Clinical trial NCT05061992
Conditions: Cirrhosis
Keywords: Hepatic Encephalopathy Liver Disease Cirrhosis and portal hypertension
Sponsor: University of Michigan
Start date: 2021-11-10; Completion date: 2022-11-01
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is being completed to evaluate whether a crystallized form of lactulose (Kristalose) will improve quality of life, sleep and cognitive function in patients with cirrhosis that have not been diagnosed with Hepatic Encephalopathy (HE), but report reduced quality of life.

Detailed description:

Arms: arm 1: None arm 2: Subjects will complete baseline and outcome assessments at 28 days and no intervention or placebo will be prescribed.
Interventions: intervention 1: Lactulose
Intervention descriptions: intervention 1: Participants will take 20 grams (dissolved in 4ounces of water/beverage) doses of lactulose twice daily (upon awakening and then 4 hours later) for 28 days.

In addition, outcome measurements will be completed at baseline and day 28.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Randomized Trial to Improve Quality of Life in 
People with Cirrhosis – the Mi-Kristal RCT 
 
 
 
 
 
 
IRB Approval Date: December 1, 2021 
 
NCT05061992 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
1 
 
 
 
 
 
A Randomized Trial to Improve Quality of Life in People with Cirrhosis – 
 the Mi-Kristal RCT 
 
 
 
 
 
Principal Investigator (PI): 
 
Elliot Tapper, MD  
Division of Gastroenterology and Hepatology 
Department of Internal Medicine 
University of Michigan, Ann Arbor, MI 
 
 
 
 
Correspondence: 
3912 Taubman Center, SPC 5362 
1500 E Medical Center Dr. 
Ann Arbor, MI 48109 
P: (734) 647-9252 
F: (734) 936-7392 
e: etapper@umich.edu 
 
 
 
 
 
Key words: Cirrhosis, Hepatic Encephalopathy, Liver Disease  
Disclosures: No conflicts of interest to disclose


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
2 
 
SUMMARY 
Study Name 
A Randomized Trial to Improve Quality of Life in People with Cirrhosis – 
 the Mi-Kristal RCT 
Subject 
Population 
At least 50 patients with cirrhosis and portal hypertension, with no previous 
lactulose use, and moderate to high self-reported daily activity impairment. 
Objective 
To determine if lactulose therapy improves health-related quality of life (HRQOL), 
cognitive function, sleep quality and activity level impairment and reduces 
number of falls. 
Design 
Randomized two-arm study of lactulose 
Arms 
Treatment: Crystalized Lactulose (Kristalose) 
Control: No intervention  
Procedures 
- 
Screen cirrhosis patients and determine if they meet inclusion and 
exclusion criteria. 
- 
Determine regular daily activity level impairment using WPAI; consent and 
randomize patients. 
- 
Collect demographic information and conduct baseline assessments: 
questionnaires assessing HRQOL, cognitive function, sleep quality, health 
history and current alcohol use.  
- 
Randomized subjects receive 28 days of crystallized lactulose therapy (20g 
twice daily (b.i.d.)) or no therapy.  
- 
Automated SMS or email follow-up at 3, 6, 9, 14, 15, 21 and 28 days with 
patients in treatment group: assess bowel movements; may be done via 
email or phone if required.  
- 
28-day follow-up evaluation consists of questionnaires assessing HRQOL, 
cognitive function, sleep quality, falls and activity level impairment.  
Site 
Michigan Medicine, Ann Arbor, MI 
Table of Contents 
SIGNIFICANCE ............................................................................................................................................... 5 
1. STUDY OBJECTIVES .......................................................................................................................... 5 
1.1 Specific Aims .............................................................................................................................. 5 
1.1.1 Primary Aims .................................................................................................................... 5 
1.1.2 Secondary Aims ................................................................................................................ 5 
 1.2 End Points .................................................................................................................................. 6 
2. STUDY DESIGN ................................................................................................................................... 6 
3. SELECTION AND ENROLLMENT OF SUBJECTS ................................................................................... 7 
3.1 Inclusion Criteria ........................................................................................................................ 7 
3.2 Exclusion Criteria ........................................................................................................................ 7 
3.3 Study Enrollment Procedures .................................................................................................... 8 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
3 
 
3.3.1 Identification & Recruitment ............................................................................................ 8 
3.3.2 Monitoring of Recruitment Targets  ................................................................................. 8 
3.3.3 Consent Procedures ......................................................................................................... 8 
4. STUDY INTERVENTIONS & PROCEDURES ................................................................................................. 9 
4.1 Assessments ............................................................................................................................... 9 
4.2 Enrollment Procedures ............................................................................................................ 10 
4.2.1 Enrollment ...................................................................................................................... 10 
4.2.2 Randomization................................................................................................................ 10 
4.2.3 Consent Procedures ....................................................................................................... 10 
4.3 Intervention Procedures .......................................................................................................... 11 
4.3.1 Lactulose Administration & Duration ............................................................................. 11 
4.3.2 Adherence Assessment .................................................................................................. 11 
      4.4 Follow-Up & Outcomes ........................................................................................................... 11 
4.5 Distinct Clinical Scenario: Patient Death .................................................................................. 12 
4.6 Distinct Clinical Scenario: Patient Hospitalization ................................................................... 12 
4.7 Early Termination ..................................................................................................................... 13 
4.8 Subject Incentives .................................................................................................................... 13 
5. MANAGEMENT OF ADEVERSE EVENTS & PROTOCOL DEVIATIONS...................................................... 13 
5.1 Protocol Deviations .................................................................................................................. 13 
5.2 Adverse & Serious Adverse Event Definitions & Reporting ..................................................... 13 
5.2.1 Adverse & Serious Adverse Event Definitions ................................................................ 13 
5.2.2 AE Relatedness & Severity .............................................................................................. 14 
5.3 Criteria of Intervention Discontinuation .................................................................................. 14 
6. STATISTICAL CONSIDERATIONS ............................................................................................................. 15 
6.1 Sample Size & Accrual .............................................................................................................. 15 
6.2 Quantittive Analysis ................................................................................................................. 15 
7. DATA COLLECTION & MANAGEMENT .................................................................................................... 15 
         7.1 Records To Be Kept ....................................................................................................................... 15 
7.2 Role of Data Management ............................................................................................................ 15 
7.2.1 Data Collection Protocol ................................................................................................. 15 
7.3 Data Security & Confidentiality ..................................................................................................... 15 
7.4 Use of Twilio Service ..................................................................................................................... 16 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
4 
 
 
8. HUMAN SUBJECTS .................................................................................................................................. 16 
8.1 Institutional Review Board & Informed Consent .......................................................................... 16 
8.2 Subject Confidentiality .................................................................................................................. 16 
8.3 Potential Risks & Benefits ............................................................................................................. 16 
8.4 Study Modification/Discontinuation ............................................................................................ 17 
9. REFERENCES ............................................................................................................................................ 18 
10. APPENDICES .......................................................................................................................................... 19 
 
