A Randomized, Parallel-group, Pilot Study on the Effect of Using the Portal724-Medication Electronic Medication System (MEMS) Smart Cap With Real-time Medication Adherence Among Patients Being Treated With Grazoprevir/Elbasvir
Conditions: Adherence
Sponsor: Saint Michael's Medical Center

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Title of the Study :  
A Randomized, Parallel group, Pilot Study on the Effect of using the Portal724-Medication 
Electronic Medication System (MEMS) Smart Cap with Real-time Clinician Feedback on  
Medication Adherence  Among  Patients   Infected with Chronic  Hepatitis C (HCV) Being 
Treated with Grazoprevir/Elbasvir 
 
  
Investigators :  
Jihad Slim, M.D,  Raymund Vincent S. Sison, M.D.,  
  
Introduction / Rationale of the Study 
 
Hepatitis C and Adherence 
  
Hepatitis C virus (HCV) infection is a very important  health problem worldwide. Majority of the 
estimated 160 million people infected globally  are unaware of their affliction [1]. It is a leading 
cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In the United States 
alone, HCV infection is the most common chronic blood-borne infection, affecting about 3.2 
million individuals [2]. It is most prevalent among persons born from 1945-1965, most of whom 
acquired it in the 1970’s and 1980’s, since identification of HCV only occurred in 1989 as 
specific pathogen and blood products screening for the virus was non-existent [4]. Because at 
least 80% of those who acquire HCV will become chronically infected, it is the number one 
cause of chronic liver disease and liver cancer in the U.S. [3], and has surpassed HIV in terms of 
number of deaths [5] and the approximate U.S. economic burden is about $6.5 billion, inclusive 
of patients needing liver transplantation [2].  
 
Steps have been taken to decrease this present and future healthcare and economic burden. 
Shortly after discovery of the virus, blood and blood-derived products started to be screened 
which led to a dramatic decrease in new incident cases. By 2001, the Needlestick Safety and 
Prevention Act was passed in the U.S., further deceasing new cases [7]. The CDC has also 
recommended a one-time screening for persons born between 1945 and 1965, as this segment of 
the population is at increased risk for HCV infection due to non-screening of blood products 
before 1989. Despite these measures, the Centers for Diseases Control and Prevention (CDC) 
estimates there are still about 17,000 new cases occurring yearly [3].  
 
Treatment of HCV has been the main focus of clinical research since vaccine research has 
proved to be difficult, as well as the necessity of treating undiagnosed individuals. Among the 7 
major HCV genotypes, genotype 1 is by far the most prevalent in Europe and in the United 
States. It has historically been the most difficult type to treat. Prior to 2011, the standard 
treatment for HCV was a combination of once-weekly injectable Pegylated Interferon with daily 

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oral Ribavirin to be taken for 48 weeks. The cure rate, measured as sustained virologic response 
(SVR) for this regimen is a dismal 40-50% [6]. Adherence to the treatment was difficult for 
many patients due to the length of therapy and the associated side effects of both interferon and 
ribavirin. The addition of new directly acting agents (DAA), Boceprevir and Telaprevir in 2011, 
revolutionized HCV treatment, increasing cure rates up to 75%. However, adherence continued 
to plague therapy because of side effects and thrice-daily dosing.  
 
In 2013, 2 new DAA’s were FDA-approved, ushering in the interferon-free era of HCV therapy. 
Sofosbuvir and Simprevir are once daily oral agents with much fewer side effects than any 
previous anti-HCV medication. Ledipasvir, another oral DAA, has been approved by the FDA in 
October 2014, to be given as a single tablet regimen together with Sofosbuvir. The length of 
treatment has also decreased, from 48 weeks to 12-24 weeks, and clinical trials of the 
combination of these drugs showed cure rates above 90%, with increased tolerability and safety 
[8]. Other DAA’s since then have been approved by the FDA such as the combinations of 
ombitasvir/paritaprevir/ritonavir (Viekira Pak) and Grazopravir/Elbasvir (Zepatier). 
 
are in clinical trials or under FDA review, increasing the chances that more patients can be cured 
from HCV infection.  
 
