Effect of Difelikefalin on CKD-Associated Pruritus in Patients on Maintenance Hemodialysis: A Randomized, Placebo-Controlled Trial
Phase: NA
Conditions: Itching Symptoms, CKD 5D, Hemodialysis
Sponsor: Chittagong Medical College

THESIS PROTOCOL
TITLE
Effect of Difelikefalin on CKD-Associated Pruritus in Patients on
Maintenance Hemodialysis: A Randomized, Placebo-Controlled Trial
NCT Number: Not Yet
Date:April 2026

INVESTIGATOR:
Dr. Md.Shariful Islam Sarker
Resident Student
MD (Nephrology) Phase-B
Session: March, 2024
GUIDE:
Prof. Dr. Md Nurul Huda
MBBS, MCPS (Medicine), FCPS (Medicine),
MD (Nephrology), FISN,FASN
Professor and Head
Department of Nephrology
Chittagong Medical College and Hospital
CO-GUIDE:
Dr. Mohammad Shafiul Haider Chowdhury
MBBS, MD (Nephrology)
Associate professor
Department of Nephrology
Chittagong Medical College and Hospital

To
The Principal
Chittagong Medical College
Chattogram.
Subject: Application for the approval of Thesis Protocol with the title“Effect of
Difelikefalin on CKD-Associated Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-Controlled Trial”
Sir,
With due respect and humble submission, I would like to state that I am a student of
MD Phase B (Nephrology), at BSMMU, Dhaka. As per requirement of the course, I
would like to perform my research work on the thesis with the above-mentioned title
under the direct supervision of Prof. Dr. Md Nurul Huda, Professor and Head,
Department of Nephrology, Chittagong Medical College and Hospital, Chattogram,
Bangladesh.
I therefore, like to request you to approve my protocol so that I can commence my
work in your esteemed institute to complete my thesis in due time.
Obediently Yours
Dr. Md.Shariful Islam Sarker
MD (Nephrology-Phase B)
Department of Nephrology
Chittagong Medical College and Hospital
Chattogram, Bangladesh

CMC Ethical Review Committee
Chattogram Medical College
Chattogram-4000, Bangladesh
Tel-031619400, Fax-630180
Application for Ethical Clearance of Studies for post-Graduate Thesis
1.
Name of the applicant
:
Dr. Md.Shariful Islam Sarker
2.
Course
:
MD (Nephrology –Phase B)
3.
Category
:
Government
4.
Title of the study
:
“Effect of Difelikefalin on CKD-Associated
Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-
Controlled Trial”
5.
Type of the study
:
Randomized, placebo-controlled,
double-blinded, single-center trial
6.
Duration of the study
:
One Year & Six months
7.
Any collaboration
:
No
8.
Conflict of interest
:
None
9.
Name of the Guide
:
Prof. Dr. Md Nurul Huda,
Professor and Head,
Department of Nephrology
Chittagong Medical College and Hospital
Chattogram, Bangladesh
10.
Name of the Co-Guide
:
Dr. Mohammad Shafiul Haider Chowdhury
MBBS, MD (Nephrology)
Associate professor
Department of Nephrology
Chittagong Medical College and Hospital.

Check Documents being submitted herewith to committee:
1.
Summary
: Attached
2.
Umbrella proposal initially
: NA
3.
Protocol and CRF
: Attached
4.
Informed consent form for subject
: Attached
5.
Verbal consent form for subjects
: NA
6.
Procedure for Maintaining Confidentiality
: Attached
7.
Schedule of the study
: Attached

Declaration
I agree to obtain approval of the Ethical Review Committee for any changes involving
the rights and welfare of subjects or any changes of the methodology before making
any such changes.
…………………………………
Principal investigator/Student
Dr. Md.Shariful Islam Sarker
MD (Nephrology-Phase B)
Department of Nephrology
Chittagong Medical College and Hospital
Chattogram, Bangladesh
Forwarding from the Guide
………………………………
Guide
Prof. Dr. Md Nurul Huda,
Professor and Head,
Department of Nephrology,
Chittagong Medical College and Hospital,
Chattogram, Bangladesh

CHITTAGONGMEDICAL COLLEGE
Application for the Ethical review of thesis protocol
1.
Name of the applicant
:
Dr. Md.Shariful Islam Sarker
2.
Course
:
MD (Nephrology Phase B)
3.
Category
:
Government
4.
Title of the study
:
“Effect of Difelikefalin on CKD-Associated
Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-
Controlled Trial”
5.
Type of the study
:
Randomized, placebo-controlled, double-
blinded trial
6.
Duration of the study
:
One Year & Six months
7.
Any collaboration
:
No
8.
Conflict of interest
:
None
9.
Name of the Guide
:
Prof. Dr. Md Nurul Huda,
Professor and Head,
Department of Nephrology
Chittagong Medical College and Hospital,
Chattogram, Bangladesh
10.
Name of the Co-Guide
:
Dr. Mohammad Shafiul Haider Chowdhury
MBBS, MD (Nephrology)
Associate professor
Department of Nephrology
Chittagong Medical College and Hospital
Chattogram, Bangladesh.
11.
Signature of the Guide
:
12.
Signature of the Co-Guide
:
13.
Submission date
:
14.
Signature of the Student
:
For Official use:
Serial No:
Received on:
Reviewed on:
Comment:
Member-Secretary ERB
Chairperson ERB