 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
5 
 
SIGNIFICANCE 
 
        Cirrhosis is the final common pathway for all chronic liver diseases.(1) It is common, with a US 
prevalence >1 million and rising owing to age-related metabolic comorbidities.(2) Two-thirds of 
contemporary patients with cirrhosis are now > 60 years old.(3) The mortality and healthcare costs 
associated with cirrhosis have nearly doubled within the last 10 years.(4, 5) More than any other factor, 
these adverse outcomes are driven by the development of hepatic encephalopathy (HE). A spectrum of 
reversible cognitive changes, HE ranges from inattention and executive function deficits with poor 
quality of life (QOL) to a severe form marked by lethargy, disorientation, and even coma.(3-6) Over 40% 
of patients with cirrhosis will develop HE.(6, 7) HE is associated with increased mortality, malnutrition, 
sarcopenia,(8) frailty,(9) debility,(10) falls,(11-13) and frequent hospitalization.(14)  
HE is caused by brain exposure to ammonia, a waste product of bacterial metabolism in the gut. 
Normally the liver converts ammonia to urea. Unfortunately, owing to technical challenges in its 
measurement and confounding factors in the pathogenesis of HE, the level of ammonia in the blood is a 
poor biomarker for the risk or presence of HE. Leveraging the concept that HE presents as a spectrum 
with early, subclinical stages presenting with poor quality of life (QOL), we have used the presence of 
poor QOL to predict the development of HE.(15) We have found that answers to a one-question 0-10 
scale rating the impact of cirrhosis on one’s daily activity efficiently distinguishes patients with low 1-
year risk of HE from those with high risk.(15) In clinical practice many clinicians detect disturbances in 
QOL or functioning that could be associated with HE and empirically start HE-directed therapy. In this 
trial we will extend our prior research by enrolling patients at high risk of overt HE and formally test the 
benefits of QOL-triggered HE therapy. 
1. STUDY OBJECTIVES 
The primary objective is to determine whether lactulose therapy in a study population of cirrhosis 
patients with portal hypertension improves their health-related quality of life (HRQOL). We will be using 
crystalized lactulose (Kristalose, Cumberland Pharmaceuticals). We have 6 specific aims, which are 
detailed below 
1.1 SPECIFIC AIMS 
1.1.1 Primary Aim 
Aim 1: To determine whether lactulose therapy improves self-reported HRQOL as assessed using the 
Short Form-8 Health Survey (SF-8).  
1a. Comparison of SF-8 scores from baseline to 28 days, between the intervention and 
control arm. 
 
1.1.2 Secondary Aim 
Secondary aim of this trial include:  
Aim 2: To determine whether lactulose therapy improves cognitive function as assessed using the 
Animal Naming Test (ANT).  
2a. Comparison of ANT scores from baseline to 28 days, between the intervention and 
control arm. 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
6 
 
1.1.3 Exploratory Aims 
Aim 3: To determine whether lactulose therapy improves overall sleep quality as assessed using the 
Pittsburgh Sleep Quality Index (PSQI).  
3a. Comparison of PSQI overall sleep quality ratings from baseline to 28 days, between the 
intervention and control arm. 
Aim 4: To determine whether lactulose therapy improves regular daily activity impairment as 
assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI). 
 4a. Comparison of self-reported regular daily activity impairment scores as part of WPAI 
from baseline to 28 days, between the intervention and control arm.  
 
1.1.3 Exploratory Adverse Event Aims 
Aim 5: To determine if lactulose therapy increases the incidence of >5 self-reported bowel 
movements per day.  
5a.  Comparison of self-reported episodes of >5 daily bowel movements from baseline to 28 
days between the intervention and control arm.  
Aim 6: To determine if lactulose therapy reduces the number of self-reported falls.  
6a. Comparison of self-reported number of falls from baseline to 28 days between the 
treatment and control arm.  
 
1.2 END POINTS 
 
All patients will be followed until death, liver transplantation or final study visit at 28 days post – 
enrollment. 
 
Primary Endpoint 
1. Comparison of SF-8 at 28 days post-baseline, between the two groups.  
Secondary Endpoints 
1. Comparison of ANT, overall sleep quality, regular daily activity impairment, falls, and 
average number of daily bowel movements at 28 days, compared between the two 
groups.  
 
2. STUDY DESIGN 
Overview: We propose a randomized two-arm parallel group trial to determine if lactulose therapy 
in cirrhosis patients with portal hypertension who report moderate to high regular daily activity 
impairment and have no history of prior lactulose use or HE within 6 months, improves their HRQOL, 
cognitive function and overall sleep quality at 28 days post-baseline. Subjects will be randomized to 
one of two groups: 
 
1) Treatment: subjects prescribed and instructed to take 20g (dissolved in 4oz of water) dose of 
lactulose twice daily (upon awakening and then 4 hours later) for 28 days.   
2) Control: subjects are asked to complete baseline and outcome assessments at 28 days and no 
intervention or placebo will be prescribed.  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
7 
 
Our goal is to have 50 patients with cirrhosis who meet study eligibility criteria (see Section 3 below) 
complete study participation, with approximately 25 subjects in each arm. We will enroll up to 75 
subjects to account for subject withdrawals, lost to follow-up, death, transplant or PI discretion.  
Figure 1. Study Design 
 
       
  
 
3.   SELECTION AND ENROLLMENT OF SUBJECTS 
3.1 INCLUSION CRITERIA 
All subjects must meet the following criteria: 
1. Adult > 18 years of age 
2. Diagnosis of cirrhosis – must meet one of the following criteria: 
a. liver biopsy, OR 
b. history of cirrhosis complication: ascites, variceal bleeding, hepatic encephalopathy, OR 
c. 2 of the following 4 criteria: 
1. US, CT or MRI imaging findings of cirrhosis (cirrhotic appearing liver, splenomegaly, 
varices, ascites) 
2. Fibroscan liver stiffness score >13 kPa 
3. Laboratory testing: AST/platelet ratio index (APRI) >2.0  
4. CT, MRI or EGD showing presence of esophageal varices 
3. Evidence of portal hypertension – must meet at least one of the following criteria: 
a. Ascites 
b. Varices (seen by endoscopy or by ultrasound or cross-sectional imaging)  
c. Fibroscan liver stiffness measurement (LSM) > 25 
d. Platelets < 80 
4. Moderate activity impairment 
a. ≥ 3 on WPAI regular daily activity impairment question (scored 0-10) 
 
3.2 EXCLUSION CRITERIA 
The following exclusion criteria applies to all subjects:  
1. Non-English speaking 
2. Unable or unwilling to provide consent 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
8 
 
3. History of liver transplant 
4. Disorientation at the time of enrollment, Dementia, or Treated Memory Disorder 
5. History of prior lactulose use or HE within 6 months 
6. Metastatic solid malignancy or blood malignancy 
7. A1C > 12 (within past year) 
8. Low galactose diet 
 
3.3 STUDY ENROLLMENT PROCEDURES 
 
3.3.1 
Identification and recruitment 
After IRB approval, patients will be identified and recruited from multiple centers including Michigan 
Medicine. Patients will be identified by one of 6 methods: 1) referral by Michigan Medicine 
Hepatology providers, 2) screening of Michigan Medicine clinic schedules on the outpatient, 
transplant or procedure liver services, 3) referral from study coordinators of pre-existing registry 
studies at Michigan Medicine, 4) screening electronic medical records of Michigan Medicine 
hospitalized patients, 5) posting of study on www.UofMHealthResearch.org, 6) direct emails sent to 
cirrhosis patients via REDCap.  
 