Adherence, however, has been a major challenge in the treatment of Hepatitis C infection, 
especially before Sofosbuvir and Simprevir were introduced. Aside from side effects, Ribavirin 
has to be taken twice daily, while Interferon is injectable. Boceprevir and Telaprevir also had 
their fair share of side effects, drug interactions and multiple daily dosing which impaired 
treatment adherence. Studies on these medications have shown that the proportion of missed 
doses increases over time, and are associated with failure of treatment [11-14]. In one analysis of 
2 clinical trials, patients who took their medications  80-85% of the time achieved SVR 86-90% 
of the time, while those < 80% adherent attained SVR only 8-32% of the time [28]. Aside from 
HCV medication-related issues, these patients may have other co-morbidities such as psychiatric 
disorders which can negatively influence patient compliance [18]. The matter of polypharmacy 
in patients co-infected with HIV and HCV can also be a major concern in terms of adherence 
[19].  
 
Treatment adherence studies for Hepatitis C were mostly small studies of patients taking 
Pegylated-Interferon and Ribavirin [11-14]. These reports showed higher treatment success for 
patients who were at least 80-90% compliant, with most failures reported in patients with 
compliance rate around 70-80%. However, most of these also relied on patient self-reporting, pill 
counting and pharmacy refill data, which are inherently imprecise.  
 
With the enhanced tolerability, lower drug-drug interactions, side effect profile and once daily 
dosing of the new DAA’s, adherence has improved but is still an area of  concern. In registration 
clinical trials, those who relapsed on Sofosbuvir were patients who did not comply to their 
treatment regimen [15]. The same holds true for Simeprevir, and these patients also developed 
resistant HCV [16]. With the standard 12-weeks  course of these medications costing in the range 

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of $100,000 - $140,000, patients needing repeat treatment after relapsing can be very expensive 
[10], making treatment compliance even more important. It would also be very costly for 
treatment-experienced patients to be re-treated because of failure due to compliance.  
 
We are conducting this study in the hope that we can ensure medication adherence to effectively 
and cost-effectively treat patients afflicted with chronic Hepatitis C infection. We have chosen 
HCV since the treatment is finite course (i.e. 12 weeks)  which will enable us to measure the 
efficacy of using Medication Electronic Monitoring System (MEMS) with real-time feedback in 
terms of increasing adherence within a specific time limit. For this study, we are going to use 
Grazopravir/Elbasvir (Zepatier), which has an inherent advantage of being a combination pill 
taken only once a day. 
 
 
 
Medication Electronic Monitoring System (MEMS) 
 
Medication Electronic Monitoring System (MEMS) has been used to measure patient 
compliance to treatment more accurately, especially in clinical trials. It has been determined to 
be a valid and objective tool to measure medication adherence [24]. Its use to improve 
compliance has been studied in patients with HIV [20-24], heart failure [26], smoking cessation 
therapy [27], and in the treatment of alcohol dependence [28]. A few studies have used MEMS in 
syringes and pill bottle caps to determine proper anti-HCV medication intake [14, 17], but data 
review and feedback to the patient were only done at each study visit. Real-time health care 
provider-to-patient feedback may be able to decrease non-adherence but  robust studies in this 
area are still lacking.  
 
There are several different types and manufacturers of commercially available MEMS. 
For this study, we are proposing to use the Portal724-MEMS Service. The Portal724-MEMS is a 
TURNKEY SERVICE.  It integrates medication bottle, Smart Cap, Pill Dispenser, Embedded 
Computer, Embedded Cellular Modem and Tamper Proof apparatus.  This device is capable of 
transmitting pill dispensing events from the patient’s home to the Cloud over Cellular and IP 
networks.  The transmission is done in real time if cellular coverage is above 1-bar, but if cell is 
not available or if the signal is below threshold, then the device Store-and-Forward feature is 
automatically activated. 
The bottle cap records the number of Pill Dispenses, with date and time and Device ID. The 
purpose of this electronic monitoring is to estimate compliance with medication regimen.  
Electronic assisted compliance is not the sole indicator of MEMS, it is also used in conjunction 
with answers about demographics, clinical state and symptoms to learn more about the patient 
characteristics that influence whether a medication regimen is adhered to. 
Portal724-MEMS is HIPAA Complaint and ISO27001 Certified.  The Electronic Data Capture, 
the Data Transfer and Data Access are all confidential and Secure in every stage of the Data 

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Flow Model. The device to be used in this study is a Smart Cap with Pill Dispensing and 
Integrated Cellular Modem. 
 
