate  
Severe 
Life-
threatening; 
disabling 
Death 
Infection-
Nasopharyngi
tis 
Infection-
Nasopharyn
gitis 
Mild 
Moderate 
Severe 
Life-
threatening; 
disabling 
Death 
Leukocytes 
(total WBC) 
Leukocytes 
<2000/m
m3 
<2.0X109/
L 
<1500-
1000/mm3 
<1.5-
1.0X109/L 
<1000-500/mm3 
1.0-0.5X109/L 
<500/mm3 
<0.5X109/L 
Death 
Hematocrit 
Hematocrit 
<34% 
<30% 
<28% 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Platelets 
Platelets 
<70,000/
mm3-
60,000/m
m3 <70.0-
60.0X109/
L 
<60,000-
40,000/mm3 
<60.0-
40.0X109/L 
<40,000-
25,000/mm3 <40.0-
25.0X109/L 
<25,000/mm3 
<25.0X109/L 
Death 
INR 
(International 
Normalized 
Ratio of 
Prothrombin 
Time) 
INR 
>1-
1.5XULN 
>1.5-2XULN >2XULN 
_____ 
_____ 


 
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51
PTT (Partial 
Thromboplast
in Time) 
PTT 
>1-1.5 
ULN 
>1.5-2X 
ULN 
>2X ULN 
______ 
______ 
Bicarbonate, 
serum-low 
Bicarbonate, 
serum-low 
<LLN-
18mmol/L 
<18-15 
mmol/L 
<15-11 mmol/L 
<11 mmol/L 
Death 
Acidosis 
(metabolic or 
respiratory) 
Acidosis 
pH<norma
l, but >7.3 
______ 
pH<7.3 
pH<7.3 with 
life 
threatening 
consequences 
Death 
Alkaline 
Phosphatase 
(U/L) 
Alkaline 
Phosphatase 
>ULN-
2.5X ULN 
>2.5-5.0X 
ULN 
>5.0-20.0X ULN 
>20.0 X ULN 
______ 
Bilirubin 
(hyperbilirubi
nemia) 
Bilirubin 
>ULN-
1.5X ULN 
>1.5-3.0X 
ULN 
>3.0-10.0X ULN 
>10.0X ULN 
______ 
Albumin, 
serum-low 
(hypoalbumin
emia)  
Hypoalbumi
nemia 
<LLN-
3g/dL 
<LLN-
30g/L 
<3-2 g/dL 
<30-20 g/dL 
<2 g/dL  
<20g/L 
_______ 
Death 
AST, SGOT 
(serum 
glutamine 
oxaloacetic 
transaminase) 
AST 
>3-5X 
patient’s 
baseline 
values 
>5-10X 
patient’s 
baseline 
values 
>10-20X patient’s 
baseline values 
>20X 
patient’s 
baseline 
values 
Death 
ALT, SGPT 
(serum 
glutamine 
pyruvic 
transaminase) 
ALT 
>3-5X 
patient’s 
baseline 
values 
>5-10X 
patient’s 
baseline 
values 
>10-20X patient’s 
baseline values 
>20X 
patient’s 
baseline 
values 
Death 
 
 
Data and Safety Monitoring 
 
 
Data and safety will be monitored by the principal and associate investigators in 
this protocol. Data and safety are reviewed weekly in clinical research rounds by the 
Liver Diseases Branch, NIDDK. These rounds are separate from regular clinical rounds 
and consist of review of all study patients including flow sheets of major safety and 
efficacy measurements. The rational for not using an outside data and safety monitoring 
committee is that this is a small, single center study using a medication with defined side 


 
Version:  08-17-2018 
52
effects. All measurements and tests are well established in clinical medicine. However, 
this study may be subject to audits to ensure compliance with the protocol and applicable 
regulatory requirements consistent with the NIDDK monitoring plan.  Audit results will 
be reported to the Principal Investigator for further reporting as appropriate.  Study 
documents and pertinent hospital or clinical records will be reviewed to verify that the 
conduct of the study is consistent with the protocol plan. Yearly reports are made to the 
NIDDK/NIAMS IRB describing any issues with safety and efficacy 
 
Adverse Events (definitions and classification) 
Definitions 
Adverse Event (AE): Any untoward medical occurrence in a human subject, including 
any abnormal sigh (for example, abnormal physical exam or laboratory findings), 
symptom, or disease, temporally associated with the subjects participation in research, 
whether or not considered related to the subject’s participation in the research. 
Serious Adverse Event (SAE): is any adverse event that: 
1. Results in death, 
2. Is life-threatening (places the subject at immediate risk of death from the 
event as it occurred) 
3. Results in inpatient hospitalization or prolongation of existing hospitalization 
4. Results in a persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions 
5. Results in a congenital anomaly/birth defect, OR 


 
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53
6. Based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition. 
Suspected adverse reaction (SAR): For the purposes of safety reporting, if evidence 
exists to suggest a causal relationship between the drug and the adverse event, it may be 
reported. 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is a 
Suspected Adverse Reaction that is both Serious and Unexpected. 
Unanticipated problem (UP): Any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved 
in the research); and 
3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. 