Patients with cirrhosis who have an email address are eligible to be contacted for recruitment by 
email via REDCap (see Appendix G). This will be conducted via a supplementary REDCap database in 
addition to the Mi-Kristal REDCap database. The supplementary REDCap database will be set to send 
a marketing email to new cirrhosis patients as they are added. The email will be shown as being sent 
from a group email: mikristalstudy@med.umich.edu. Anyone interested can fill out an interest form 
via supplementary REDCap database and provide their contact information to the study team on this 
form. Once we receive the contact information, we will proceed to contact the patient via phone 
and proceed with enrollment and consent if they are interested. The study team will subsequently 
reach out to the patient by phone or email to complete the screening and enrollment process. 
Eligible patients at Michigan Medicine will be contacted by phone, email, or in-person to see if they 
are interested in participating in the study. To verify patient eligibility prior to enrollment, study 
staff will ask patients final screening questions as outlined in (see Appendix F).  
3.3.2 
Monitoring of recruitment targets 
Data will be collected on all patients who are screened. A screening log will be maintained and will 
include the inclusion/exclusion criteria in Sections 3.1 and 3.2 above, and hence confirm eligibility or 
provide the reasons for ineligibility, as well as reasons for nonparticipation of eligible subjects. This 
will include: 1) the number of all persons screened with cirrhosis, 2) reasons for exclusion (specific 
criteria), 3) the number approached for participation, 4) the number enrolled, 6) the number who 
declined participation and 7) reasons for nonparticipation. 
3.3.3 
Consent Procedures  
We will obtain written informed consent for participation from at least 50 subjects. A study 
coordinator will obtain informed consent. If recruitment procedures are being conducted in person, 
patients will be approached at the time of scheduled clinic appointments, procedures, or during 
hospitalizations. The study coordinator will obtain written informed consent during the in-person 
interaction. A copy of the informed consent form (ICF) will be provided to the subject.  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
9 
 
If recruitment procedures are being conducted via email or phone, they will be consented 
electronically via SignNow, a third-party service to digitally collect informed consent which meets 
the requirements for HIPAA-compliance in the US. A copy of the informed consent form will be 
made available to the patient via email, or they can download a copy through SignNow.  
 
4. STUDY INTERVENTIONS AND PROCEDURES 
 
4.1 ASSESSMENTS  
 
4.1.1 Baseline Assessments 
 
1. Demographics Questionnaire (DQ) (Appendix A) 
Participants will be asked to provide the following demographic information: 
1. Sex  
2. Age 
3. Ethnicity 
4. Race 
5. Highest education level attained 
6. Marital status 
7. Occupation status 
8. Income 
9. Rural/Urban residence 
 
2. Health History Questionnaire (HHQ) (Appendix B)  
Participants will be asked to provide the following information: 
1. Cause of cirrhosis  
2. History of liver cancer  
3. Liver transplant waitlist status 
4. Driving status 
5. Disability status (Katz-ADL) 
6. Hospitalization within past 90 days 
7. Emergency Room visit within past 90 days 
8. Ascites status 
9. Currently taking diuretics  
10. Paracentesis within past 90 days 
11. Hepatic encephalopathy status 
12. Medications taken for HE  
13. Dialysis status 
14. Diabetes status 
15. Congestive heart failure status 
16. Chronic obstructive pulmonary disease status 
17. Overall sleep quality (PSQI) 
18. Falls in past 4 weeks 
19. Average number of bowel movements per day 
 
3. Short Form-8 Health Survey (SF-8) (Appendix C) 
The SF-8 is an abbreviated version of an original 36-item health survey (SF-36). It is a generic 
multipurpose quality of life instrument. It contains psychometrically based physical and mental 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
10 
 
health summary measures. The eight domains include general health, physical functioning, role 
physical, bodily pain, vitality, social functioning, mental health and role emotional.  
 
4. Animal Naming Test (ANT) (Appendix D) 
The animal naming test is a timed test that consists of subjects listing as many unique animals as 
possible in 60 seconds. This is a validated test used for the assessment of hepatic 
encephalopathy.  
 
5. Alcohol Use Disorders Identification Test-C (AUDIT-C) (Appendix E) 
The AUDIT-C is a brief 3-item alcohol screening instrument that reliably identifies persons who 
are hazardous drinkers or have active alcohol use disorders.  
 
4.1.2 28-Day Follow-Up Assessments 
 
1. Health Follow-Up Questionnaire (HFUQ) (Appendix G)  
Participants will be asked to provide the following information: 
1. Hospitalizations during study period 
2. Overall sleep quality (PSQI) 
3. Falls during study period 
4. Average number of bowel movements per day 
5. Ability to do regular daily activities (WPAI) 
 
2. Short Form-8 Health Survey (SF-8) (Appendix C) 
3. Animal Naming Test (ANT) (Appendix D) 
 
4.2 ENROLLMENT PROCEDURES 
 
4.2.1  
Enrollment  
 
After informed consent procedures, all subjects will complete enrollment procedures in the following 
order: 
a. Provide their contact information 
b. Randomization  
c. Baseline assessments 
d. Kristalose allocation and intervention counseling (only if randomized to treatment 
group) 
 In the control group, the date subjects are randomized and complete the baseline assessments is 
Study Day 1. These procedures can be conducted in person or via phone. In the treatment group, the 
date subjects receive Kristalose and receive intervention counseling is Study Day 1.  
4.2.2 
 Randomization 
 
After informed consent and baseline procedures are completed, the study coordinator will 
randomize the subject via reandomize.net. Subjects will be randomized in approximately equal 
allocation to each arm 1:1 lactulose therapy or the control group. Randomization is stratified by 
subject self-reported activity impairment level. Activity impairment level is determined by the 
baseline WPAI regular daily activity impairment score collected as part of the final screening 
questions (Appendix F): mild/moderate is a score of ≤7, severe is a score of >7. To ensure 
approximate balance within arms, the randomization will be implemented using a randomly 
permuted blocks design to ensure approximate balanced assignments within subject self-reported 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
11 
 
activity impairment severity level. The sequence of assignments for each stratum will be prepared in 
advance by a biostatistician.  
 
 
4.2.3 
 Baseline Assessments 
The study coordinator will conduct the following assessments with all subjects via phone, REDCap 
survey email or in person, after consent and randomization processes are complete: 
 
1. 
Demographics Questionnaire 
2. 
Health History Questionnaire 
3. 
SF-8 
4. 
ANT 
5. 
AUDIT-C 
 
4.3 INTERVENTION PROCEDURES 
 
4.3.1  
Lactulose Administration and Duration 
Subjects randomized to the control are not required to complete any intervention activities or 
treatments. For subjects randomized to lactulose therapy, the following steps to implement the 
intervention will occur on Study Day 1:   
1. 
The Principal Investigator (PI) will prescribe lactulose to subjects enrolled at Michigan 
Medicine. Lactulose (Kristalose) will be allocated to the patient in person at the 
University of Michigan through the Investigational Pharmacy. If enrollment procedures 
were conducted remotely, the patient will be allowed up to two weeks to schedule an 
appointment with the study coordinator to receive Kristalose.  
 