 
Objective 
Primary: To determine the effect of the use of Portal724-MEMS Service on medication 
adherence in the treatment of Hepatitis C patients with grazopravir/elbasvir with or without 
Ribavirin, defined as compliance to regimen  95% of the time. 
 
Methods 
  
Study design: Open-label, randomized, single center  pilot study. 
 
Treatment Arms: 
 
Genotype 1a, treatment naïve or PegIFN/RBV experienced without baseline NS5A polymorphisms 
with elbavir/grazoprevir for 12 weeks 
 
Genotype 1a, treatment naïve or PegIFN/RBV experienced with baseline NS5A polymorphisms 
with elbasvir/grazoprevir/ribavirin for 16 weeks 
 
Genotype 1b, treatment naïve or PegIFN/RBV experienced for 12 weeks 
 
Genotype 1a or 1b, PegIFN/RBV/PI-experienced with elbasvir/grazoprevir/ribavirin  for 16 weeks 
 
Genotype 4: treatment naïve with elbasvir/grazoprevir for 12 weeks 
 
Genotype 4: PegIFN/RBV- experienced with elbasvir/grazoprevir/ribavirin  for 16 weeks 
 
  
Proposed number of participants: 40 patients  infected with HCV (20 for each group) 

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Data Collection Time Period: approximately 1 year 
  
Site of Enrollment:  
Liver Center at Saint Michael’s Medical Center. 3rd Floor, Bldg. A, 111 Central Avenue, Newark 
NJ, USA 07102.  
 
In the Liver Center, the main Hepatitis / Infectious Diseases Physician that this study will 
collaborate with is Dr. Jihad Slim, MD. 
 
 Study Patient Population 
    Treatment-naïve and treatment-experienced genotype 1  and 4 HCV patients with or without 
compensated cirrhosis will be enrolled in this study.  
The inclusion criteria for study are as follows: 
1. Male or female 18 years old and above. 
2. Be HCV treatment naïve 
3. HCV RNA PCR >  10,000 IU/L 
4. Confirmed  infection  with Hepatitis C virus (HCV)  by HCV serum antibody assay and 
by HCV Ribonucleic Acid (RNA) Polymerase Chain Reaction (PCR) and Confirmed 
chronicity with 2 PCR’s  6 months apart. 
5. Patients with HCV Genotype 1, 4  
6. Genotype 1a patients will be required to have historical resistance-associated variants 
(RAV) testing ot done at screening if not previously performed 
7. Patients are candidates for treatment of HCV with oral Direct-Acting Agents (DAA) 
8. understand the study procedures, alternative treatments available, risks involved with 
the study, and voluntarily agrees to participate by giving written informed consent 
9. Abstain from sexual intercourse will taking study medications and for 14 days after the 
last dose of study medications 
         
Patients will be  excluded from the study if they  fulfill any of the following criteria: 
 
1. Patient not willing to sign written informed consent 
2. Patients deemed not suitable  for HCV treatment as deemed by the treating physician at 
the liver center 
3. Patients with decompensated liver cirrhosis, defined as follows:  
a. Liver biopsy within the last year showing Scheuer Stage 4 or transient 
elastography (Fibroscan®) in the last year with a reading of >12.5 kPa;  

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                         AND 
b. Any clinical sign of hepatic decompensation such as ascites (fluid in the 
abdomen), jaundice (yellowing of eyes and skin), esophageal varices with 
bleeding (enlarged veins of the esophagus seen on endoscopy) or hepatic 
encephalopathy (tremors, confusion, sleepiness) 
4. Co-Infection with the Hepatitis B virus 
5. Any liver disease of non-HCV etiology such as Hemochromatosis, Wilson’s Disease, 
Alcoholic liver disease or Non-Alcoholic Steato-Hepatitis (NASH) 
6. Hepatocellular carcinoma or any other malignancy 
7. Untreated psychiatric conditions such as major depression, schizophrenia, bipolar 
disorder which in the opinion of the Principal Investigator will not interfere with 
protocol visit and/or procedures 
8. Current and untreated substance abuse (cocaine, opiates, alcohol, marijuana, other 
recreational drugs, controlled substances) 
9. Patient is pregnant or breastfeeding. 
10. Patients unwilling to use cellular phones 
11. Patients unwilling to follow specific instructions for medication intake 
12. Patient has any of the following conditions: 
•Organ transplants (including hematopoietic stem cell transplants) other than cornea 
and hair. 
•Poor venous access that precludes routine peripheral blood sampling required for this 
trial. 
•History of gastric surgery (e.g., stapling, bypass) or subject with a history of 
malabsorption disorders (e.g., celiac sprue disease). 
•History of a medical/surgical condition that resulted in hospitalization within the 3 
months prior to enrollment, other than for minor elective procedures 
•Medical/surgical conditions that may result in a need for hospitalization during the 
period of the study 
•Any medical condition requiring, or likely to require, chronic systemic administration 
of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the 
course of the trial 
13. has exclusionary laboratory values as listed below: 
Noncirrhotic/Cirrhotic Subjects 
Creatinine clearance < 50 mL/min 
Hemoglobin <9.5 g/dL for both male and female subjects 
Platelets <50 x 103/μL 
serum albumin < 3.0 g/dL 
INR >1.7, unless subject has a stable INR on an anticoagulant regimen. 
HbA1c >10% 
ALT >10XULN 
AST >10XULN 
 