Circle the appropriate answer to each of the following
(If not Applicable write NA)
1. Source Population:
4. Are subjects clearly informed about:
(a) Ill Subjects
√Yes
No
(a) Nature and purpose
of the study
√Yes
No
(b) Non* ill subjects
Yes
√No
(b) Procedures to be
followed including
alternatives used
√Yes
No
(c) Minors or persons under
guardianship
Yes
√No
(c) Physical risks
√Yes
No
(d) Private questions
√Yes
No
2. Does the study involve:
(e) Invasion of the Body
√Yes
No
(a) Physical risks to subjects
√Yes
No
(f) Benefits to be
Derived
√Yes
No
(b) Social risks
Yes
√No
(g) Right to refuse to
participate or
withdraw from the study
√Yes
No
(c) Psychological risks to
subjects
Yes
√No
(h) Confidential handling
of data
√Yes
No
(d) Discomfort to
Subjects
√Yes
No
(i) Compensation where
there are risks or loss of
working time or privacy
is involved in any
particular procedure
√Yes
No
(e) Invasion of the body
√Yes
No
(f) Invasion of privacy
Yes
√No
(g) Disclosure of information
damaging to subject or others
Yes
√No
5. Will informed consent be required
(a) From subject
√Yes
No
(b) From parent or
Guardians
Yes
√No
3. Does the study involve:
(a) Use of records (hospital,
medical, death, birth or
other)
Yes
√No
6. Will precautions will
be taken to protect
anonymity of subjects
√Yes
No
(b) Use of fetal tissue or
abortus
Yes
√No
(c) Use of organs or body
fluids
Yes
√No

Chittagong Medical College
Chattogram-4000, Bangladesh
Tel-031619400, Fax-630180
Research Proposal
For Post Graduate Thesis/Dissertation
Part - A
1.
Title of the study
:
“Effect of Difelikefalin on CKD-Associated
Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-
Controlled Trial”
2.
Name of the applicant
:
Dr. Md.Shariful Islam Sarker
3.
Course
:
MD (Nephrology Phase B)
4.
Place of Study
:
Department of Nephrology, Chittagong
Medical College Hospital, Chattogram.
5.
Sponsoring
:
Not Applicable
6.
Duration of the study
:
One and half years.
7.
Date of Commencement
:
8.
Date of completion
9.
Total cost
:
3,75,120/=
10.
Other support of proposed research
i.
: In this research project being supported by any other source?
N
o
ii.
Has an application for funding of this project has been submitted to any other
organization (s)?
N
o
11.
Date of submission
:
12.
Signature of student
:
13.
Signature of Guide
:
14.
Endorsement of the course coordinator
Name and Signature
Designation
Official Seal

Part – B
Student’s Information Sheet
…………………………..
Signature of the Student
1.
Name
:
Dr. Md.Shariful Islam Sarker
Designation
:
Student, MD (Nephrology Phase B)
Official address with telephone & mail
:
Department of Nephrology, Chittagong
Medical College Hospital, Chattogram
Phone:01738647201
Email:sobujshariful@gmail.com
Present residential address
:
2.
Academic Background
:
Degree
Institute
University/Board
Field
Year
M.B.B.S
Passed
3.
Field of study
:
Nephrology
4.
Research experience
:
None
5.
Percentage of time to be devoted to this
project
:
100%
6.
Number of Scientific Publication
:
None

3
PART-C
Summary
Background: Pruritus is a common and distressing symptom among hemodialysis
patients with chronic kidney disease (CKD), significantly impacting their quality of life.
Difelikefalin, a selective kappa-opioid receptor agonist, has shown promise in alleviating
CKD associatedpruritus(CKDaP) However, its efficacy and safety in the Bangladeshi
population remain under-explored. Objectives:This study aims to evaluate the effect of
Difelikefalin, compared to placebo, in reducing pruritus, improving quality of life in CKD
patients on maintenance hemodialysis.Materials and Methods: A randomized, placebo-
controlled trail, double-blinded, will be conducted in the Department of Nephrology of
chittagong Medical College Hospital ,Chattogram ,Bangladesh for one and half years. A
total of one hundred two CKD patients on maintenance hemodialysis will be included in
this study.Patient with moderate-to-severe pruritus (Worst Itching Intensity Numerical
Rating Scale [WI-NRS] score ≥4) will be enrolled and randomly assigned in a 1:1 ratio
to receive either Difelikefalin (0.5 mcg/kg) or a placebo intravenously after each
heamodialysis for 6 weeks. The primary outcome measure will be the change in WI-NRS
score from baseline to week 6. Secondary outcomes will be measured by Skindex 10
scale.Adverse events and safety measures will also be recorded. The primary analysis
will follow either an intention-to-treat or a per-protocol approach and will be performed
using SPSS version 27.Discussion:Data from previous studies indicate that Difelikefalin
can reduce the severity of itching and improve the quality of life in CKD patients on
maintenance hemodialysis. Clinical trials are needed to better understand the safety and
efficacy of Difelikefalin in CKD patients in our population.

34
PART-D
1. Introduction:
Chronic kidney disease-associated pruritus (CKD-aP), alternatively termed Uremic
pruritus (UP), represents a frequent, distressing, and often incapacitating clinical
manifestation among individuals diagnosed with chronic kidney disease (CKD) or
end-stage renal disease (ESRD) (Elhag et al., 2022; Elsayed et al., 2023).
Characterized by persistent, intense itching—typically generalized but occasionally
localized—CKD-aP disproportionately affects patients undergoing hemodialysis, with
epidemiological studies reporting a strikingly variable prevalence ranging from 22%
to 84% in this population. Notably, a substantial subset of these patients,
approximately 20–40%, endure moderate-to-severe pruritus, which profoundly
diminishes their quality of life (Daraghmeh et al., 2022; Rehman et al., 2018).
The ramifications of CKD-aP extend far beyond superficial discomfort. The condition
is intricately linked to a constellation of physical and psychological burdens,
including chronic sleep disturbances such as insomnia, relentless fatigue, and
dermatological complications arising from repetitive scratching, such as excoriations,
lichenification, and secondary infections (Lu et al., 2021; Lu et al., 2022).
Psychosocially, patients frequently grapple with emotional distress, including feelings
of embarrassment, social withdrawal, and stigmatization due to visible skin lesions,
which may exacerbate preexisting mental health challenges like anxiety, depression,
and irritability. Furthermore, emerging evidence underscores a concerning association
between CKD-aP and elevated mortality risks; dialysis-dependent patients with CKD-
aP exhibit higher rates of all-cause mortality, as well as increased fatalities linked to
cardiovascular events and systemic infections, suggesting a potential interplay
between chronic inflammation, immune dysregulation, and disease progression
(Grochulska et al., 2019; Sukul et al., 2021).There is, therefore, a need for effective
interventions for the treatment of CKD-aP.Off-label treatments may include
antihistamines, topical corticosteroids, and gabapentin or pregabalin; although there
are reports that treatments like gabapentin and pregabalin are effective at reducing
itch, their side effects sometimes prevent their use in this patient population (Hercz et
al., 020; Skrzypczak et al., 2024).

