Clinical Trials Register

Summary
EudraCT Number:	2013-004657-24
Sponsor's Protocol Code Number:	7985
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-05
Trial 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-004657-24

A.3

Full title of the trial

A randomised, double-blind, placebo controlled, feasibility study exploring the role of Chinese herbal medicine in the treatment of women with recurrent urinary tract infections.

A.3.1

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

Chinese herbal medicine for recurrent urinary tract infections

A.3.2

Name or abbreviated title of the trial where available

CHM for RUTIs

A.4.1

Sponsor's protocol code number

7985

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	Southampton University
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	NIHR
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Southampton University
B.5.2	Functional name of contact point	Barbara Halliday
B.5.3	Address:
B.5.3.1	Street Address	Building 37 Room 4079 University Road Highfield
B.5.3.2	Town/ city	Southampton
B.5.3.3	Post code	SO17 1BJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	004402380595058
B.5.6	E-mail	B.Halliday@soton.ac.uk

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	Preventative Herbal Formula
D.3.2	Product code	RUTI-p
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Astragalus membranaceus Moench
D.3.9.2	Current sponsor code	PH1
D.3.9.3	Other descriptive name	Huang Qi
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sophora flavescens Aiton
D.3.9.2	Current sponsor code	PH2
D.3.9.3	Other descriptive name	Ku Shen
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lindera aggregata var. aggregate
D.3.9.2	Current sponsor code	PH3
D.3.9.3	Other descriptive name	Wu Yao
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Acute Herbal Formula
D.3.2	Product code	RUTI-a
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Oldenlandia diffusa (Willd.) Roxb.
D.3.9.2	Current sponsor code	AH1
D.3.9.3	Other descriptive name	Bai Hua She She Cao
D.3.9.4	EV Substance Code	AS4
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cortex Phellodendron Amurense
D.3.9.2	Current sponsor code	AH2
D.3.9.3	Other descriptive name	Huang Bai
D.3.9.4	EV Substance Code	AS5
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lysimachia christinae Hance
D.3.9.2	Current sponsor code	AH3
D.3.9.3	Other descriptive name	Jin Qian Cao
D.3.9.4	EV Substance Code	AS6
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Recurrent urinary tract infections

E.1.1.1

Medical condition in easily understood language

Infections affecting the bladder that occur at least three times in 12 months.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	HLT
E.1.2	Classification code	10046577
E.1.2	Term	Urinary tract infections
E.1.2	System Organ Class	100000004862

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 compare outcomes observed during and after the 16-week trial from participants in each of the 4 arms of the trial. In particular the:

• duration and severity of acute urinary tract infections
• rates of re-infection within the 4 month treatment period
• quality of life measured by a validated questionnaire (MYMOP) and in depth
qualitative research
• rates of acute and prophylactic antibiotic use
• adverse effects experienced during treatment
• To assess the safety of CHM
• long term changes (6 months after stopping the trial) from each intervention

E.2.2

Secondary objectives of the trial

• To explore the feasibility of developing, implementing and evaluating a CHM intervention within the primary care networks with particular regard to recruitment, referral patterns, patient compliance, the use of a plausible herbal placebo, and drop out rates.

• To evaluate the acceptability and sensitivity to change of different outcomes measures and to provide a provisional estimation of any effect size relating to CHM treatment that could inform a more definitive future study.

• To use nested qualitative research and quantitative quality of life outcome measures to explore the experience of women taking CHM and to investigate any perceived differences between the delivery of standardised remedies via GPs and individualised remedies via CHM practitioners.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Women will be eligible for the trial if they are aged over 18 and under 65 years of age and have reported 3 or more uncomplicated recurrent lower UTIs in the previous 12 months where at least one episode has been documented as bacterial UTI.

The reason for the upper age limit of 65 years is that Chinese medicine differentiates several different diagnostic patterns relating to RUTIs. The herbal formulae used for this trial have been designed for a pattern more common in women aged under 65 years. Women over the age of 65 will tend to present with a different pattern to a younger age group and therefore the standardised formula may not be appropriate for them.

