Clinical Trials Register

Summary
EudraCT Number:	2019-002592-34
Sponsor's Protocol Code Number:	RID-TB:Dx
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-02-10
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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-002592-34

A.3

Full title of the trial

Research to Improve the Detection and Treatment of Latent Tuberculosis Infection: Diagnostics (RID-TB:Dx)

A randomised controlled trial to evaluate the effectiveness of using the RD-1 based C Tb skin test as a replacement for blood-based interferon-γ release assay for detection of latent TB infection and initiation of TB preventive treatment in the UK

A.3.1

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

Research to Improve the Detection and Treatment of Latent Tuberculosis Infection: Diagnostics (RID TB:Dx)
A randomised trial to evaluate the effectiveness of a new C-Tb skin test to replace the current IGRA blood test for diagnosing latent TB infection

A.3.2

Name or abbreviated title of the trial where available

RID-TB:Dx

A.4.1

Sponsor's protocol code number

RID-TB:Dx

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	University College London
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	National Institute for Health Research (NIHR)
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	National Institute for Health Research Clinical Research Network (NIHR CRN).
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	MRC Clinical Trials Unit at UCL
B.5.2	Functional name of contact point	Clinical Trials Manager
B.5.3	Address:
B.5.3.1	Street Address	90 High Holborn 2nd Floor
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC1V 6LJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 (0)20 7670-4619
B.5.5	Fax number	020 7670 4814
B.5.6	E-mail	mrcctu.rid-tb@ucl.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	C-Tb
D.3.2	Product code	N/A
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	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	rdESAT-6
D.3.9.3	Other descriptive name	rdESAT-6
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	rCFP-10
D.3.9.3	Other descriptive name	rCFP-10
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Latent Tuberculosis infection (LTBI)

E.1.1.1

Medical condition in easily understood language

Latent TB is where people have been infected with the bacteria that cause TB, but do not have symptoms. It may develop into "active" TB where the person becomes unwell and can pass on the infection.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10065048
E.1.2	Term	Latent tuberculosis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study hypothesis is that using new C-Tb skin test for the diagnosis and subsequent management of Latent Tuberculosis Infection (LTBI) will be as good as the current standard-of-care IGRA blood test. This will be evaluated based on the number of participants who then accept and start treatment for LTBI, based on a positive C-Tb test result (intervention arm) or IGRA test result (control arm).

E.2.2

Secondary objectives of the trial

We will be looking at factors that impact on the LTBI testing pathway, and whether C-Tb skin test can replace the current IGRA blood test. This will include:

- How many people agree to start treatment for LTBI, and whether there is a difference in this between the two tests.

- How many people are lost to follow up (do not attend appointments) between LTBI diagnosis and starting treatment, and whether there is a difference in this between the two tests.

- Whether people who do not come back to the clinic to have their C-Tb test read 2-3 days later. Tests assessed outside this timeframe do not give a valid result.

- Whether there are any delays in starting treatment, and whether these are different depending on what test was used.

- How many people finished their course of LTBI treatment, and whether these are different depending on what test was used.

We will also be looking at participant safety, including local and systemic (whole body) reactions to the tests.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1. C-Tb Diagnostic Accuracy Study (date and version as per main protocol)

A head-to-head diagnostic accuracy evaluation of C-Tb versus IGRA will be conducted based on participants in the main RID TB:Dx trial randomised to the C-Tb arm.

Diagnostic accuracy estimates for C-Tb including sensitivity, specificity, positive and negative predictive values will be estimated using Bayesian latent class. This will initially be based on data within the RID TB:Dx trial only, but a meta-analysis approach including other relevant studies is also planned for the future.

2a. Quantitative Behavioural Study (date and version as per main protocol)

Quantitative surveys consisting of validated questionnaires will be used to assess beliefs about LTBI, and factors influencing testing and treatment uptake within the RID TB:Dx trial. This work will also assess reasons for declining participation in the diagnostic trial, and participant acceptability and impact of the test in terms of psychosocial and behaviour outcomes.