3
The pathogenesis of CKD-aP is incompletely understood.Several hypotheses have
been proposed, including metabolic disturbances, dysregulated immune response, and
imbalances in the endogenous opioid system, with peripherally distributed kappa
opioid receptors potentially playing a role (Brennan 2024; Skrzypczak et al., 2024).
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that
exerts antipruritic effects by means of activation of kappa opioid receptors on
peripheral neurons and immune cells (Gardell, et al., 2008). The hydrophilic small-
peptide structure restricts passive diffusion across membranes, thereby limiting access
to kappa opioid receptors in the central nervous system (O’Connor et al., 2010).
European Medicines Agency (EMA) and Federal Drug Administration (FDA)
approved difelikefalin, the first drug specifically indicated for CKD-aP in dialyzed
patients, which demonstrated efficacy in two Phase 3 clinical trials (Topf et al., 2022).
The development of this targeted medication, supported by solid evidence of its
effectiveness and safety, increased awareness and understanding of this condition
(Buades et al., 2024). According to the most current expert recommendations,
difelikefalin should be first-line medication for patients with moderate-to-severe
CKD-aP undergoing dialysis (Agarwal et al., 2022; Skrzypczak et al., 2024).13 Other
therapies should only be considered as first-line choice for those patients only if
difelikefalin is not available (Agarwal et al., 2022; Skrzypczak et al., 2024).
Although difelikefalin showed promise as a treatment for CKD-aP in dialyzed
patients, particularly through its selective κ-opioid receptor agonist activity, the
current body of evidence has limitations. Approximately 20% of patients did not
report clinically meaningful reductions in itch intensity, 30% did not present clinically
relevant improvements in QoL (Weiner et al., 2022). Several studies, including the
pivotal KALM-1 and KALM-2 trials, demonstrated significant efficacy in reducing
itch intensity and improving quality of life in hemodialysis patients (Topf et al.,
2022).

3
Defelikefalin's safety varies according to dose. Regarding safety, the majority of
research revealed that adverse effects increased in frequency in a way that was dose
dependent. Across all trials, nausea, vomiting, dizziness, diarrhea, and disturbances in
gait were the most frequently reported adverse events (Enggalhardjo, et al., 2024). A
dosage of 0.5 μg/kg of difelikefalin proved to have the most favorable benefit-risk
profile, and it was safe to use up to 1.0 μg/kg (Narita et al., 2022).
Though difelikefalin appears to be a promising agent for the management of CKD-aP,
evidence is still under-powered due to the paucity of the current data; therefore, more
robustrandomized controlled trials (RCTs)are required to confirm the benefit of
difelikefalin (Saeed et al., 2024).
While
recent
clinical
trials
in
Western
populations
have
demonstrated
its
efficacy, data from low- and middle-income countries, such as Bangladesh, are
scarce. The prevalence of CKD in Bangladesh surpasses the global and even South
Asian averages.About 20 million people are suffering from chronic kidney disease,
and
of
them,
approximately
35,000–40,000
develop
ESRD
each
year
(MostafiandJabin 2023). This trial aims to evaluate the superiority of Difelikefalin
over placebo in reducing pruritus severity among hemodialysis patients in a tertiary-
level teaching hospital in Bangladesh.

3
2. Rationale
Pruritus in hemodialysis patients is a chronic and highly irritating condition associated
with chronic kidney disease (CKD) that adversely affects sleep, mood, social
participation and overall quality of life. The commonly used agents for CKD-
associated pruritus often have limited efficacy or tolerability in many patients. Oral
medications used to manage this condition are frequently associated with poor
compliance due to a high pill burden. On the other hand, intravenous administration
of difelikefalin after hemodialysis offers a practical and patient-friendly alternative. It
uses the same dialysis access, avoiding the need for extra needle insertions. Previous
studies have demonstrated that difelikefalin improves outcomes in patients with CKD-
associated pruritus and enhances their quality of life. To my extensive search, data
regarding the use of difelikefalin for CKD-associated pruritus in our population is
scarce. This study aims to explore the effect of difelikefalin on CKD-associated
pruritus in maintenance hemodialysis (MHD) patients in our population.
.

3
3.1. Research questions:
What is the effect of difelikefalin on CKD-associated pruritus in patients on
maintenance hemodialysis?
3.2 Research hypothesis:
Difelikefalin effectively reduces CKD–associated pruritus in maintenance
hemodialysis patients.
4. Objectives
4.1 General objective:

To evaluate the effect of difelikefalin in CKD-associated prurituson
maintenance hemodialysis patients.
4.2 Specific objectives:
I.
To determine the baseline scores of the WINRS scale and Skindex-10 scale in
CKD-associated pruritus on maintenance hemodialysis patients..
II.
To estimate and compare the changes in the WINRS scale, and Skindex-10
Scale between the experimental and control groups.
III.
To assess the tolerability and detect any adverse effect of Difelikefalin in
patients with CKD-associated pruritus on maintenance hemodialysis
throughout the study period.