2. 
Subjects will be instructed to take 20g of Kristalose (1 packet) in 4oz water twice daily 
for 28 days. All patients randomized to lactulose will receive standard counselling.  
 
3. 
First, all subjects will be instructed to take the first dose on awakening and the second 
dose approximately 4 hours after the first dose.  
 
4. 
Second, subjects will be asked to monitor their bowel movements (see section 4.3.2 
Adherence Assessment below). If they achieve ≥ 4 bowel movements in one day 
outside of the adherence assessments, they will be asked to contact the study team 
directly and will be instructed to reduce their lactulose frequency to one 20g dose 
daily. No dose adjustments will be made to increase bowel movements. Study staff will 
be alerted via email if a subject reports more than 4 bowel movements per day. 
Subjects will be instructed to call the study phone line if their bowel movements do not 
decrease with a reduced dose. They will also be instructed to notify the study team if 
they are undergoing proctoscopy or colonoscopy and to avoid taking nonabsorbable 
antacids (like aluminum or magnesium hydroxide) with Kristalose since these may 
interfere with the lactulose activity.  
 
5. 
Third, patients will be counselled on the side effects of lactulose including mild 
bloating, cramping or diarrhea. If the symptoms worry the patient, they will be 
instructed to reduce lactulose to one 10g dose on awakening and then to increase to 
10g twice daily as tolerated. 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
12 
 
4.3.2  
Adherence Assessment 
During the 28-day intervention phase, all subjects will be contacted on Study Days 3, 6, 9, 14, 15, 21 
and 28 via automated REDCap email or SMS text messages via Twilio service. Study Day 28 will only 
be collected via REDCap email or phone. These points of contact are to collect data about stool 
frequency and consistency among all subjects and therefore lactulose adherence in the treatment 
group. If the subject opts out of Twilio service, the subject can also receive these questions via 
REDCap automated email or a study coordinator will collect this data from the subject directly via 
phone or email. On Study Days 3, 6, 9, 14, 21 and 28 subjects will be asked the following questions:  
1. “How many bowel movements did you have yesterday? Please respond with a whole number.” If 
0-4 bowel movements are reported the subject will exit the survey. If >4, the subject will receive 
the following instructions:  
 
Since you had > 4 bowel movements yesterday, please reduce to one 20g dose of 
kristalose (1 packet) packet per day. Please call the study line at 734-232-4182 if you 
continue to have more than 4 bowel movements daily or with any questions or 
concerns.  
 
On Study Day 15 subjects will be asked: 
 
2. “Please reference the Bristol Stool Chart we provided to you to answer this question. How would 
you describe your stool looks today? Please respond with the applicable number, between 1-7. 
All subjects exit survey after response.  
1. Separate hard lumps 
2. Sausage-shaped but lumpy 
3. Like a sausage but with cracks on its surface 
4. Like a sausage or snake, smooth and soft  
5. Soft blobs with clear cut edges 
6. Fluffy pieces with ragged edges, a mushy stool 
7. Watery, no solid pieces, entirely liquid 
4.3.3 
 Handling of Study Drug 
Kristalose is an FDA approved drug. We established an agreement with the manufacturer 
Cumberland to provide Kristalose supply. Kristalose will be distributed through Cumberland to the 
investigational drug pharmacy at Michigan Medicine. The study team will liaise with the 
investigational pharmacy and manufacturer to ensure that an adequate supply of drug is available for 
dispensing.  
The investigational pharmacy is responsible for receipt, storage, dispensing, and reconciliation of the 
study drug. Pharmacy accountability will be monitored. The investigational pharmacy will maintain 
accountability logs for all supplies of Kristalose. These logs will include the purchase date (date 
received), lot number, expiration date, and quantity of all Kristalose supplied for the trial. In addition, 
every dose dispensed will also be recorded in a subject-specific accountability log. The Kristalose lot 
number for each dose dispensed will be recorded and the inventory balance will also be noted on the 
accountability log. Study drug shipping receipts will be retained.  The investigational pharmacy will 
dispense 2 packages (30 20g dose packets in each package) of Kristalose to each subject randomized 
to the treatment group upon receipt of randomization notification either in person at Michigan 
Medicine or shipped directly to the patient via FedEx.  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
13 
 
 
4.4 FOLLOW-UP AND OUTCOMES 
The final follow-up study visit will occur 28 days post-baseline (SD 28±5). Primary and secondary 
outcome data will be collected at this visit. The SF-8, ANT and Health Follow-Up Questionnaire (see 
Appendix H) will be conducted with all subjects.  The Health Follow-Up Questionnaire contains several 
questions from the baseline Health History Questionnaire including hospitalization data, overall sleep 
quality (PSQI), number of falls, number of bowel movements per day and regular daily activity 
impairment score (WPAI). This visit will be conducted via REDCap email and/or phone.  
 
              Table 1. Procedure Table  
STUDY 
DAY  
 
Entry/ Day 1* 
 
 
3  
 
 
6  
 
 
9  
 
 
14 
 
 
15 
 
 
21 
 
 
28  
(SD 28 ± 
5 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Contact Information 
X 
 
 
 
 
 
 
 
Demographics Questionnaire 
X 
 
 
 
 
 
 
 
Health History Questionnaire 
X 
 
   
 
 
 
 
 
Short Form Health Survey 8 
X 
 
 
 
 
 
 
X 
Animal Naming Test 
X 
 
 
 
 
 
 
X 
AUDIT-C 
X 
 
 
 
 
 
 
 
Health Follow-Up Questionnaire 
 
 
 
 
 
 
 
X 
Twilio/REDCap Email Automated Messages 
 
X 
X 
X 
X 
X 
X 
X 
Lactulose Therapy 
X 
  X                        →                           X 
* Control Group: Study Day 1 is defined as the calendar day on which the subject is randomized.      
Treatment Group:  Study Day 1 is defined as the calendar day on which the subject receives Kristalose.  
4.5 DISTINCT CLINICAL SCENARIO: PATIENT DEATH  
In the event of a subject’s death during the study period we will attempt to ascertain the date and cause 
of death, and hospitalization data that is available in the subject’s Michigan Medicine electronic medical 
record.  
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
14 
 
4.6 DISTINCT CLINICAL SCENARIO: PATIENT HOSPITALIZATION 
In the event of a subject’s hospitalization during the study period, we will record the event as an 
Adverse Event (AE). If the subject’s hospitalization coincides with study activities, we will revise each 
procedure as follows: 
1) Lactulose therapy: If a subject in the treatment group is hospitalized at Michigan 
Medicine during the study, the study PI and/or coordinator will contact the Michigan 
Medicine care team to discuss continuation of lactulose therapy during the 
hospitalization. If the hospitalization is a result of an AE from lactulose use, this will be 
discussed with the PI and lactulose may be paused or discontinued.    
2) Follow-up phone study visits: If the hospitalization coincides with the Day 28 follow-up 
visit, we will provide the subject an opportunity to reschedule the visit after discharge, 
under PI discretion.  
 