 
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Expected Adverse Events become unanticipated problems when they occur at a 
greater frequency or severity than was previously known.  
 
Unanticipated problems that are not also an Adverse Event: Unanticipated 
problems that are not also AEs may involve greater risk of social or economic harm 
(to subjects or others) rather than physical/psychological harm. 
Protocol Deviation (PD): Any change, divergence, or departure from the IRB approved 
research protocol.  A protocol deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety welfare or rights of subjects or others.  
Assessment of Adverse Event Severity and Relationship to Treatment 
Events will be collected, tracked and evaluated for expectedness, seriousness, severity 
and relatedness.   
Investigators will “grade” the severity of all AEs using the CTCAE Version 3.0 as 
described earlier (Table 2).  
The nomenclature for assessing the causal relationship between an AE and the study drug 
is listed in Table 3.  The investigator / sponsor will determine the category that overall 
best “fits” the relationship between the AE and the study drug.  
Table 3.  AE or SAE Relatedness 
Relatedness 
Description 


 
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Unrelated 
• No temporal association to study drug. 
• An alternate etiology has been established.  
• The event does not follow the known pattern of response to 
study drug. 
• The event does not reappear or worsen with re-challenge. 
Probably not 
related / remotely 
related 
• No temporal association to study drug. 
• Event could readily be produced by clinical state, 
environmental or other interventions. 
• The event does not follow the known pattern of response to 
study drug. 
• The event does not reappear or worsen with re-challenge. 
Possibly related 
• Reasonable temporal relationship to study drug. 
• The event is not readily produced by clinical state, 
environmental, or other interventions. 
• The event follows a known pattern of response to the study 
drug or as yet unknown pattern of response. 
Probably related 
• There is a reasonable temporal association with the study 
drug. 
• The event is not readily produced by clinical state, 
environmental, or other interventions. 
• The event follows a known pattern of response to the study 
drug. 
• The event decreases with de-challenge. 
Definitely related 
• There is a reasonable temporal relationship to the study 
drug. 
• The event is not readily produced by clinical state, 
environmental, or other interventions. 
• The event follows a known pattern of response to the study 
drug. 
• The event decreases with de-challenge and recurs with re-
challenge. 
 
Assessment of Adverse Event Outcome 
The clinical investigator will follow every AE to a satisfactory outcome or stabilization 
of the event. This is particularly applicable to SAEs.   
Actions taken in response to an AE and follow-up results (including lab results) will be 
recorded in the subject’s medical record.  When subjects are discontinued from the study 


 
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due to an AE, relevant clinical assessments and laboratory tests will be repeated as 
necessary until final resolution or stabilization occurs. 
Waiver of Reporting to the IRB of Anticipated Adverse Events 
Anticipated non-UP adverse events and serious adverse events will not be reported to the 
IRB at each occurrence unless they occur at a rate or severity greater than that known to 
occur in the natural history of chronic hepatitis C infection.8,75 However, any episodes of 
acute hepatic decompensation or newly diagnosed hepatocellular carcinoma during the 
subjects participation in this trial will be reported to the IRB expeditiously.  This waiver 
clarifies for the investigator(s) that these anticipated AEs and SAEs will be tracked, 
reported annually to the Sponsor and IRB, but do not need to be reported within the 14 
day period as with the UPs in the section described below. 
Required time frames for investigator expeditious reporting to the IRB and the 
Institute Clinical Director (CD): 
The PI will report unanticipated problems, deaths, and protocol deviations to the IRB 
Chair and the CD according to the following schedule: 
A.  Serious Events 
Serious unanticipated problems and protocol deviations will be reported to 
the IRB Chair and the CD, as soon as possible, preferably by phone or 
secure email and in writing not more than 7 days after the PI first learns of 
the event. Any other SAE unrelated to the research procedures associated 
with this protocol will not be reported expeditiously. 
B.  Non-Serious Events 


 
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All protocol unanticipated problems that are not serious will be reported to 
the IRB Chair and the CD, in writing, not more than 14 days after the PI 
first learns of the event. 
 