3
5. Materials and method:
5.1. Type of study:Randomized, placebo-controlled,double-blinded trial,
5.2 Place of Study: Department of Nephrology, Chittagong Medical College
Hospital, Chattogram, Bangladesh.
5.3 Study period: One and half years from acceptance of protocol.
5.4 Study population: Adult CKD stage-5 patients on MHD in the dialysis unit ofthe
Department of Nephrology,CMCH during the study period.
5.5 Study groups: Based on the interventions,there will be two groups in the study
I. Experimental group:
Standard symptomatic treatment for itching + Intravenous difelikefalin
II. Control group:
Standard symptomatic treatment for itching + Placebo
5.6 Sampling technique: Consecutive sampling. From the Selected participants, the
intervention and control will be randomly assigned in a 1:1 ratio (block size of four)
through computer- generated randomization.

40
5.7. Inclusion criteria:
i.
Adults aged ≥18 years.
ii.
Patient with chronic kidney disease on HD for ≥3 months.
iii. Moderate-to-severe pruritus (WI-NRS score ≥4).
iv. Able to communicate clearly with the Investigator .
v.
Willing and able to provide written informed consent prior to participating in this
study.
5.8 Exclusion criteria
i.
Known case of Primary skin disesease associated with Itching.
ii.
Known case of liver disease.
iii. Known case of iron defeciency anaemia ,hematological malignancy.
iv. Known case of hypothyroidism & hyperthyroidism.
v.
Known case of allergic reaction to Opiates .
vi. Pregnancy.
vii. Drug abuse, or substance dependence.

4
5.9. Sample size: Sample size calculation for hypothesis testing of difference between
two proportions:
𝑛= 𝑝100 −𝑝+ 𝑞100 −𝑞
𝑝−𝑞2
𝑧𝛼+ 𝑧𝛽
2
Where,
Zα = Z value of standard normal distribution at a definite level of significance
Zβ = Z value of standard normal distribution at a definite level of power
p = Proportion of patients with expected outcome (response rate) in the
experimental group
q= Proportion of patients with expected outcome (response rate) in the control
group
Here,
Z∝= 1.96 at 95% Confidence Interval
Zβ =1.63 at 95 % power
p= 64% (Fishbane et al., 2020b)
q= 29% (Fishbane et al., 2020b)
So,
𝑛= 64 100.0 −64 + 29 100.0 −29
64 −29 2
1.96 + 1.63 2 ≈46
Considering 10% lost to follow-up final sample will be
(46 + 46 × 10%) ≈50.6≈51
That means 51 patients in each group will be needed in each group to test the
hypothesis.

4
5.10. List of variables
Variables
Type
Value
Expression
Clinical
Age
Discrete
In completed years
Mean±SD
Sex
Categorical
Male/Female
Frequency (%)
Duration of HD
Discrete
In completed years
Mean±SD
Duration of prutitus
Discrete
In completed months
Mean±SD
Cause of CKD
Categorical
GN/HTN/DM
Frequency (%)
Baseline use of antipruritic
medication
Categorical
Absent/Present
Frequency (%)
WI-NRS score
Discrete
0-10
Mean±SD
Skindex-10 scale total score
Discrete
0-60
Mean±SD
Biochemical
Calcium
Continous
mmol/l
Mean±SD
Phosphate
Continous
mmol/l
Mean±SD
PTH
Continous
pg/ml
Mean±SD

4
Operational definitions:

Chronic Kidney Disease-Associated Pruritus: CKD-aPis defined as severe and
persistent itching directly related to kidney disease, without other underlying skin
or systemic causes to explain the itching. (Hector alve..et al 2020)

MHD: Maintenance haemodialysis was defined as regular haemodialysis
treatment for at least 3 months for the management of ESKD.(Mambap, A.T.,
Che, I.A., Mahamat, M. et al. 2022)

Skindex-10: The Skindex-10 scale was developed specifically for uremic pruritus
and measures the weekly effect of itch across three domains (disease, mood and
emotional distress, and social functioning) Scores on the Skindex-10 scale range
from 0 to 60, with higher scores indicating worse itch-related quality of life.
(Mathur et al., 2010).

Moderate-to-severe pruritus will be defined as a mean score of >4 points on the
24-hour WI-NRS score calculated.Itching severity scores have been categorized
in the literature as mild (<4), moderate (≥4 to<7), or severe (≥7) (Reich et al.,
2012).

Efficacy outcomes: The primary efficacy outcome will be the percentage of
patients who will have an improvement (decrease) of at least 3 points from
baseline at week 6 in the weekly mean score on the daily WI-NRS (Fishbane et
al., 2020). The prespecified secondary efficacy outcomes will be the mean change
from baseline at week 6 in the Skindex-10 scale total score (Fishbane et al.,
2020).

Standard Symptomatic Treatment for Itching:
Standard Symptomatic
treatment
using
antihistamin
is
useful.
Gabapentin
or
Pregabalin
UVB
therapy ,oral charcoal or nalfuralfine might be the next line of therapy.(Mettang
and kremer 2014)

44
5.11. Data collection instrument: A structured pretested case record form.
5.12. Data collection procedure:
Baseline assessment: CKD patients in HD will be screened consecutively and
prospectively by the above inclusion and exclusion criteria to select eligible patients.
Eligible patients and their legal relatives will then fully explain the study protocol,
their role in the study, and the risks of the study. They will be informed of their right
to withdraw from the study at any stage. After getting written informed consent, they
will be finally enrolled in the study. Detailed history clinical examination and relevant
investigation
will
be
done.
Baseline
demographic,
clinical
and
biochemical
information will be collected from the patients using the case record form and the
scales. Blood samples will be collected after an overnight fasting period, with all
aseptic precaution 5 mL of venous blood drawn into appropriate vacutainers. iPTH
will be measured using a chemiluminescence immunoassay (CLIA).Serum calcium
and phosphate will be analyzed using colorimetric methods on a Beckman Coulter
AU480 or equivalent validated clinical chemistry analyzer.
Allocation: Once a participant is enrolled in the study and consents to participate,
they will be assigned to a treatment group according to the randomization sequence.
This assignment will be done immediately after the baseline assessment to ensure that
it is truly random. Patients will be randomly assigned to either experimental group or
placebo group with a 1:1 allocation. Randomization will be carried out using online
software (Research Randomizer Version 4.0 at https://www.randomizer.org).
Blinding: The study will be conducted as a double-blind trial, meaning that both the
participants and the investigators will be unaware of the treatment assignments.
Interventions:
In the experimental group:
Standard symptomatic treatment for itching + Difelikefalin Dose : 0.5 μg per
kilogram of weight after each dialysis session.
Duration: 6 wks
In the control group:
Standard symptomatic treatment for itching + Placebo
Duration: 6 wks