4.7 DISTINCT CLINICAL SCENARIO: OVERT HE DIAGNOSIS & INITIATION OF LACTULSOE 
THERAPY 
If a subject in either group (treatment or control) is diagnosed with Overt HE, or prescribed lactulose for 
any clinical reason outside of study participation during the study period, their participation in the study 
will be terminated. An early termination visit will be conducted with the subject to collect outcome data 
including the SF-8, ANT and Follow-Up Health Questionnaire. 
4.8 EARLY TERMINATION VISIT 
 
If a subject discontinues participation in the study, the subject will be asked to complete all 28 Day 
Follow Up Assessments at the time of discontinuation including the SF-8, ANT and Follow-Up Health 
Questionnaire. If they choose not to complete them, their participation will be terminated immediately. 
All data collection prior to termination will be retained by the study team.  
 
4.9 SUBJECT INCENTIVES 
Participants will be offered a $50 compensation for completing all activities in the trial.  
5. MANAGEMENT OF ADVERSE EVENTS AND PROTOCOL DEVIATIONS 
 
5.1 PROTOCOL DEVIATIONS 
 
Minor protocol deviations that do not impact the safety of participants or the integrity of data must be 
recorded and reported to the Institutional Review Board (IRB) on an annual basis as part of standard 
continuing review. Major protocol deviations that may impact participant safety or the integrity of data 
are required to be reported to the IRB as an ORIO within 7 days of knowledge of the event. 
 
5.1.2 Protocol Deviations may include the following items, among others: 
- Enrollment despite meeting exclusion criteria 
- Enrollment despite not meeting inclusion criteria 
- Consent not obtained in accordance with IRB guidelines 
- Baseline assessments not collected 
- Outcome assessments collected outside of prescribed study window 
- Outcome assessments not collected 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
15 
 
5.2 ADVERSE AND SERIOUS ADVERSE EVENT DEFINITIONS & REPORTING 
 
5.2.1 Adverse and Serious Adverse Event Definitions (AE & SAE) 
In the Mi-Kristal study an AE is defined as any untoward or unfavorable physical, social or 
psychological occurrence in a participant that can be temporally associated with the subject’s 
participation in the study, whether or not considered directly related to the subject’s participation in 
the research. An AE is considered an SAE if the event results in death or permanent disability and is 
definitely related to the subject’s participation in the study. However, due to the nature of the 
participants enrolled and low risk nature of the treatments, the AEs and SAEs recorded and reported 
to the IRB will be limited using the following guidance.  
 
All hospitalizations will be reported as AEs. Other events that are not attributable to their 
participation in the study will not be reported as AEs, even if the data are collected for study 
purposes (e.g. car accident, stroke, myocardial infarction etc.). The exception to this standard is 
death, which will always be reported as either an AE or SAE. Additionally, expected clinical issues 
that subjects experience related to their ongoing medical care or chronic health problems will not 
be considered AEs unless it involves any of the above mentioned AE examples. Any AEs that are 
attributable to the study will be reported and adhere to the AE Reporting Timeline (see Table 3 
below). The 28±7 days end point is our final contact with subjects in which we will collect AE and 
SAE information. Events which qualify as AEs will be classified using the following IRB standards: 
 
5.2.2 AE Relatedness and Severity 
 
For all AEs, the PI (Dr. Elliot Tapper) will use his best judgment and indicate how related the AE is to 
the research procedures and intervention. He will assign the AE to one of the four categories below: 
 
 Definitely related: The AE is clearly related to the intervention 
 Probably related: The AE is likely related to the intervention 
 Possibly related: The AE may be related to the intervention 
 Unlikely to be related: The AE is doubtfully related to the intervention 
 Definitely not related: The AE is definitely not related to the intervention 
 
The PI will provide an AE severity:  
 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; no 
intervention indicated 
 Moderate: minimal, local, or noninvasive intervention indicated 
 Severe: Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling 
 Life-threatening: Life-threatening consequences; urgent intervention indicated 
 Fatal 
 
The PI will AE level of expectedness: 
 
 Unexpected adverse events: (i.e., has NOT been addressed or described in one or more of 
the following: informed consent document for this study, IRB application for this study, 
grant application or study agreement, protocol or procedures for this study, investigators' 
brochure or equivalent (for FDA regulated drugs or devices), DSMB/DSC Reports, published 
literature, other documentation)  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
16 
 
 Expected adverse events: (i.e., has been addressed or described in one or more of the 
following: informed consent document for this study, IRB application for this study, grant 
application or study agreement, protocol or procedures for this study, investigators' 
brochure or equivalent (for FDA regulated drugs or devices), DSMB/DSC Reports, published 
literature, other documentation, or characteristics of the study population. 
 
5.2.3 IRBMED Reporting 
 
AEs, SAEs, UaPs and protocol deviations will be reported to IRBMED following IRBMED reporting 
guidelines.  
 
5.3 CRITERIA OF INTERVENTION DISCONTINUATION 
 
If the subject experiences any SAE that might be considered related to Mi-Kristal participation, the study 
coordinator will inform the subject to stop all intervention activities. The PI will decide whether to 
continue study activities thereafter. Every effort will be made to maintain the subject’s participation in 
follow-up activities. If lactulose therapy is terminated before 28 days, the Day 28 outcome assessments 
will be collected within 5 days of lactulose termination. 
 
6. STATISTICAL CONSIDERATIONS 
6.1 SAMPLE SIZE AND ACCRUAL  
 
While no studies of lactulose enrolling patients exclusively with deficits in quality of life, one high quality 
study of lactulose therapy have been performed for patients with cognitive dysfunction defined by 
psychometric testing. Lactulose was associated with a 6.81 95%CI (5.2-8.4) point or 65% relative 
improvement in health-related quality of life using the Sickness Impact Profile compared to control. 
Given this magnitude of effect, very few patients need to be enrolled. However, if we hypothesize an 
attenuated effect (30% improvement), seeking to enroll with a 1:1 randomization, assuming an alpha of 
0.05, we will have 90% power to detect a difference among 42 subjects. We will therefore proceed with 
a study of 50 patients to allow for additional adjustment of baseline covariates and drop-outs. 
 
6.2 QUANTITATIVE ANALYSIS 
 
We will compare differences in all outcomes, each continuous variable, using MANOVA. Multiple linear 
regression will be used to adjust for baseline covariates. 
 
7. DATA COLLECTION AND MANAGEMENT 
 
7.1 RECORDS TO BE KEPT 
 
All data will be entered into case report forms (CRFs) using a REDCap platform. These forms include 
enrollment, baseline, intervention and outcome assessments. All data recorded in REDCap is identified 
by a unique Study Identification Number (Subject ID). The subject must read, understand, and sign an 
IRB approved informed consent form (ICF). The Investigator will retain the original signed consent form 
in a secured location. Additionally, we will upload a copy of original signed ICF into the subject’s 
Michigan Medicine electronic medical record. Separate documents will be de-identified and stored in 
the University Share Drive.  
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
17 
 
7.2 ROLE OF DATA MANAGEMENT 
 
The primary study coordinator will be responsible for data management. The study portal will provide a 
highly structured repository to store and process study data from electronic case report forms (e-CRFs), 
as well as to protect its integrity and confidentiality. This tool will assist study staff by providing efficient 
protocol management and study retention and oversight. Access to the study portal will be granted by 
the Investigator or primary study coordinator with differential access rights based on role.   
 