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14. is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial. 
 
15. agree to the following: 
•The subject is a female who is not of reproductive potential, defined as a female who 
either: (1) is postmenopausal (defined as at least 12 months with no menses in women 
≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
OR (3) has a congenital or acquired condition that prevents childbearing. 

•The subject is a female who is of reproductive potential and agrees to avoid becoming 
pregnant while receiving study drug and for 14 days after the last dose of study drug 
by complying with one of the following: (1) practice abstinence† from heterosexual 
activity OR (2) use (or have her partner use) acceptable contraception during 
heterosexual activity. Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
•intrauterine device (IUD) 
•vasectomy of a female subject’s male partner 
•contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
•diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
•cervical cap with spermicide (nulliparous women only) 
•contraceptive sponge (nulliparous women only) 
•male condom or female condom (cannot be used together) 
•hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestinonly 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
0455LH 
 
 
Enrollment 
 
Upon signing the informed consent, the following data will be gathered prior to start of 
treatment: demographic data such as age, gender, race/ethnicity, highest educational attainment,  
employment status, co-morbid conditions as documented in the patient’s records, current 
medications, vital signs (blood pressure, heart rate, respiratory rate, temperature), CBC with 
differential count, complete metabolic panel, 12-Lead Electrocardiogram (EKG), Cardiac stress 
test results if applicable, echocardiogram results if applicable, , BMI, baseline HCV RNA PCR 

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viral load, HCV genotype, baseline HCV resistance testing (if indicated), results of the 
Fibroscan® test or liver biopsy. 
 
Once the informed consent is signed and the patient is deemed eligible for treatment, the 
patient will be randomized to either ARM 1 or ARM 2 in a 1:1 ratio.  ARM 1 will be prescribed 
elbasvirir/grazoprevir with/or without ribavirin for 12 or 16 weeks 1 tablet daily with MEMS 
Smart Cap with real-time monitoring.  Arm 2: elbasvir/grazoprevir with/or without ribavirin for 
12 or 16 weeks 1 tablet daily MEMS Smart Cap without real-time monitoring.  
 
For Group 1, the cap of the study drug bottle will be replaced with the Portal724- MEMS Smart 
Cap. A cellular phone per patient will also be provided. The Smart Cap in this study is to be 
outfitted to send messages to a website to which only the investigators and the research assistants 
have access to monitor medication adherence. Patients are to be instructed to open their study 
drug bottles in areas where there is at least 1 cellular signal bar. Patients will also be instructed to 
take their medications at specific agreed upon times. Once the agreed upon times are set, these 
will be programmed into the Smart Caps through a software program. The Smart Caps are 
encoded to not only record each pill bottle opening, it also will transmit an alert to the 
aforementioned website when the bottle is not opened within 2 hours of the agreed upon time. 
This alert is then seen by the Investigator or the Research assistant through a computer or their 
smartphone. The Investigator or Research Assistant in turn calls the cellular phone provided to 
the patient to remind the participant to take their medication, thus providing real-time feedback. 
Group 2 (the control group) will be provided MEMS Smart Cap to record study drug bottle 
opening, but without real-time feedback and will be managed as per the standard of care at the 
Liver Center SMMC. 
 