4
Follow-up:
i.
At the end 3 wks by- WI-NRS scale,Skindex 10 scale & Adverse events
ii.
At the End of 6 wks: WI-NRS scale,Skindex 10 scale & Adverse events
During the 6-week intervention period, patients will report their worst itching
intensity using the WI-NRS, and their quality of life will be assessed using the
Skindex-10 questionnaire at prespecified follow-up intervals throughout the 6-week
period.
Safety will be evaluated by monitoring adverse events, vital signs, clinical laboratory
measurements in both group.
5.13. Data analysis:
Data will be entered into an Excel sheet to generate the master sheet. After
compelition of data collection, master sheet will be fed into SPSS (Windows version
27.0) for analysis.This study has two types of data: Categorical and quantitative data.
Kolmogorov–Smirnov (K-S) test will be used to determine the data distribution.
Finding if there is a significant difference between the data, independent samples t-
test (or Mann–Whitney test in case of non-parametric data) and Chi-square test for
continuous and categorical data, respectively will be used. The difference between the
repeated variable in distinct visits using repeated ANOVA with the change from
baseline in the weekly mean WI-NRS scale,Skindex 10 Scale. The adjusted mean
difference between the groups and its two-sided 95% CI will be presented. A
p-
value<0.05 will be considered significance.

4
5.14. Expected outcomes: Difelikefalin will significantly reduce pruritus severity
compared to placebo. Participants receiving difelikefalin will report improvements in
quality of life and will exhibit a favorable safety profile, with no major adverse
events.
5.15. The utilization of results: This trial will provide critical evidence on the
effectiveness and safety of difelikefalin in a resource-limited setting, addressing a
significant unmet need in the management of CKD-aP. If proven effective,
difelikefalin could become a standard treatment option for CKDaP and improve the
quality of life for hemodialysis patients in Bangladesh and similar populations
globally. Efforts will also be made to present these results at conferences and publish
them
in
peer-reviewed
national
and
international
journals.
The
results
and
observations of the study will be published as a thesis and submitted to the respective
university as a part of the requirement for the MD (Nephrology) Phase B examination
purpose. The results of the study will be presented to the Department of Nephrology,
CMCH.
5.16. Ethical implication: Voluntary written consent will be taken from the
patient/and legal guardians. All measures will be taken to protect anonymity.The
interviews of the patient, clinical examination and investigations will be performed at
the respective hospital after explaining the nature and purpose of the study to them,
assuring that the information given by them will be used for the interest of the
community and that the particulars of the patients will not be disclosed anyway. An
independent safety monitoring committee conducted unblinded monitoring of patient
safety throughout the trial. The trial protocol will be approved by the Ethical Review
Committee of Chittagong Medical College.

4
Schedule:
Time Schedule (GANTT CHART)
1st
2nd
3rd
4th
5th -6th
7th -18th
19th -
21th
22th
-23th
24th
Problem
definition
Literature
review
Research
design
IRB clearance
Data
collection
Data analysis
Report
writing
Submission

4
5.17 Study flow chart:
Adult hemodialysis patients with CKD associated pruritus visited in the Department
of Nephrology of CMCH
↓
↓
Any exclusion criteria--àwill be excluded from study
↓(Fulfills inclusion criteria)
Consent given à No
àexclude
yes
Assessed for selection
Will be submitted to the university
Thesis writing
Result and discussion writing
Data Analysis by comparing different
variables Among two groups
Group 1: Experimental group
(Standard symptomatic treatment
for itching + IV difelikefalin)
Group 2: Control group
(Standard symptomatic treatment
for itching + Placebo)
Follow up
Follow up
Randomization
History & Clinical evaluation will be recorded in CRF

4
5.18 References:
Agarwal, R., Burton, J., Gallieni, M., Kalantar-Zadeh, K., Mayer, G., Pollock, C., and
Szepietowski, J. C., 2022.Alleviating symptoms in patients undergoing long-term
hemodialysis: a focus on chronic kidney disease-associated pruritus. Clinical kidney
journal, 16(1), pp.30–40.
Brennan, F., 2024. The Pathogenesis of CKD–Associated Pruritus (CKD-aP): A
Theoretical Model and Relevance for Treatment. Kidney360, pp.10-34067.
Buades, J.M., Figueras-Nart, I., Goicoechea, M., Villanueva, R.J.S. and Serra-
Baldrich, E., 2024. Information and consensus document for the diagnostic and
therapeutic management of pruritus associated with chronic kidney disease in patients
on haemodialysis in Spain. Nefrología, 44(4):465–474
Daraghmeh, M., Badran, M., Janajreh, A., Hassan, M., Taha, A.A., Koni, A.A. and
Zyoud, S.E.H., 2022. Prevalence of pruritus associated with hemodialysis and its
association with sleep quality among hemodialysis patients: a multicenter study. BMC
nephrology, 23(1), p.213.
Elhag, S., Rivas, N., Tejovath, S., Mustaffa, N., Deonarine, N., Hashmi, M.A.,
Yerneni, S., Hamid, P. and Hashmi, M.A., 2022. Chronic kidney disease-associated
pruritus: a glance at novel and lesser-known treatments. Cureus, 14(1), e.21127.
Brennan F. Emerging insights into the mechanisms of CKD-associated
pruritus.JNephrol Res. 2024;12(1):15–22.
Skrzypczak M, Piotrowski W, Wozniak A. Opioid receptor imbalances in CKD-
associated pruritus: A review of current evidence. Renal Med Int. 2024;10(2):89–96.
Elman, S., Hynan, L.S., Gabriel, V. and Mayo, M.J., 2010. The 5‐D itch scale: a new
measure of pruritus. British Journal of Dermatology, 162(3), pp.587-593.
Elsayed, M.M., Elgohary, I.E., Abdelhamid, H.H.S. and Zaki, S.A., 2023. The
effectiveness of sertraline in alleviating uremic pruritus in hemodialysis patients: a
randomized clinical trial. BMC nephrology, 24(1), p.155.

