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Clinical Trial Results:
A Phase IV, Randomised, Double-Blind, Controlled, Parallel Group Trial to Evaluate the Effectiveness and Safety of Balneum Plus vs Emollient in the Treatment of Uraemic Pruritus in Haemodialysis Patients.

Summary
EudraCT number	2014-005594-36
Trial protocol	GB
Global end of trial date	26 Dec 2017

Results information
Results version number	v1(current)
This version publication date	04 Oct 2019
First version publication date	04 Oct 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PHT/2014/107

ISRCTN number

ISRCTN13971661

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Portsmouth Hospitals NHS Trust

Sponsor organisation address

Queen Alexandra Hospital, Cosham, Portsmouth, United Kingdom, PO6 3LY

Public contact

Jacqueline Nevols, Portsmouth Hospitals NHS Trust, +44 02392286000, jacqueline.nevols@porthosp.nhs.uk

Scientific contact

Jacqueline Nevols, Portsmouth Hospitals NHS Trust, +44 02392286000, jacqueline.nevols@porthosp.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Dec 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Dec 2017

Global end of trial reached?

Yes

Global end of trial date

26 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

To compare itch intensity as measured by a Visual Analogue Scale after 4 weeks treatment with Balneum Plus cream vs emollient control in patients with uraemic pruritus.

Protection of trial subjects

Trial subjects had contact with study staff on a weekly basis - and had contact details to report problems outside of scheduled visits.

Background therapy

All trial subjects were on maintenance haemodialysis for treatment of end-stage renal disease. Most of the trial subjects were on multiple medications -for example antihypertensives and phosphate binders. All medications were recorded at the time of study entry and subjects were stratified according to antihistamine use.

Evidence for comparator

For the comparator group - a basic emollient was used (E45). There is no evidence in the literature that simple emollients (without active ingredients) improve the symptoms of uraemic pruritus.

Actual start date of recruitment

04 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 58

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited from the Wessex Kidney Centre's dialysis units. The research nurse visited each patient to inquire about symptoms of pruritus and their potential willingness to take part in a clinical trial.

Screening details

Potential subjects were screen according to the inclusion and exclusion criteria for the trial by the research nurse at the dialysis centre.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Assessor, Subject

Blinding implementation details

Randomisation list generated by the study statistician. The list was kept securely in the Trust Pharmacy. Study team (CI and research nurses) had no access to the randomisation list. Upon successful recruitment of a trial subject - the patient was randomised and prescribed the trial cream. Both the study cream and comparator looked identical and were dispensed in identical containers.

Are arms mutually exclusive

Yes

Treatment arm

Arm description

Balneum Plus - to be applied topically twice daily.

Arm type

Experimental

Investigational medicinal product name

Balneum Plus

Investigational medicinal product code

PL33016/0010

Other name

Pharmaceutical forms

Cream

Routes of administration

Cutaneous use

Dosage and administration details

The cream was to be applied to affected areas of skin, topically, twice daily, for four weeks.

Comparator arm

Arm description

E45 cream was used as base cream/control cream

Arm type

Placebo

Investigational medicinal product name

E45

Investigational medicinal product code

PL00063/0404

Other name

Pharmaceutical forms

Cream

Routes of administration

Cutaneous use

Dosage and administration details

To be applied to affected areas of skin, topically, twice daily, for four weeks.

Number of subjects in period 1	Treatment arm	Comparator arm
Started	29	29
Completed	26	26
Not completed	3	3
Adverse event, serious fatal	-	1
Consent withdrawn by subject	1	2
Not complete the course of treatment	1	-
Received transplant, no longer eligible	1	-

Baseline characteristics

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Reporting group title

Treatment arm

Reporting group description

Balneum Plus - to be applied topically twice daily.

Reporting group title

Comparator arm

Reporting group description

E45 cream was used as base cream/control cream

Reporting group values	Treatment arm	Comparator arm	Total
Number of subjects	29	29	58
Age categorical
Adult haemodialysis patients.
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	12	15	27
From 65-84 years	17	11	28
85 years and over	0	3	3
Age continuous
Units: years
arithmetic mean (standard deviation)	64.0 ( 13.9 )	63.4 ( 16.2 )	-
Gender categorical
Units: Subjects
Female	9	9	18
Male	20	20	40
Smoking status
We documented smoking status as a baseline characteristic.
Units: Subjects
Never smoked	11	11	22
Ex-smoker	13	12	25
Current smoker	5	6	11
Cause of End-stage renal disease
We identified the cause of end-stage renal disease in study participants.
Units: Subjects
Glomerulonephritis	9	3	12
Diabetic Nephropathy	3	8	11
Hypertension/renovascular disease	8	4	12
Obstructive Uropathy	2	5	7
Polycystic kidney disease	1	2	3
Other	4	3	7
Unknown	2	4	6
Dialyser size
We documented the size of dialyser for each participant.
Units: Subjects
Small	6	7	13
Medium	11	12	23
Large	12	10	22
Allergic drugs
Units: Subjects
No	20	21	41
Yes	9	8	17
Antipruritics
Units: Subjects
No	17	17	34
Yes	12	12	24
Emollient use
Units: Subjects
No	16	14	30
Yes	13	15	28
Antihistamines use
Units: Subjects
No	26	26	52
Yes	3	3	6
Other medication
Units: Subjects
No	0	0	0
Yes	29	29	58
Allergies
Units: Subjects
No	20	21	41
Yes	9	8	17
Time on Haemodialysis
Units: Years
median (inter-quartile range (Q1-Q3))	1.5 (0.7 to 3.4)	2.6 (0.9 to 4.7)	-
C-reactive protein
Units: milligram(s)/litre
median (inter-quartile range (Q1-Q3))	12 (6 to 20)	10 (5 to 19)	-
Phosphate Level
Units: millimole(s)/litre
arithmetic mean (standard deviation)	1.7 ( 0.6 )	1.7 ( 0.6 )	-
Urea Level
Units: millimole(s)/litre
arithmetic mean (standard deviation)	18 ( 6 )	17 ( 5 )	-
Visual Analogue Scale
Units: Arbitrary Unit
median (inter-quartile range (Q1-Q3))	6.5 (4.4 to 8.0)	6.3 (5.1 to 7.3)	-

End points

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Reporting group title

Treatment arm

Reporting group description

Balneum Plus - to be applied topically twice daily.