E.4

Principal exclusion criteria

Women will be excluded from the trial if they have symptoms of complicated UTI’s such as acute pyelonephritis; have known hepatic or renal disease; are pregnant or breast feeding; have diabetes; have commenced a new treatment for RUTIs in the previous 6 months; are taking drugs which may interact with Chinese herbal medicine: cardiac glycosides (Digoxin), warfarin and lithium; have psychosis, dementia or terminal illness that may prevent completion of symptom diaries. During the trial women will be excluded if they develop significantly raised liver (ALT > 90 U/l) or renal function tests (GFR < 90 mL/mm/1.73m2). Any women who also become pregnant during the trial will also be advised to stop taking the CHM and to inform a member of the study team for further advice. If pregnancy is confirmed, the participant will be asked to withdraw from the intervention in the study and asked for their consent to remain for safety monitoring purposes.

E.5 End points

E.5.1

Primary end point(s)

The primary outcomes will be the number episodes of recurrent UTIs during the trial period and after 6 months follow up and the number of days of symptoms rated moderately bad or worse based on patient diaries.

E.5.1.1

Timepoint(s) of evaluation of this end point

All participants will receive treatment lasting 16 weeks. Subsequent to this there will be a 6 month follow up period to assess any lasting benefits from the intervention.

E.5.2

Secondary end point(s)

After 6 months treatment we will be evaluating:

• Symptom diaries indicating the severity of acute and recurrent UTI symptoms (reporting dysuria, haematuria, frequency during day and night, “smelly urine,” “tummy pain,” generally feeling unwell, and restriction of daily activities). Use of these diaries in this format for acute respiratory infections has been validated and shown to be sensitive to change (Watson et al 2001) and now have been shown to be sensitive to change, reliable, and having construct validity in UTIs (Little et al 2010a,b).

• Rate of UTI recurrence-as reported in the symptom diaries completed for each acute UTI episode during the active phase of the trial.

• In addition to the diary for acute UTIs participants will be asked to complete a monthly end of month diary in which they record number of days with symptoms, time lost from work etc. These diaries would provide information on the rate and severity of acute infection but also on the impact of low grade, chronic infection on the lives of women. Participants will be asked to complete both an acute and a monthly diary for the 6 month follow up of the trial to enable the evaluation of any longer term changes in infection rates.

• Use of antibiotics for acute UTIs-elicited from symptom diaries and cross-referenced with GP notes.

• The Borkevic and Devilly questionnaire will be used to assess participants’ attitudes relating to the effectiveness of CHM prior to and on completion of the trial (Devilly & Borkevic 2000).

• MYMOP a validated patient centred QoL outcome completed every 4 weeks (Patterson 1996)

• Economic assessment (EQ5D) to be completed prior to and on completion of the trial (also reduction in GP appointments gathered from a review of GP patient notes/ days lost to work). We will also estimate the quality of life during acute UTI episodes by the EQ5D and Euroqol thermometer at the beginning and end of each episode. The EQ5D cannot feasibly be used on a daily basis to estimate the quality of life profile during the episode, but the Euroqol thermometer can be used for this - as we are currently doing in the group’s studies in respiratory infections (the NIHR PRIME Programme)

• Liver (ALT) and renal function tests (serum creatinine used to calculate GFR by using a conversion algorithm) conducted at weeks 0, 4 & 16.

After 6 months there will be a phase of qualitative research:

On completion of the trial semi-structured phenomenological interviews with 6-12 participants per group will be conducted to provide an in depth exploration of their experience of taking CHM and conventional care during the trial. We will also investigate the enablers and barriers that the affected the decision of women to participate in the trial. Purposive sampling will be used to include women taking standardised and individualised herbs during the trial. Once again the study will proceed iteratively and analysis will begin before completing all the interviews to allow emerging insights to inform subsequent interviews.

E.5.2.1

Timepoint(s) of evaluation of this end point

Symptom diaries will be completed if symptoms of UTIs occur. Antibiotic use will be assessed at 16 weeks and then again at the end of the 6 month follow up.

Monthly diaries will be completed monthly.

The Devilly and Borkevic questionnaire will be completed prior to the trial.

MYMOP will be completed prior to the trial and thereafter on a monthly basis.

Economic assessment (EQ5D) to be completed prior to and on completion of the trial

Liver and Renal function tests will be conducted at weeks 0, 4 and 16.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

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

Yes

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

The trial will involve a 6 month follow up after the LVLS.Completion of this will be considered as the end of the trial.

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