50
Enggalhardjo, M., Tumiwa, G.H. and Khosasih, Y., 2024.A Systematic Review of
Efficacy and Safety of Difelikefalin in Treating Pruritus in Hemodialysis Patients
with Chronic Kidney Disease. Medicinus, 13(2), pp.126-133.
Fishbane, S., Jamal, A., Munera, C., Wen, W. and Menzaghi, F., 2020a.A phase 3
trial of difelikefalin in hemodialysis patients with pruritus. New England Journal of
Medicine, 382(3), pp.222-232.
Fishbane, S., Mathur, V., Germain, M.J., Shirazian, S., Bhaduri, S., Munera, C.,
Spencer,
R.H.,
Menzaghi,
F.,
Aaronson,
M.,
Alford,
K.
and
Awad,
A.,
2020b.Randomized
controlled
trial
of
difelikefalin
for
chronic
pruritus
in
hemodialysis patients. Kidney international reports, 5(5), pp.600-610.
Gardell, L.R., Spencer, R.H., Chalmers, D.T. and Menzaghi, F., 2008. Preclinical
profile
of
CR845:
a
novel,
long-acting
peripheral
kappa
opioid
receptor
agonist. Poster Presentation at the International Association for the Study of Pain,
Glasgow, United Kingdom.
Grochulska, K., Ofenloch, R., Mettang, T. and Weisshaar, E., 2019. Mortality of
Haemodialysis Patients With and Without Chronic Itch: A Follow-up Study of the
German
Epidemiological
Hemodialysis
Itch
Study
(GEHIS). ActaDermato-
Venereologica, 99(4), pp.423-428.
Handelsman, L., Cochrane, K.J., Aronson, M.J., Ness, R., Rubinstein, K.J. and Kanof,
P.D., 1987. Two new rating scales for opiate withdrawal. The American journal of
drug and alcohol abuse, 13(3), pp.293-308.
Hercz, D., Jiang, S.H. and Webster, A.C., 2020. Interventions for itch in people with
advanced chronic kidney disease. Cochrane database of systematic reviews, (12),
CD011393.
Lu, P.H., Tai, Y.C., Yu, M.C., Lin, I.H. and Kuo, K.L., 2021. Western and
complementary alternative medicine treatment of uremic pruritus: A literature
review. Tzu Chi Medical Journal, 33(4), pp.350-358.
Lu, P.H., Chung, C.H., Chuo, H.E., Lin, I.H. and Lu, P.H., 2022. Efficacy of acupoint
stimulation as a treatment for uremic pruritus: a systematic review and meta-
analysis. Frontiers in Medicine, 9, p.1036072.

5
Mathur, V.S., Lindberg, J., Germain, M., Block, G., Tumlin, J., Smith, M., Grewal,
M., McGuire, D. and ITCH National Registry Investigators, 2010.A longitudinal
study of uremic pruritus in hemodialysis patients. Clinical Journal of the American
Society of Nephrology, 5(8), pp.1410-1419.
Mostafi,
M.
and
Jabin,
M.,
2023.Renal
disease
in
Bangladesh
perspective. Bangladesh Journal of Medicine, 34(3), pp.180-185.
Narita, I., Tsubakihara, Y., Uchiyama, T., Okamura, S., Oya, N., Takahashi, N.,
Gejyo, F., Yamamoto, A., Ichikawa, A., Ohishi, A. and Ishimura, A., 2022. Efficacy
and safety of difelikefalin in Japanese patients with moderate to severe pruritus
receiving hemodialysis: a randomized clinical trial. JAMA Network Open, 5(5),
pp.e2210339-e2210339.
O’Connor, S., Labissiere, G., Spencer, R., Chalmers, D. and Menzaghi, F., 2010,
August. Safety, pharmacokinetic and pharmacodynamic profile of CR845, a novel
peptidergic kappa opioid agonist in development for the treatment of acute pain and
itch [poster PT371]. In Biennial World Congress on Pain.
Rehman, I.U., Munib, S., Ramadas, A. and Khan, T.M., 2018. Prevalence of chronic
kidney disease-associated pruritus, and association with sleep quality among
hemodialysis patients in Pakistan. PloS one, 13(11), p.e0207758.
Reich, A., Heisig, M., Phan, N.Q., Taneda, K., Takamori, K., Takeuchi, S., Furue, M.,
Blome, C., AUgUSTIN, M., STäNDER, S. and SzEPIETOWSKI, J.C., 2012. Visual
analogue
scale:
evaluation
of
the
instrument
for
the
assessment
of
pruritus. ActaDermatoVenereologica, 92(5), p.497.
Saeed, A., Elshnoudy, I.A., Khlidj, Y., Radwan, R., Kamal, M., Hamdi, M., Alsaid,
A., Turkmani, M. and Abuelazm, M., 2024. The efficacy and safety of difelikefalin
for pruritus in hemodialysis patients: a systematic review and meta-analysis of
randomized controlled trials. Renal Failure, 46(2), p.e.2384590.
Skrzypczak, T., Skrzypczak, A., Nockowski, P. and Szepietowski, J.C., 2024.
Identification
and
Management
of
CKD-Associated
Pruritus:
Current
Insights. International Journal of Nephrology and Renovascular Disease, pp.339-354.