Reporting group title

Comparator arm

Reporting group description

E45 cream was used as base cream/control cream

Primary: Visual Analogue Scale score

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End point title

Visual Analogue Scale score

End point description

Patients marked their Itch symptom score on a visual analogue scale.

End point type

Primary

End point timeframe

VAS score after four weeks treatment.

End point values	Treatment arm	Comparator arm
Number of subjects analysed	26	26
Units: cm
number (not applicable)	2.6	2.0

Visual Analogue Scale at 4 weeks

Statistical analysis description

Primary outcome was compared between groups using ANCOVA. The itch intensity at end of the study was considered as the outcome variable, with the itch intensity at baseline and the use of anti-histamines used as covariates in the analysis. The VAS scores were found to have a positively skewed distribution, and to meet the assumptions of the analysis methods, a log transformation of scores was made, with the analysis performed on the log scale.

Comparison groups

Treatment arm v Comparator arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

ANCOVA

Parameter type

Adjusted difference ratio

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.64

Adverse events

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Timeframe for reporting adverse events

Data on adverse events were collected weekly during the study period and for one week afterwards.

Assessment type

Systematic

Dictionary name

Not used

Dictionary version

Reporting group title

Balneum Plus

Reporting group description

Reporting group title

Control Emollient

Reporting group description

Serious adverse events	Balneum Plus	Control Emollient
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 29 (13.79%)	3 / 29 (10.34%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	0
Cardiac disorders
Dyspnoea
Additional description: Patient presented at hospital with breathlessness due to previously known heart failure. Patient prescribed bisoprolol and eplerenone and was discharged home later.
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
Additional description: Patient admitted with Non ST elevation myocardial infarction in a patient with known ischaemic heart disease.
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
Additional description: End stage cardiac disease, not fit for further angiography/ intervention. Patient died at home under DNAR order
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Surgical and medical procedures
Surgery
Additional description: Patient was treated on Day Case Unit and was admitted overnight. Admitted for formation of left bracho basilic transposition fistula. This was considered routine surgery.
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access malfunction
Additional description: Patient admitted with blocked dialysis access. Patient required new tunnelled dialysis line (haemodialysis continues).
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transplant
Additional description: Patient admitted for planned transplant surgery. Patient withdrawn from trial as now transplanted and there is an improvement expected in uraemic pruritus. Patient remains in hospital for post surgery monitoring.
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
Additional description: Patient presented at hospital with diarrhoea as a known clostridium difficile carrier. Patient prescribed oral vancomyn and was considered for faecal transplant, but no longer needed it when symptoms resolved.
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dysphonia
Additional description: Patient admitted with shortness of breath and possible pleural effusion. Patient had a chest x-ray
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
urge to urinate & mild hematuria
Additional description: Patient experienced urgency in urinating and passed small amount of blood. Patient referred to urologist for cystoscopy
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Balneum Plus	Control Emollient
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 29 (13.79%)	1 / 29 (3.45%)
Surgical and medical procedures
fistuloplasty
Additional description: Planned fistuloplasty
subjects affected / exposed	1 / 29 (3.45%)	1 / 29 (3.45%)
occurrences all number	1	1
Surgery
Additional description: Planned admission for removal of ischaemic finger
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Inflamed spots
Additional description: Inflamed spots on abdominal skin.
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences all number	1	0
itching
Additional description: Itching around cannula site
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

01 Aug 2017

The amendment includes: 1) change of Chief Investigator from Dr Robert Lewis to Dr Jacqueline Nevols, Consultant Nephrologist, who is currently a Co-Investigator and protocol author on the trial; 2) Changes to the study management team due to changes in staffing and their roles; 3) protocol update with the changes from the latest summary of product characteristics for Balneum Plus cream with the safety profile of the drug and expected adverse events; 4) Amended the study inclusion and exclusion criteria to widen the available patient population so that further recruitment is possible; 5) to allow patient questionnaires and case report form to be completed by the patient and returned to the study team by post, with a follow up phone call for any data queries; 6) update to the study questionnaires - a body outline has been replaced by tick boxes for patients to indicate where on the body they are itching in order to make data entry on the study database simpler and more consistent across all patients.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase IV, Randomised, Double-Blind, Controlled, Parallel Group Trial to Evaluate the Effectiveness and Safety of Balneum Plus vs Emollient in the Treatment of Uraemic Pruritus in Haemodialysis Patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Visual Analogue Scale score

Primary: Visual Analogue Scale score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase IV, Randomised, Double-Blind, Controlled, Parallel Group Trial to Evaluate the Effectiveness and Safety of Balneum Plus vs Emollient in the Treatment of Uraemic Pruritus in Haemodialysis Patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Visual Analogue Scale score

Primary: Visual Analogue Scale score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase IV, Randomised, Double-Blind, Controlled, Parallel Group Trial to Evaluate the Effectiveness and Safety of Balneum Plus vs Emollient in the Treatment of Uraemic Pruritus in Haemodialysis Patients.