7.2.1     Data Collection Protocol 
• For enrollment, study staff will access the REDCap study portal via the web, and 
provide screening information about the patient.  
• Study-related data, as outlined in the intervention procedures above, will be entered 
online by research staff into the CRFs within the REDCap study portal.  
 
7.3 DATA SECURITY AND CONFIDENTIALITY 
 
We will keep a separate password protected screening log and subject tracker on the University shared 
drive in a secured location. Only study personnel will have access to the electronic screening log that 
maps the Subject ID number and Screening ID number (if applicable) to the subject’s name, medical 
record number (MRN) and contact information. Only limited identifiable data will be collected. All 
subject data recorded on paper are maintained in locked file cabinet with limited access by research 
staff. No one other than the research team at the University of Michigan will be given or have access to 
the patient’s name, mailing address, email address, phone number, and other personal identifying 
information.  
 
7.4 USE OF TWILIO SERVICE 
 
We will work with the Michigan Institute for Clinical and Health Research (MICHR) to construct our 
REDCap database and connect it with Twilio. Twilio (https://www.twilio.com) is a third-party service 
used to send automated SMS messages and phone call surveys to users for a variety of purposes. We 
will use Twilio to send follow-up communications to subjects in the intervention groups on Study Days 3 
3, 9, 9, 14, 21 and 28. The only piece of information transmitted from our REDCap database to Twilio will 
be the phone number of the participant. Participants will choose to either opt-in or opt-out of using 
Twilio service. Participants that choose to opt-in to the service must provide informed consent to use 
the service and must agree to Twilio’s privacy policy and terms of service. All participants who refuse to 
use the Twilio service will be offered alternative means of follow-up including phone, text, and/or email 
communications directly sent from the study coordinator. No protected health information (PHI) will be 
requested from the patients or sent by the study team through Twilio. The only information transmitted 
through Twilio SMS text messages or phone calls will be non-identifiable responses to questions about 
the number of times per day the subject has bowel movements. 
 
8. HUMAN SUBJECTS 
 
8.1 INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT 
 
This protocol, the informed consent document, and any subsequent modifications will be reviewed and 
approved by the Michigan Medicine IRB (IRBMED). The consent form will describe the purpose of the 
study, the procedures to be followed and the risks and benefits of participation. A copy of the consent 
form will be given to the participant, a copy uploaded to MiChart (if the subject is a Michigan Medicine 
patient), and the original signed consent will be stored by the coordinator in a secure location.  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
18 
 
 
8.2 SUBJECT CONFIDENTIALITY 
 
All subject evaluation forms and other records will be identified only by the Subject ID and date of 
completion, to maintain subject confidentiality. All records will be kept in a locked file cabinet. All 
computer entry will be performed using Subject ID only. Any clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by the IRB.  
 
8.3 POTENTIAL RISKS AND BENEFITS 
 
There is minimal medical risk to any participant in this study. Patients will be counselled on the risk of 
cirrhosis complications (ascites, HE) that may be related to their underlying disease as well as side 
effects associated with lactulose: abdominal discomfort, bloating, diarrhea, dehydration and rarely 
hypernatremia and/or hypokalemia. Participants can withdrawal at any time. The potential benefits to 
participants include an improvement in HRQOL, cognitive function and overall sleep quality and 
reduction in the risk of developing HE.  
 
The known or expected risks are: 
• 
Questionnaires: Many of the questions relate to how the subjects are feeling, and this may lead 
to an emotional reaction. To minimize these risks, questions will not ask explicitly sensitive 
information and study coordinators will be available for support. Additionally, should the 
questionnaires or surveys become uncomfortable, subjects can choose to skip any question that 
they do not wish to answer or stop at any time. 
• 
Loss of confidentiality: There is rare risk of loss of confidentiality or privacy. To reduce the risk 
of loss of confidentiality, trained members of the research team will ask subjects questions in a 
private patient room. This information will be limited to the subject’s name, date of birth, sex, 
and subject ID. Information such as the subject’s full name and phone number will be recorded 
along with their baseline data however, this information will be stored in a locked cabinet. This 
data will be entered into a password-protected database where all data will be coded using a 
study number and only staff involved in this research will have access to the data.  
• 
Lactulose: There is the possibility that that lactulose can cause physical symptoms such as 
abdominal pain, diarrhea, and bloating. Lactulose can rarely cause dehydration and 
hypernatremia (low blood sodium) and/or hypokalemia (low blood potassium).   
 
There may be additional risks that are unknown or unexpected. 
8.4 STUDY MODIFICATION/DISCONTINUATION 
 
The study may be modified or discontinued at any time by Michigan Medicine IRB as part of their duties 
to ensure that research subjects are protected. Any changes to the protocol or consent form require a 
written protocol amendment that must be approved by the IRB prior to implementation. These 
amendments, should they be required, will become part of the protocol and maintained by the 
Investigator as part of study documentation. If the Investigator or study coordinator implements a 
protocol change prior to IRB approval, the coordinator must notify the IRB via an ORIO report.  
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
19 
 
References  
1. 
Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838-51. 
2. 
Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al. Compensated cirrhosis: 
natural history and prognostic factors. Hepatology. 1987;7(1):122-8. 
3. 
Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN. Trends in burden of cirrhosis 
and hepatocellular carcinoma by underlying liver disease in US veterans, 2001–2013. Gastroenterology. 
2015;149(6):1471-82. e5. 
4. 
Allen AM, Kim WR, Moriarty JP, Shah ND, Larson JJ, Kamath PS. Time trends in the health care 
burden and mortality of acute on chronic liver failure in the United States. Hepatology. 2016;64(6):2165-
72. 
5. 
Tapper EB, Parikh ND. Mortality due to cirrhosis and liver cancer in the United States, 1999-
2016: observational study. BMJ. 2018;362:k2817. 
6. 
Tapper EB, Parikh ND, Sengupta N, Mellinger J, Ratz D, Lok AS-F, et al. A risk score to predict the 
development of hepatic encephalopathy in a population-based cohort of patients with cirrhosis. 
Hepatology. 2018;68(4):1498-507. 
7. 
Tapper EB, Halbert B, Mellinger J. Rates of and Reasons for Hospital Readmissions in Patients 
with Cirrhosis: A Multistate Population-based Cohort Study. Clinical Gastroenterology and Hepatology. 
2016. 
8. 
Carey EJ, Lai JC, Sonnenday C, Tapper EB, Tandon P, Duarte‐Rojo A, et al. A North American 
Expert Opinion Statement on Sarcopenia in Liver Transplantation. Hepatology. 
9. 
Tapper EB, Konerman M, Murphy S, Sonnenday CJ. Hepatic encephalopathy impacts the 
predictive value of the Fried Frailty Index. American Journal of Transplantation. 2018;18(10):2566-70. 
10. 
Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, Lai M. Standard assessments of frailty are 
validated predictors of mortality in hospitalized patients with cirrhosis. Hepatology. 2015;62(2):584-90. 
11. 
Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, et al. Minimal hepatic 
encephalopathy is associated with falls. The American journal of gastroenterology. 2011;106(3):476-82. 
12. 
Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco J, Varma RR, et al. Minimal hepatic 
encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. 
Hepatology. 2009;50(4):1175-83. 
13. 
Murphy SL, Tapper EB, Blackwood J, Richardson JK. Why Do Individuals with Cirrhosis Fall? A 
Mechanistic Model for Fall Assessment, Treatment, and Research. Digestive diseases and sciences. 
2018:1-8. 
14. 
Patidar KR, Thacker LR, Wade JB, Sterling RK, Sanyal AJ, Siddiqui MS, et al. Covert hepatic 
encephalopathy is independently associated with poor survival and increased risk of hospitalization. The 
American journal of gastroenterology. 2014;109(11):1757-63. 
15. 
Tapper EB, Zhao L, Nikirk S, Baki J, Parikh ND, Lok AS, et al. Incidence and Bedside Predictors of 
the First Episode of Overt Hepatic Encephalopathy in Patients With Cirrhosis. Official journal of the 
American College of Gastroenterology| ACG. 2020. 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
20 
 
