Clinical Trials Register

Summary
EudraCT Number:	2018-001930-17
Sponsor's Protocol Code Number:	CR845-CLIN3103
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-08-08
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-001930-17

A.3

Full title of the trial

A MULTICENTER, DOUBLE-BLIND, RANDOMIZED,
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND
EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS
WITH MODERATE-TO-SEVERE PRURITUS, WITH A 52-WEEK
OPEN-LABEL EXTENSION

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.3.2

Name or abbreviated title of the trial where available

CR845-CLIN3103

A.4.1

Sponsor's protocol code number

CR845-CLIN3103

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cara Therapeutics INC
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cara Thetrapeutics Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Icon clinical Research Ltd
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	100 Milton Park
B.5.3.2	Town/ city	Abingdon
B.5.3.3	Post code	Ox14 4RY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	4407831653684
B.5.6	E-mail	markas.marriott@iconplc.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Difelikefalin
D.3.2	Product code	CR845
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

PRURITUS,

E.1.1.1

Medical condition in easily understood language

REDUCTION OF MODERATE-TO-SEVERE PRURITUS,IN HEMODIALYSIS PATIENTS

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg
compared to placebo in reducing the intensity of itch in
hemodialysis patients with moderate-to-severe pruritus.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg
compared to placebo in improving itch-related quality-of-life
measures in hemodialysis patients with moderate-to-severe
pruritus.
To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in
hemodialysis patients with moderate-to-severe pruritus.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
To be eligible for inclusion into the Double-blind Phase of the study, a
patient must meet the following criteria:
1. Willing and able to provide written informed consent prior to
participating in this study;
2. Able to communicate clearly with the Investigator and staff,
able to understand the study procedures, and able and willing
to comply with the study requirements; 3. Male or female 18 years of age or older;
4. Has end-stage renal disease (ESRD) and has been on
hemodialysis 3 times per week for at least 3 months prior to
the start of screening;
Note 1: Patients who require an occasional additional dialysis
treatment to manage fluid overload or electrolyte excesses
may be enrolled as long as it is anticipated that no more than
1 such treatment will be required in any given week and no
more than 4 occasions during the 12-week double-blind
period. Patients routinely on 4 dialyses a week will not be
eligible.
Note 2: Patients receiving in-home hemodialysis may
participate as long as they have switched to in-center
hemodialysis at least 2 weeks prior to screening and plan to
remain on in-center hemodialysis for the duration of the
study.
5. If female, is not pregnant or nursing during any period of the
study;
6. If female:
a. Is surgically sterile; or
b. Has been amenorrhoeic for at least 1 year and is over the
age of 55 years; or
c. Has a negative serum pregnancy test at screening and
agrees to use acceptable contraceptive measures
(eg, hormonal contraceptives, barrier with spermicide,
intrauterine device, vasectomized partner, or abstinence)
from the time of informed consent until 7 days after the
last dose of study drug;
7. If male, agrees not to donate sperm after the first dose of study
drug until 7 days after the last dose of study drug, and agrees to
use a condom with spermicide or abstain from heterosexual
intercourse during the study until 7 days after the last dose of
study drug. (Note: No restrictions are required for a
vasectomized male provided his vasectomy was performed
≥4 months prior to screening);
8. Has a prescription dry body weight between 40.0 and 135.0 kg,
inclusive;
9. Has at least 2 single-pool Kt/V measurements ≥1.2, or at least
2 urea reduction ratio measurements ≥65%, or 1 single-pool
Kt/V measurement ≥1.2 and 1 urea reduction ratio
measurement ≥65% on different dialysis days during the
3 months period prior to screening;
10. Prior to randomization:
a. Has completed at least four out of eight Worst Itching
Intensity Numerical Rating Scale (NRS) worksheets fromhe start of the 7-day Run-in Period up to and including the
pre-randomization assessment on Day 1;
b. Has a mean baseline Worst Itching Intensity NRS score
≥5, defined as the average of all non-missing scores
reported from the start of the 7-day Run-in Period up to
and including the pre-randomization assessment on Day 1.

E.4

Principal exclusion criteria

Exclusion Criteria:
A patient will be excluded from the Double-blind Phase of the study if
any of the following criteria are met:
1. Known noncompliance with dialysis treatment that in the
opinion of the Investigator would impede completion or
validity of the study;
2. Scheduled to receive a kidney transplant during the study;
3. Known history of allergic reaction to opiates, such as hives
(Note: side effects related to the use of opioids, such as
constipation or nausea, would not exclude patients from the
study).
4. Has a concomitant disease or a history of any medical
condition that, in the opinion of the Investigator, could pose
undue risk to the patient, impede completion of the study
procedures, or would compromise the validity of the study
measurements, including, but not limited to:
a. Known or suspected history of alcohol, narcotic, or other
drug abuse, or substance dependence within 12 months
prior to screening;
b. Significant systolic or diastolic heart failure (eg, New
York Heart Association Class IV congestive heart failure
[Appendix 1, Section 14.1]);
c. Severe mental illness or cognitive impairment (eg,
dementia);
d. Any other relevant acute or chronic medical or
neuropsychiatric condition within 3 months prior to
screening (eg, diagnosis of encephalopathy, coma,
delirium);
5. New or change of treatment received for itch including
antihistamines and corticosteroids (oral, IV, or topical) within
14 days prior to screening; 6. New or change of prescription for opioids, gabapentin, or
pregabalin within 14 days prior to screening;
7. Received another investigational drug within 30 days prior to
the start of screening or is planning to participate in another
clinical study while enrolled in this study;
8. In the opinion of the Investigator, has pruritus attributed to a
cause other than ESRD or its complications (eg, patients with
concomitant pruritic dermatological disease or cholestatic liver
disease) (Note: Patients whose pruritus is attributed to ESRD
complications, such as hyperparathyroidism,
hyperphosphatemia, anemia, or the dialysis procedure or
prescription may be enrolled);
9. Has localized itch restricted to the palms of the hands;
10. Has pruritus only during the dialysis session (by patient
report);
11. Is receiving ongoing ultraviolet B treatment and anticipates
receiving such treatment during the study;
12. Participated in a previous clinical study with CR845.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint
• Proportion of patients achieving at least a 3-point improvement
from baseline with respect to the weekly mean of the daily 24-
hour Worst Itching Intensity NRS score at Week 12 of the
Double-blind Treatment Period

E.5.1.1

Timepoint(s) of evaluation of this end point

week 12

E.5.2

Secondary end point(s)

Secondary Efficacy Endpoints
• Change from baseline in itch-related quality of life at the end
of Week 12 of the Double-blind Treatment Period, as assessed
by the 5-D Itch Scale total score
• Change from baseline in itch-related quality of life at the end
of Week 12 of the Double-blind Treatment Period, as assessed
by the Skindex-10 Scale total score
• Proportion of patients achieving ≥4-point improvement from
baseline with respect to the weekly mean of the daily 24-hour
Worst Itching Intensity NRS at Week 12 of the Double-blind
Treatment Period. Additional efficacy endpoints are described in Section 8.7.4. of the protocol
Safety Endpoints
The safety endpoints used to evaluate the overall safety and tolerability
of CR845 will be adverse events, ECG, vital signs, and clinical safety
laboratory evaluations.

E.5.2.1

Timepoint(s) of evaluation of this end point

week 12

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Czech Republic

Germany

Hungary

Korea, Republic of

New Zealand

Poland

Romania

Taiwan

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

350

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

350

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

extension phase- open label 52 weeks

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-09-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-31

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IMP with orphan designation in the indication
Orphan Designation Number:
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