Patients from both groups will be seen in the Liver Center at Day 1, weeks 2, 4, 8 and 12 from 
start of treatment. They will be seen by Liver Center Physician together with the Investigator and 
Research Assistant at each visit. They will also be counseled about the importance of medication 
adherence at every visit by the Liver Center physician. At each visit, patients are instructed to 
bring with them all of their anti-HCV study drug bottles for pill counting to be done by the 
Investigator and Research Assistant. Patients in ARM 1 will also get feedback about their 
medication compliance using the Smart Caps per visit.  
 
After completion of treatment as determined by the Liver Center Physician, patients from both 
groups are to follow-at week 4 and week 12 post-treatment. At that time, an HCV RNA PCR 
viral load will be obtained to determine if patient has an undetectable viral load, or Sustained 
Virologic Response (SVR). SVR is the marker for a functional cure of HCV, or treatment 
success. Non-SVR would mean treatment failure. 
 
 
 

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Study Procedures 
  
  
  
Pre-Treatment 
Treatment Assessments 
Post Tx  
Post tx 
Screening 
(Day 35 to -1) 
Baseline 
(Day 0)  
WK2 
Wk4 
Wk8 
Wk12/16 
Wk 4 
Wk 12 
Informed Consent w/ 
Med Hist inc HIV 
status 
  
x 
  
  
  
  
  
  
  
Complete PE inc. 
Vital Signs 
  
x 
x 
  
  
  
  
  
  
Symptom Directed 
PE inc. Vital Signs 
  
  
  
x 
X 
X 
X 
x 
x 
12-lead ECG 
  
x 
  
  
  
  
  
  
  
Chemistry( 
Comprehensive 
Metabolic Panel) 
  
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 
  
x 
x 
x 
x 
x 
x 
x 
x 
Virology(HCV) 
  
x 
x 
x 
x 
x 
x 
x 
x 
AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
 
X 
X 
X 
X 
X 
X 
X 
 
MEMS download 
  
  
x 
x 
x 
x 
x 
  
  
 
Data Collection 
 
At each visit, the following data are to be collected: HCV RNA PCR viral load, CBC, complete 
metabolic profile, number of pills missed. For both groups, Number of times pill bottles were 
opened will also be collected. 
 
Primary outcome measures: 
 
Primary endpoint in the study is the effect of the use of Portal724-MEMS Service on 
medication adherence, defined as compliance to regimen  95% of the time.  
 
Secondary outcome measures: 
 
The secondary endpoints for the  study include  the effect of the use of Portal724-MEMS 
Service on SVR, factors that affect medication adherence, such as race/ethinicity, age, 
educational attainment. Additionally, the feasibility of using MEMS adherence technology in an 
inner city urban population will be evaluated. 
Statistical Analysis 
This is a pilot study intended to generate initial data on the use of MEMS technology in an inner 
city population  to assess its feasibility and impact on treatment outcomes in HCV infected patients. 
Wilcoxon signed-rank test will be used to compare Groups 1 and 2 in terms of achieving adherence  95%. 

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SVR between the groups will also be analyzed in the same manner. A descriptive analysis will be done 
outlining patients’ profiles. Fischer’s exact test will be used to compare baseline characteristics between 
Groups 1 and 2. Alpha level for all statistical analysis will be set at 0.05. 
 
Toxicity management 
 
 
Grazoprevir/elbasvir  
The following side effects have been reported when MK-5172 in doses ranging from 25 mg to 800 
mg or placebo (a tablet that looks the same as the MK-5172 but has no active ingredient) was given 
for up to 12 continuous weeks to 389 HCV-infected men and women at the same time as other 
drugs commonly given to HCV patients (pegylated interferon and ribavirin).   These side effects 
were considered to be related to the treatment. 
  
• Decrease in the blood cells that carry 
oxygen 
• Decrease in blood cells that fight 
infection  
• Stomach pain  
• Diarrhea 
• Upset stomach 
• Dry mouth  
• Nausea  
• Vomiting  
• Weakness  
• Chills  
• Fatigue  
• Flu-like illness  
• General pain  
• Fever  
• Decreased appetite  
• Back pain 
• Muscle pain 
• Dizziness  
• Metallic taste 
• Headache 
• Trouble falling asleep or staying 
asleep 
• Feeling Irritable 
• Cough 
• Shortness of breath 
• Hair loss 
• Dry skin 
• Itchiness 
• Rash  
• Pain in the joints 
 
Most of these side effects were mild to moderate in intensity and short lived. While receiving MK-
5172 with pegylated interferon and ribavirin, about half the patients had increases in serum total 
bilirubin (a substance in your blood that is made in the body that is removed by the liver) and these 
values decreased in these patients over time while continuing MK-5172.  In some patients, blood 
tests of the liver called 'transaminases' which may be related to liver injury were increased at or 
after 6 weeks of therapy with MK-5172.  In one case a patient was hospitalized.  The highest 
transaminase increases were observed at the two highest MK-5172 doses (400 and 800 mg) given 
to patients in the study. In most patients the transaminase levels decreased after the dosing was 
stopped including in the patient who was hospitalized.   
 