Non-serious protocol deviations that result from normal subject scheduling 
variations or technical issues associated with sampling that does not 
impact the health of the subject or the interpretation of the study data will 
not be reported.  All other protocol deviations that are not serious will be 
reported to the IRB in writing, not more than 14 days after the PI first 
learns of the event. 
C.  Deaths 
All deaths (whether or not they are unanticipated problems) will be 
reported to the CD and IRB as soon as possible preferably by phone or 
secure email and in writing not more than 7 days after the PI first learns of 
the event.   
 Investigator’s reports to the IRB at the time of continuing review 
A. All unanticipated problems will be reported.   
B. All serious protocol deviations will be reported.  Non-serious protocol 
deviations that result from normal subject scheduling variations or technical 
issues associated with sampling that does not impact the health of the subject 
or the interpretation of the study data will not be reported.  Other non-serious 
protocol deviations will be tracked, summarized and reported at the time of 
continuing review. 


 
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C. All adverse events thought to be possibly, probably, or definitely related to 
study drug will be summarized, tracked, and reported at the time of 
continuing review.  Adverse events that arise after the Informed Consent is 
signed until 30 days after the last dose of study drug will be reported.  Any 
adverse events with known relation to the natural history of the disease or to 
other pre-existing conditions will not be reported unless they occur at a rate 
or severity greater than that known to occur in the natural history of liver 
disease related to chronic HCV infection.  Any accident, which results in an 
AE and is unrelated to the protocol, will not be reported.    
Conflict of Interest 
The Principal Investigator will assure that each associate investigator listed on the protocol title 
page receives a copy of the NIH Guide to preventing conflict of interest.  Any potential conflicts 
will be reported to the IRB and the resolution of the conflict summarized.    
 
Recruitment Strategy 
We will advertise on the NIH web site and through local physicians and clinics for 
patients. 
Recruitment of Women, Minority Individuals and Children 
 
In recent trials of therapy for chronic hepatitis C performed by the Liver Diseases 
Branch, NIDDK, for the chronic hepatitis C (02-DK-0065), 35 of the 87 patients (40%) 
were women and 26 (30%) were minority individuals (17 African-Americans, 5 
Hispanic-Americans and 3 Asian-Americans). Response rates to therapy have been lower 
in African American than other ethnic/racial groups in studies of interferon monotherapy, 


 
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but have been reported to be similar to other groups with interferon-ribavirin and 
interferon-ribavirin-direct acting antiviral combination therapy. 
 
Hepatitis C is more common in men than women perhaps accounting for the 
higher proportion of males in most studies of hepatitis C. In the current study, we expect 
a slight under-representation of young women. The reason for this is the potential 
teratogenicity of ribavirin. We will not include women who intend to become pregnant 
during the 1-2 years of this study. In our recent study of alpha interferon in chronic 
hepatitis C, only 6 of the 87 patients enrolled were women below the age of 45 years and 
only 1 of the 6 expressed interest in having children in the future. 
The epidemiology of hepatitis C in the United States indicates that this disease is 
more common among blacks and Hispanic whites than among non-Hispanic whites.76 A 
major determining factor in the prevalence of hepatitis C is lower socio-economic class.  
To increase the representation of minority individuals in this trial, we will write to all 
hepatologists and gastoenterologists in the Washington DC area advertising this study. 
This study will be limited to adults with chronic hepatitis C. The reasons for 
excluding children are that hepatitis C is uncommon in children and ribavirin has not 
been approved for use or adequately evaluated in children with hepatitis C. 
Risk / Benefit Assessment 
This study involves greater than minimal risk but offers the prospect of direct benefit to 
subjects and is likely to yield generalizable knowledge about hepatitis C.  


 
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Informed consent 
The investigational nature and research objectives of the trial, the procedures and its 
attendant risks and discomforts, and alternative forms of therapy will be carefully 
explained to the subject and a signed informed consent document will be obtained prior 
to entry onto this study.  The principle investigator, an associate investigator, or the 
attending protocol investigator will lead this discussion.  Informed consent will be 
obtained using forms approved by the Institutional Review Board (IRB) in accordance 
with good clinical practice for research involving human subjects.  Each patient will be 
informed of the right of the patient to withdraw from the trial at any time without 
prejudice.  After this explanation and before entering the trial, the patient will voluntarily 
sign and date an informed consent. 
 
At any time during participation in the protocol that new information becomes available 
relating to risks, adverse events, or toxicities, this information will be provided orally in 
writing to all enrolled or prospective patient participants.  Documentation will be 
provided to the IRB and if necessary, the informed consent amended to reflect relevant 
information. 
 
Subjects will be provided with a copy of the informed consent that explains the purpose 
of the study, the medication(s) used in the study, procedures, and assessments.  Subjects 
will also be provided with the telephone numbers of the investigator and qualified 
personnel who can assist with their questions and concerns. 
 