5
Smidt, A.C., Lai, J.S., Cella, D., Patel, S., Mancini, A.J. and Chamlin, S.L.,
2010.Development and validation of Skindex-Teen, a quality-of-life instrument for
adolescents with skin disease. Archives of dermatology, 146(8), pp.865-869.
Sukul, N., Karaboyas, A., Csomor, P.A., Schaufler, T., Wen, W., Menzaghi, F.,
Rayner, H.C., Hasegawa, T., Al Salmi, I., Al-Ghamdi, S.M. and Guebre-Egziabher,
F., 2021.Self-reported pruritus and clinical, dialysis-related, and patient-reported
outcomes in hemodialysis patients. Kidney medicine, 3(1), pp.42-53.
Topf, J., Wooldridge, T., McCafferty, K., Schömig, M., Csiky, B., Zwiech, R., Wen,
W., Bhaduri, S., Munera, C., Lin, R. and Jebara, A., 2022. Efficacy of difelikefalin for
the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis
of KALM-1 and KALM-2 phase 3 studies. Kidney Medicine, 4(8), e.100512.
Weiner, D.E., Vervloet, M.G., Walpen, S., Schaufler, T., Munera, C., Menzaghi, F.,
Wen, W., Bhaduri, S. and Germain, M.J., 2022. Safety and effectiveness of
difelikefalin in patients with moderate-to-severe pruritus undergoing hemodialysis: an
open-label, multicenter study. Kidney Medicine, 4(10), e.100542.

5
Part E
Budget:
Sl. No.
Head of expense
1stinstalment
1
Research tools development
10,000/-
2
Office assistance for organizing the materials
5,000/-
3
Lab Cost
156480/-
4
Drugs
152640/-
5
Report composing
20,000/-
6
Printing
15,000/-
7
Stationaries
5,000/-
8
Data analysis
5000/-
9
Transport/conveyance
1000/-
10
Miscellaneous
5000/-
Total amount
3,75,120/-

54
Appendix
Case record form
Protocol Title: “Effect of Difelikefalin on CKD-Associated Pruritus in Patients
on Maintenance Hemodialysis: A Randomized, Placebo-Controlled Trial“
Patient’s identification
1
Patient ID No.
2
Patient name :
3
Adress
4
Contact no:
5
Study group
Experimental=1 Control=2
Demographic characteristics
1
Age:
….……..…years
2
Sex:
0=Female 1=Male
Clinical characteristics
1
Duration of HD
….………..Months/years
2
Duration of pruritus
….………..Months/years
3
Etiology of CKD
1=HTN 2=DM 3=GN
4=Others
4
Baseline use of antipruritic
medication
Anti histamin-
Others-
5
Online Kt/V
Biochemical
1
Calcium(mmol/l)
2
Phosphate(mmol/l)
3
PTH(pg/ml)
Follow-up data
Baseline
At 3-wk
At 6-wk
1
WI-NRS score
2
Skindex-10 scale total score

5
Adverse Effect
3 weeks
6weeks
1
Nausea
N0= 0 Yes= 1
2
Vomiting
N0= 0 Yes= 1
3
Dizziness
N0= 0 Yes= 1
4
Abdominal pain
N0= 0 Yes= 1
5
Muscle spasm
N0= 0 Yes= 1
6
Fall
N0= 0 Yes= 1
7
Withdrawal
N0= 0 Yes=1
8
Expired
N0= 0 Yes= 1
9
Others
N0= 0 Yes= 1
Complete the study per the Protocol
0= No 1= yes
If not reason for drop-out
1. Adverse experience
2. Failure to return for follow-up
3. Patients refuse treatment
4. Patient died
5. Non-co-operation
6.Insufficient therapeutic response
Signature of the researcher:
Signature of the Guide/Co-guide

5

5

5
INFORMED CONSENT FORM
Department of Nephrology, Chittagong Medical College Hospital, Chattogram,
Bangladesh.
ERC Research approval number: _ _ _ _ _ _ _ _ _ _ _ _ _ _
Title of Research :Effect of Difelikefalin on CKD-Associated Pruritus in Patients on
Maintenance Hemodialysis: A Randomized, Placebo-Controlled Trial”
Name(s) and affiliation(s) of researcher(s): This research is being conducted by
Dr.Md.Shariful Islam Sarker, a MD Phase-B Resident, MD (Nephrology) in the
Department of Nephrology, Chittagong Medical College, Chattogram, Bangladesh.
Sponsor(s) of Research: This research is self-sponsored
Purpose(s) of Research:The broad aim of this research is to determine whether
therapeutic effects of treatment with Difelikefalinis better than treatment with
placebo in patients suffering from pruritus in hemodialysis patients with chronic
kidney disease.
Procedure for the Research, what shall be required of each participant and the
approximate total number of participants that would be involved in the
research: Using a block randomization technique, 102 patients will be grouped by the
researcher into two equal group 51 patients in Experimental Groups (that will receive
Difelikefalin) and 51 patients in Control Group (that will receive matched placebo).
The symptomatic improvement and quality of life will be studied till 6 weeks.
Expected duration of research and participant(s) involvement: You will be
involved in the research till 6 weeks from the enrollment.
Risk(s):.The risk or disadvantage to taking part in this study may be the exposure to
the common side effect of Difelikefalin are diarrhea, nausea.Dizziness, problems
with walking., falling, headache.drowsiness., sudden changes in mental status.
However, if any adverse events occur, we will manage the conditions as per guideline
Costs to the participants, if any, of joining the research:You will not require to pay
for the drugs, or any related procedure related to the research.
Benefits(s):The finding from this research will help in the management of patients
withpruritus in hemodialysis patients with chronic kidney diseasein the future.
Confidentiality: All information obtained from participants involved in this research
will be coded and personal details will be anonymize.