In two treatment studies of MK-5172 given with pegylated interferon and ribavirin, three patients 
who received MK-5172 reported drug-related, serious side effects (a side effect that caused 
hospitalization) while on MK-5172 therapy.  One patient who received the 400 mg dose of MK-

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5172 reported severe dehydration.  A second patient who received the 800 mg dose of MK-5172 
had a high increase in transaminase levels which went back to normal after the drug was stopped.  
A third patient who received the 200 mg dose of MK-5172 reported severe anemia (a decreased 
number of red blood cells).  In all three cases the patients were treated for the serious side effect 
which resolved.   
 
Fourteen patients have discontinued the MK-5172 therapy early due to a side effect.  In some cases 
the patients discontinued only MK-5172 and in other cases the patients discontinued all therapy.  
The side effects that led to the study drug being stopped included decrease in the blood cells that 
carry oxygen, increased bilirubin, low blood pressure, weakness, headache, flu-like illness,  
irritability, shortness of breath, dehydration, fear/nightmares, anxiety/depression, increased levels 
of transaminases, nausea, reactivation of chronic pancreatitis (inflammation of an abdominal 
gland) and myositis (inflammation of the muscles).  Not all of these side effects were considered 
to be related to MK-5172. 
 
Ribavirin  
COMMON ADVERSE EVENTS 
 
The most common side effects when taking ribavirin combined with pegylated interferon are flu-
like symptoms consisting of:  
• Body aches and pains 
• Fever 
• Chills 
• Headache 
• Overall feeling of sickness  
• Rash 
 
Other common side effects are: anxiety, mood changes, depression and irritability. 
The most serious side effect seen with RBV is anemia (a decrease in the number of red blood 
cells in your body that carry oxygen).  Which may cause tiredness and lack of energy.  Other side 
effects may occur which are not listed here or were not seen before.   
Ribavirin can cause severe damage and even death of an unborn child or fetus.  Extreme care 
should be taken to prevent pregnancy while you are taking RBV and afterwards.  Patients 
will be required to abstain from sexual course while taking ribavirin and for 6 months after 
the last dose of ribavirin 
 
DILI 
In the event of a discontinuation of  grazoprevir/elbasvir for suspected DILI, other clinically 
significant liver chemistry elevations (defined under “Liver Chemistry Stopping and Follow up 
Criteria", below), severe skin reaction or hypersensitivity reaction, subjects should not restart 
grazoprevir/elbasvir  due to the risk of a recurrent reaction; such subjects should be withdrawn 
from study and seek/be reviewed for alternative HCV  therapy. 

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Allergic Reaction 
Subjects may continue study medication for Grade I or 2 allergic reactions at the discretion of 
the Investigator. The subject should be advised to contact the Investigator immediately if there 
is any worsening of symptoms or if further systemic signs or symptoms develop. 
Antihistamines, topical corticosteroids,  or antipruritic agents may be  prescribed. 
 
Subjects with Grade 2/3 allergic reactions that are considered to be possibly or probably related 
to the study medication should permanently discontinue the regimen and the subject should be 
withdrawn from the study. Subjects should be treated as clinically appropriate and followed 
until resolution of the AE. 
 
Adverse events 
 
Adverse Experience (Event) 
An adverse experience means any unfavorable and unintended change in the structure, function, or 
chemistry of the body temporally associated with any use of the Merck product whether or not considered 
related to the use of the product.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the 
product, is also an adverse experience. 
 
Serious Adverse Experience 
 
A serious adverse experience (SAE) is any adverse experience occurring at any dose that: 
• 
Results in death 
• 
Is life threatening (places the subject/patient, in the view of the investigator, at immediate risk of 
death from the experience as it occurred) 
• 
Results in a persistent or significant disability/incapacity 
• 
Results in or prolongs an existing inpatient hospitalization 
• 
Is a congenital anomaly/birth defect 
• 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject/patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that did not require hospitalization, or development of 
drug dependency or drug abuse. 
• 
Is an overdose (whether accidental or intentional) 
• 
Cancer (that is not the condition under the study)* 
 

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*If disease progression is noted during a protocol-specified reevaluation of the status of a patient’s cancer 
and the progression is manifested solely by results of tumor markers and/or radiologic imaging, that 
occurrence of progressive disease will NOT be recorded as an adverse experience. 
 