APPENDICES 
Appendix A.  Demographics Questionnaire 
Appendix B.  Health History Questionnaire 
Appendix C.  Short Form Health Survey-8 (SF-8) 
Appendix D.  Animal Naming Test (ANT) 
Appendix E.  Alcohol Use Disorder Identification Test (AUDIT-C) 
Appendix F.  Final Screening Questions 
Appendix G.  Health Follow-Up Questionnaire  
Appendix H.  Bristol Stool Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
21 
 
Appendix A.  Demographics Questionnaire 
Mi-Kristal Trial Demographics Questionnaire 
   
Instructions: Please answer the following demographics questions. Please note that your answers will be kept 
completely confidential. Please record the date the form was completed on the top of this page.  
 
1. 
What is your age in years?   
 
Age: ______________ 
 
2. 
What is your sex? 
 Male                                 
 Female                 
 Other (please state): _____________    
3.  What is your ethnicity? 
 Hispanic or Latino 
 Not Hispanic or Latino 
 Unknown 
 Not Reported  
4.   What is your race? (select all that apply)    
 American Indian or Alaska Native                                   
 White                 
 Asian                                                                           
     
 Unknown 
 Black or African-American                                                
 Not Reported 
 Native Hawaiian or Other Pacific Islander                                                                              
 
5.   What is the highest education level that you have completed? 
 No schooling completed 
                                    
 Nursery school to 8th grade 
 
 Some high school, no diploma 
                                    
 High school graduate 
 
 GED or equivalent 
                                    
 Some college, no degree  
 Associate degree: occupational, technical, or vocational program  
 Associate degree: academic program    
  
 Bachelor's degree (e.g., BA, AB, BS, BBA) 
 
 Master's degree (e.g., MA, MS, MPH, MEng, MEd, MBA) 
 Professional school degree (e.g., MD, DDS, DVM, JD) 
 
 Doctoral degree (e.g., PhD) 
                                    
 Unknown       
                    6.  What is your marital/partner status? 
 Never Married/Single            
 
 Separated  


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
22 
 
 Married                                    
         
 Divorced 
 Domestic Partnership            
         
 Widowed 
7.  What is your current employment status?  
 Employed full-time 
 
 
 Employed part-time   
 
 Retired  
 
 
 
 On disability  
 
 Not employed 
 
8.   What is your annual income? 
 Less than $10,000 
       
 $75,000 to $99,999 
 
 $10,000 to $14,999 
       
 $100,000 to $149,999 
 
 $15,000 to $24,999 
       
 $150,000 to $199,999 
 
 $25,000 to $34, 999                                    
 $200,000 or more 
 $35,000 to $49,999 
       
 Unknown        
 $50,000 to $74,999 
 
9.  What type of geographic area do you live in?  
 Rural 
 
 
 
 Suburban  
 
 
 
 
 
 Urban 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
23 
 
 Appendix B. Health History Questionnaire 
 
Mi-Kristal Trial Health History Questionnaire 
   
Instructions: Please answer the following questions about your health history to the best of your knowledge. 
Please record the date the form was completed on the top of this page.  
 
1. 
What is the underlying cause of your cirrhosis? (check all that apply) 
 Alcohol                             
 
 Nonalcoholic fatty liver disease (NAFLD)                
 Hepatitis C                        
 
 Primary biliary cirrhosis (PBC) 
 Hepatitis B                               
 
 Primary sclerosing cholangitis (PSC) 
 Autoimmune Hepatitis          
 
 Other (please specify): _____________________ 
2. 
Do you currently have liver cancer? 
 Yes                                 
 No                 
 Unknown                                
a. If “No” or “Unknown,” do you have any history of liver cancer?                                        
 Yes                                
 
 No                 
 Unknown                                
3.  Are you on the liver transplant waiting list? 
 Yes 
 No 
 Currently undergoing transplant evaluation 
 Recently removed from the transplant waiting list 
4.1 If recently removed, how long ago was removal (in months): _____________________ 
4.2 If recently removed, specify reason for removal: _______________________________ 
4.   Have you stopped driving within the past 6 months? 
 Yes  
 Stopped driving more than 6 months ago 
 No                                                                                                     
 
5.   Are you dependent upon assistance from anyone for any of the following (check all that apply)? 
 Bathing 
 
                  
 Getting out of bed or chair 
 
 
 Dressing 
  
                  
 Eating 
 Using the toilet/going to the bathroom             
 None 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
24 
 
6.  Have you been hospitalized in the past 90 days?  
 No  
 
 
 
 
 
 Yes  
6.1  If yes, number of hospitalizations:    
 1   
 
 2  
 3   
 More than 3 
7.  Have you had an Emergency Room (ER) visit in the past 90 days?  
 No  
 
 
 
 
 
 Yes  
      7.1  If yes, number of ER visits:      
                
 1        
 2  
 3   
 More than 3 
8.  Do you have ascites (accumulation of fluid in the abdomen)?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
 
 
 
9.   Do you currently take diuretics/water pills (e.g. Lasix/Furosemide,  Aldactone/Spironolactone)?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
10.  Have you had a paracentesis (a procedure to remove fluid from the abdomen) within the last 90 
days? 
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
11.  Have you have a Transjugular intrahepatic portosystemic shunt (TIPS)? 
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
12.  Are you currently receiving dialysis?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
13.  Do you have diabetes?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
25 
 
14.  Do you have congestive heart failure (CHF)?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
15.  Do you have chronic obstructive pulmonary disease (COPD)?  
 Yes  
 
 
 
 No   
 
 
 
 
 Unknown 
16.   During the past month, how would you rate your sleep quality overall?  
 Very Good 
 
 
 
 
 Fairly Good   
 
 
 
 
 Fairly Bad 
 Very Bad 
17.  Have you had any falls in the past 4 weeks?  
 Yes  
 
 
 
 No  
      17.1  If yes, number of falls: _________ 
18.  What is the current (past 2 weeks) average number of bowel movements you have per day? 
_________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
26 
 
Appendix C.  SF-8 
 
Mi-Kristal Trial SF-8 Health Survey  
   
Instructions: This survey asks for your views about your health. This information will help you keep track of how 
you feel and how well you are able to do your usual activities. Answer every question by selecting the answer as 
indicated. If you are unsure about how to answer a question, please give the best answer you can. For each of the 
following questions, please mark an [x] in the one box that best describes your answer. Please note that your 
answers will be kept completely confidential. Please record the date the form was completed on the top of this 
page.  
 