5
Voluntariness: Your participant in this research is entirely voluntary. You are free to
withdraw your consent at any time during the research. It will not in any way
influence the way and manner your condition will be managed.
Alternatives to participation: If you choose not to participate, this will not affect
you in any way. You will still have treatment in the routine way and at the usual
manner.
Due inducements: No patient will be induced to participate in this research.
Consequences
of
participants’
decision
to
withdraw
from
research
and
procedure for orderly termination of participation: If you decide to withdraw
from the research after you have initially consented, it will have no bearing on the
modality of managing your conditions at the hospital. The attending physicians will
attend to you in the standard way without any discrimination.
Modality of providing treatments and action(s) to be taken in case of injury or
adverse event(s): There is no expected serious injury or adverse effects other than the
recognized adverse events of the investigating drug. Nevertheless, if any such
condition arises it will be managed entirely free of cost.
What happens to research participants and communities when the research is
over: The research participants and the community will be informed about the
research findings through scientific publications. Any of the research participants
willing to obtain any non-confidential information about the research will also be
obliged.
Statement about sharing of benefits among researchers and whether this
includes or excludes research participants: No direct benefit will be shared among
researchers.
Any apparent or potential conflict of interest: No conflict of interest is declared.
Statement of person obtaining informed consent: I have fully explained this
research to and have given sufficient information, including the risks and benefits, to
guide him to make an informed decision.
DATE:______/_____/____________________
SIGNATURE:_________________________
NAME:
_____________________________________________________________________
_

60
Statement of person giving informed consent:The purpose of this research has been
explained to me in details. I consent to taking part know that I will be treated either by
Difelikefalin or placebo for my itching. The risks have been explained to me in
details. My participant is entirely voluntary. I understand that am free to withdraw my
participant at any time. If I withdraw my participation, it will not alter the standard of
my care. All information provided by me will be anonymized and kept in confidence.
DATE:____/____/_______
SIGNATURE/THUMB
PRINT:
________________________
SERIAL NUMBER: _ _ _ _ _ _ _ _ _
WITNESS’
SIGNATURE
(if
applicable):
__________________________________________
WITNESS’
NAME
(if
applicable):
________________________________________________
Detailed contact information including contact address, telephone, e-mail and
any other contact information of researcher(s), instructional ERC and head of
the institution: This research has been approved by the Ethical Review Committee of
Chittagong Medical College and they can be contacted at the College Building,
Chittagong Medical College. Also, if you have any question about your participation
in this research, you can contact the researcher, Name: Dr.Md.Shariful Islam Sarker,
MD Phase-B Resident, MD (Nephrology) in the Department of Nephrology,
Chittagong Medical College, Chattogram, Bangladesh.
Cell No: 01738647201
Email:sobujshariful@gmail.com

6
Consent Form
“Effect of Difelikefalin on CKD-Associated Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-Controlled Trial”
After being fully informed about the objectives, consequences of the study, and any
right to withdraw myself from the study at any time for any purpose whatsoever, I
am………………………………………….
Here by giving consent to participate in the study conducted by Dr. Md.Shariful
Islam Sarker (Nephrology), Phase B student, CMCH.
I fully recognize that my participation in this study will generate valuable medical
information that might be used for the interest of patients in the future.
In this research, if any adverse effects of drugs are found, investigators will take
immediate measures for treatment.
I shall try my best to comply with the instruction given by the investigator throughout
the whole period of study.
Signature/Thumb impression of the
patient’s guardian
Date………………
Signature/Thumb impression of the
Subject
Date………………
Signature of the Investigator
Date………………
Signature of the Witness
Date………………

6
Data and Safety Monitoring Board
Title: “Effect of Difelikefalin on CKD-Associated Pruritus in Patients on Maintenance
Hemodialysis: A Randomized, Placebo-Controlled Trial”
Name of the researcher: This study is being conducted by Dr.Md.Shariful Islam
Sarker, Phase-B Resident, MD (Nephrology), Department of Nephrology, Chittagong
Medical College.
Place of the study: Department of Nephrology, Chittagong Medical College Hospital,
Chattogram.
Type of Study: Randomized Controlled Trial
Membersoftheboard:
• ……………………. Professor, Department of Nephrology Chittagong Medical
College and Hospital, Chattogram, Bangladesh
• …………… Assistant professor, Department of Medicine, Chittagong Medical
College and Hospital, Chattogram, Bangladesh
• …………….. Assistant professor, Department of Dermatology, Chittagong Medical
College and Hospital, Chattogram, Bangladesh

6
DATA AND SAFETY MONITORING PLAN
Once a protocol is referred to the data and safety monitoring committee (DSMC). The
first steps for the principle investigator to develop a Data and Safety Monitoring Plan
(DSMP) A DSMP is a written plan that specifies a system for appropriate study
oversight to ensure: (1) safety of clinical research subjects, (2) validity and integrity
of research data, and (3) appropriate termination study. Once the plan elements listed
here are submitted to the DSMC, the DSMC will work with the investigator to
finalize the plan and assure that it is implemented.
Enrollment of the study participants by months:
Month
Approached
Eligible
Randomized
Withdrawn
Actual #
Cumulative #
1
2
3
4
Subject Status:
Pati
ent
ID
Date
enrolle
d
Date
complete
d
Status
(Active/
completed/Withdr
awn)
Reason of
withdrawal
Adherence
Interventio
n duration
1
2
3
4
Adverse events (AE) Patient ID
Patient
ID
AE
Onset
AE
End
Severity
Related to
intervention
Action
taken
Outcome
Comment
1
2
3
4

64
Appendix
Withdrawal Form
I. ...................................
myself
thesis
case
no......................................
of
Dr.Md.Shariful Islam Sarker Hereby I withdraw myself/ my patient from signed
protocol of treatment. I will continue the treatment of myself/my patient according to
standard protocol
Name....................Signature/Thumb Impression:
Name of Witness: ........Signature/Thumb Impression: ........
Date: ..........................
Name & Signature of researcher.............................