All Serious Adverse Experiences, regardless of causal relationship to the investigational product, must be 
forwarded to Merck Worldwide Product Safety via fax (215-993-1220) within 2 working days of the 
investigator becoming aware of the event and no later than 3 calendar days. 
 
MiŶiŵuŵ pƌotoĐol ƌeƋuiƌed laŶguage ;ie, site has ŵost of the laŶguage Ŷoted aďoveͿ: 
 
Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) will be provided with copies of all serious 
adverse experiences regardless of causality to use of a Merck product within two working days.  
Additionally, any pregnancy occurring in association with use of a Merck Product will be reported (Attn: 
Worldwide Product Safety; FAX 215 993-1220). 
 
A copy of all 15 Day Reports  and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators by the 
investigator. This submission will be cross referenced according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally, a copy of 
these reports will be submitted to Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) at the 
time of submission 
 
Ethics 
Institutional review board 
Before initiation  of the study, the Investigator(s)  will  submit the study protocol,  sample Informed 
Consent  Form, and  any other documents to the IRB  for approval.   The study will  not  commence until  
there  is full !RB approval.   All IRB regulatory  material  will  be properly  filed and available for review 
by the proper organizations. 
  
 
Confidentiality 
 
         Patients will be assigned research participant numbers which will be used by the 
investigators to identify them. This number plus other data that will be collected from the 
participants will be kept in password-protected file, only accessible to the Investigator and 
Research Assistant. Data transmitted by the Portal724- MEMS Smart Cap will only be identified 
through the research participant number. 
 
  
Statistical Analysis 

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This is a pilot study intended to generate initial data  on the use of MEMS technology in 
an inner city population  to assess its feasibility and impact on treatment outcomes in HCV 
infected patients. Wilcoxon signed-rank test will be used to compare Groups 1 and 2 in terms of 
achieving adherence  95%. SVR between the groups will also be analyzed in the same manner. 
A descriptive analysis will be done outlining patients’ profiles. Fischer’s exact test will be used 
to compare baseline characteristics between Groups 1 and 2.  
 
 
Scientific Data Dissemination 
 
It is the intention of the study investigators to submit abstracts & present results of this pilot 
study at major scientific  congresses  such as  AASLD (American Association for Study of Liver 
Diseases)  or DDW (Digestive Disease Week). The final results of study will be submitted for 
publication in a major peer reviewed medical  journal in Infectious Diseases or Gastroenterology 
as deemed appropriate at the end of study. 
 
 
Significance  of  Research Outcomes 
 
 
The findings of this research study will have significant implications on our understanding of 
patient adherence to treatment and health care outcomes. If the use of MEMS technology proves 
feasible &  useful in this inner city environment  based on this pilot trial, the investigators 
envision embarking on a larger research initiative to fully use the technology in patients with 
HCV, HIV and other chronic infectious and non-infectious disease conditions. 
 
 
 
 
References 
 
[1] European Association for Study of Liver. EASL Clinical Practice Guidelines: 
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[2] Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing 
burden of hepatitis C virus infection in the United States: model-based 
predictions. Ann Intern Med. 2014 Aug 5;161(3):170-80. 
 
[3] Centers for Disease Control and Prevention. (2014). Hepatitis C information for health 
professionals. Retrieved  from http://www.cdc.gov/hepatitis/hcv/ 
[4] Irshad M, Ansari MA, Singh A, Nag P, Raghvendra L, Singh S, Badhal SS. 
HCV-genotypes: a review on their origin, global status, assay system, 
pathogenecity and response to treatment. Hepatogastroenterology. 2010 
Nov-Dec;57(104):1529-38. 
 

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[5] Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 
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[19] Cantudo-Cuenca MR, Jiménez-Galán R, Almeida-Gonzalez CV, Morillo-Verdugo R. 
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[27] Mooney ME, Sayre SL, Hokanson PS, Stotts AL, Schmitz JM. Adding MEMS feedback  to 
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