3. Overall, how would you rate your health during the past 4 weeks? 
 
 Excellent           
 Very good         
 Good  
       
 Fair 
  
 Poor 
 Very poor 
 
4. During the past 4 weeks, how much did physical health problems limit your usual physical activities (such as 
walking or climbing stairs)? 
 
   
 None at all      
 Very little     
 Somewhat     
 Quite a lot    
 Could not do physical activities  
 
5. During the past 4 weeks, how much difficulty did you have doing your daily work, both at home and away 
from home, because of your physical health? 
 
   
 None at all          
 A little bit          
 Some              
 Quite a lot        
 Could not do daily work 
 
6. How much bodily pain have you had during the past 4 weeks? 
 
   
 None           
 Very mild           
 Mild             
 Moderate        
 Severe         
 Very Severe 
 
7. During the past 4 weeks, how much energy did you have? 
 
 
 Very much             
 Quite a lot            
 Some                
 A little               
 None 
 
8. During the past 4 weeks, how much did your physical health or emotional problems limit your usual social 
activities with family or friends? 
 
   
 None at all       
 Very little       
 Somewhat     
 Quite a lot      
 Could not do social activities 
 
9. 
During the past 4 weeks, how much have you been bothered by emotional problems (such as feeling 
anxious, depressed or irritable)? 
 
   
 None at all             
 Slightly              
 Moderately              
 Quite a lot           
 Extremely 
 
10. During the past 4 weeks, how much did personal or emotional problems keep you from doing your usual 
work, school or other daily activities? 
 
   
 None at all        
 Very little       
 Somewhat     
 Quite a lot     
 Could not do daily activities  
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
27 
 
Appendix D.  ANT 
 
 
Mi-Kristal Trial Animal Naming Test 
Instructions: Instruct the subject to recall and name as many animals as possible and track the subject’s 
performance for 60-seconds. Set your stopwatch and tell the subject to start when you say GO. Tell the subject 
to STOP when the stopwatch reads 60-seconds. Keep track of the number of animals they say with the space 
provided below. When the test is done add your tally marks and indicate the total in the box below. The score is 
the number of correctly produced animal names during the 60-seconds. Please record the date the form was 
completed on the top of this page.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use this space to keep tally of the number of correctly pronounced 
animal names 
 
 
 
 
 
 
 
 
SCORE (The sum of all correctly produced animal names)      
                                                                
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
28 
 
Appendix E.  AUDIT-C 
 
Mi-Kristal Trial AUDIT-C Questionnaire 
   
Instructions: Please answer the following questions related to alcohol use to the best of your knowledge. Please 
note that your answers will be kept completely confidential. Please record the date the form was completed on 
the top of this page. 
   
1.   How often did you have a drink containing alcohol in the past year? 
 Never           
 
 Monthly or less       
 2-4 times per month           
 
 2-3 times per week       
 4 or more times a week       
2.   How many drinks containing alcohol did you have on a typical day when you were drinking in the 
past year? 
 1 or 2 drinks 
 3 or 4 drinks       
 5 or 6 drinks           
 
 7 to 9 drinks       
  10 or more drinks            
3.   How often did you have six or more drinks on one occasion in the past year? 
 Never           
 
 Less than monthly       
 Monthly           
 
 Weekly       
 Daily or almost daily             
 
        
      
 
 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
29 
 
Appendix F.  Final Screening Questions 
 
Mi-Kristal Trial Final Screening Questions 
   
Instructions: Below are the final screening questions for potential subjects. Ask potential subjects these 
questions prior to consent to confirm eligibility. Please record the patient’s Screening ID and the date the form 
was completed on the top of this page. If the patient is enrolled as a subject, this document should be retained 
in their study chart.  
   
1.   Have you ever had a liver transplant? (patient must answer NO to be eligible) 
 Yes           
 
 No       
2.   Have you ever taken lactulose? (patient must answer NO to be eligible) 
 Yes           
 
 No       
3.   Have you been told by doctor that you have hepatic encephalopathy (HE) within the past 6 months? 
(patient must answer NO to be eligible) 
 Yes           
 
 
 No       
4.    Are you currently eating a low galactose diet? (patient must answer NO to be eligible) 
 Yes           
 
 
 No       
5.   During the past seven days, how much did your CIRRHOSIS affect your ability to do your regular 
daily activities, other than work at a job? (patient must answer ≥ 3 to be eligible) 
 
By regular activities we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If CIRRHOSIS affected your daily activities only a little, 
choose a low number. Choose a high number if CIRRHOSIS affected your activities a 
great deal.   
 
CIRCLE A NUMBER 
 
 
CIRRHOSIS had no 
effect on my work 
 
 
 
 
 
 
 
 
 
 
 
CIRRHOSIS completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
30 
 
                      6.  Based on preliminary screening and these responses, is the patient eligible to participate in this study? 
 Yes, they are eligible, and they have been enrolled. Their subject ID is ____________. 
  
 Yes, they are eligible, but they have not been enrolled because _________________.          
 No, they are not eligible because _________________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
31 
 
Appendix G.  Health Follow-Up Questionnaire  
 
Mi-Kristal Trial Follow-Up Health Questionnaire 
   
Instructions: Please answer the following questions to the best of your knowledge. Please record the date the 
form was completed on the top of this page.  
 
1.  Have you been hospitalized since you enrolled in this study?  
 No  
 
 
 
 
 
 Yes  
6.1  If yes, number of hospitalizations: _________ 
2.   During the past month, how would you rate your sleep quality overall?  
 Very Good 
 
 
 
 
 Fairly Good   
 
 
 
 
 Fairly Bad 
 Very Bad 
3.  Have you had any falls since you enrolled in this study?  
 Yes  
 
 
 
 No  
      18.1  If yes, number of falls: _________ 
4.  What is the current average number of bowel movements you have per day? _________ 
5.   During the past seven days, how much did your CIRRHOSIS affect your ability to do your regular 
daily activities, other than work at a job?  
 
 
By regular activities we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If CIRRHOSIS affected your daily activities only a little, 
choose a low number. Choose a high number if CIRRHOSIS affected your activities a 
great deal.   
 
CIRRHOSIS had no 
effect on my work 
 
 
 
 
 
 
 
 
 
 
 
CIRRHOSIS completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
 
 


 
Mi-Kristal Protocol 
Version 1.1 (November 1, 2021) 
 
 
32 
 
Appendix H.  Bristol Stool Chart 
 
Mi-Kristal Trial Stool Chart 
   
Instructions: This Stool Chart (see below) shows pictures of seven different types of stool. In 15 days, we will 
contact you and ask you to describe what your stool looks like in reference to this chart.