 
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Research Use, Storage and Disposition of Human Subject’s Samples and Data 
Patients will have serum stored from selected time points during this study. These 
specimens will be used for repeat virological testing and special tests as needed. Samples 
may be used to assess factors associated with response or non-response to therapy. 
These samples will be tested in the Liver Diseases Branch or the routine clinical and 
surgical pathology services of the Clinical Center. If residual samples are evaluated by 
outside collaborators in the future, this will be done so only after all identifying data have 
been removed from all samples. Samples will be numbered and a key to the number 
system will be stored and backed up by the principal investigator of this study. Research 
records and data as well as sera will be stored indefinitely in our locked offices and 
freezers and the medical record department. These materials will be protected and tracked 
by standard operating procedures in the medical record as well as a compulsive filing 
system in our locked offices and freezers. There will be redundant storage of clinical 
information in the medical record department and our offices. Computer files will be 
maintained on password-protected computers and servers. Serum samples will be 
processed and stored by the NIDDK core laboratory facility. These samples will be stored 
in locked freezers inside locked rooms. Access to these samples will require written 
approval from the Liver Diseases Branch chief, and will be recorded by the LDB and by 
the core laboratory. This should minimize the risk of loss or destruction of information 
and specimens. If that were to occur we would report it to the IRB. We do not plan to 
destroy this personal medical information or research subject sera after completion of the 
study because it may be critically important for physicians (here or elsewhere) to have 
access to this information when caring for these patients in the future.  


 
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Remuneration/Compensation 
No compensation is offered to study participants. 
Alternatives to Therapy 
For patients infected with chronic hepatitis C, genotype 1, the FDA approved 
combination therapy with two direct-antiviral agents (boceprevir and telaprevir) in 
combination with pegylated interferon and ribavirin.  The rate of sustained virological 
response with this triple therapy is 65-75%, which is significantly improved from the 40-
50% with peginterferon and ribavirin. Thus, the recent guidelines issued by the American 
Association for the Study of Liver Disease state that the optimal regimen to treat 
previously untreated patients with chronic hepatitis C, genotype 1, is boceprevir or 
telaprevir in combination with peginterferon and ribavirin.9 
However, not all patients with genotype 1 infection will be able or willing to 
tolerate the DAAs and/or peginterferon and their associated side effects, which can be 
significant. Others may not have access to the medications. Patients who are not 
interested in interferon-free regimens and interested in the standard of care treatment 
regimen may undergo treatment with a DAA-containing regimen, by a practitioner 
outside the NIH, in a clinical trial elsewhere or in studies at the Liver Diseases Branch if 
these become available. These options will be discussed clearly with the patients and will 
be documented in the patients’ chart. If, following this discussion, a patient still elects to 
enroll in this study, knowing that he/she is receiving treatment that is not the current 
standard of care. Neither refusal to enroll in the current study nor enrollment in the 
current study will be an exclusion criterion in future studies.  Patients who choose to 


 
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enroll in this study will be eligible for subsequently planned Liver Diseases Branch 
clinical trial utilizing interferon-free DAA-containing regimens. The subsequent trial is 
currently in the planning stages and is designed as definitive therapy for sustained 
virological response.  Participation in the current study will not exclude patients from and 
in fact they will be offered the opportunity to participate in the planned DAA study. 
For patients chronically infected with all other genotypes of HCV, the current 
standard of care therapy involves treatment with combination therapy of peginterferon 
and ribavirin for varying durations of therapy.8  Patients who are not interested in 
interferon-free regimens and interested in the standard of care treatment may undergo 
therapy by a practitioner outside the NIH, in a clinical trial elsewhere or in other studies 
at the Liver Diseases Branch if these become available. These options will be discussed 
clearly with the patient and will be documented in the patients’ chart. If, following this 
discussion, the patient still elects to enroll in this study, knowing that he/she is receiving 
treatment that his not the current standard of care. Neither refusal to enroll in the current 
study nor enrollment in the current study will not be an exclusion criterion in future 
studies. 
 
 


 
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Appendix 1 
SYMPTOM SCALE 
 
 
Name: ______________________   Date: (M/D/Yr) ____/____/____   
 
 
Mark with an "x" the place on the lines below that best describes how you 
have felt during 
the past week.  
 
             None  
 
 
 
 
 
 
 Worst ever           
 
 
        
 
 
 
 
 
 
      
Drowsiness  
 
|____________________________________________________| 
 
Nausea 
 
 
|____________________________________________________| 
 
Dryness of Mouth 
 
|____________________________________________________| 
 
Headaches  
 
|____________________________________________________| 
 
Light Headedness 
 
|____________________________________________________| 
 
Nervousness 
 
|____________________________________________________| 
 
Inability to Concentrate 
 
|____________________________________________________| 
 
Numbness or Tingling 
 
|____________________________________________________| 
 
Difficulty Urinating 
 
|____________________________________________________| 
 
 
In general, how do you feel overall? 
 
     Very Good  
 
 
 
 
 
                   Awful 
 
|____________________________________________________|


 
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