2b. Qualitative Behavioural Study (date and version)

A qualitative sub-study will also be conducted as part of Work Package 2. Qualitative work will explore participants’ experiences of LTBI testing and treatment in greater depth to inform the development of an intervention to improve adherence to LTBI treatment. Cognitive interviews will assess user acceptability of questionnaires, and patient and public advisors will be invited to attend group discussions to refine intervention materials. However, since this work also aims to conduct qualitative interviews on individuals who cannot participate in the trial (decline or are not eligible), a separate protocol has been developed: Research to Improve the Detection and Treatment of Latent TB Infection: Qualitative Study (RID TB:Q); IRAS Project ID 270249.

3. Health Economics (date and version as per main protocol)

Health Economic evaluation will be undertaken as part of Work package 4 of the RID TB programme. Work package 4 and will employ economic analysis to calculate if changes to diagnosis and/or treatment offer value for money. An integrated transmission-dynamic health-economic model will synthesise data obtained within the entire RID TB programme and evidence from sources including the scientific literature, census data and life-tables from national statistics, LTBI/TB screening and TB surveillance data. The model will consider different age-groups, and different social/ethnic groups, subdivided into UK-born and foreign-born individuals, which can differ in their size, age-structure, rates of migration, rates of occurrence of latent and active TB, and in the patterns of social mixing within and between different groups that affect TB transmission rates. This will allow estimation of the long-term, national-level benefits of the studied interventions.

4. T-Spot and C-Tb Concordance (date and version as per main protocol)

Two IGRA tests are currently in use within the NHS, the QuantiFERON Gold technology (QFT) and the T-SPOT test (Oxford Immunotec, Abingdon, UK). QFT is the currently named standard-of-care in the RID TB:Dx trial. There are currently no data available on the concordance between C-Tb and IGRA T-SPOT. Thus RID TB:Dx trial will initially recruit from sites or centres where QFT is conducted; this restriction thus has the potential to limit recruitment rates. This substudy will set out to estimate the concordance(%) between these two tests. A total of 175 participants will be enrolled from select sites that use IGRA T-SPOT for standard-of-care LTBI testing. These participants will be tested using both IGRA T-SPOT and C-Tb (ie. paired assessments), but will be managed according to their IGRA result only.
Of note, these participants will not contribute towards the overall sample size for the main RID-TB:Dx trial (N=1530), and their data will be analysed separately.

E.3

Principal inclusion criteria

1. Age ≥16 years
2. Eligible for LTBI testing with IGRA and treatment for LTBI according to UK guidance
3. Willing and able to provide written informed consent
4. Willing and able to comply with the trial, including the randomised test(s) and adherence to follow up visits

E.4

Principal exclusion criteria

1. Allergy to C-Tb product or any of its constituents

2. Displaying any symptoms or signs of active TB disease:
Unexplained fever; Cough (more than three weeks); Haemoptysis (Blood in sputum); Unexplained weight loss; Drenching night sweats; Lymph node swelling

3. Women who are breastfeeding, pregnant or plan to become pregnant during the study
4.
Women of childbearing potential not using contraception
A woman of child bearing potential (WOCBP): 12 years of age or older having had their first menstruation and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

Effective contraception includes barrier (including spermicidal gel), hormonal or intrauterine contraceptive measures within the trial period

E.5 End points

E.5.1

Primary end point(s)

The proportion of participants who have positive test results and initiate LTBI treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

All participants will reach the end of diagnostic follow up 24 weeks after randomisation. At this point treatment initiation will be confirmed for those who tested positive for LTBI.

However, participants may initiate treatment sooner than this which will be at the point of prescription dispensing and collection.

E.5.2

Secondary end point(s)

1)Related to impact on the LTBI pathway process outcomes:
i) Acceptance of LTBI treatment among participants with test positive results in each arm

ii) Losses to follow up (default rate) between diagnosis with LTBI and starting treatment

iii) Proportion of participants randomised to C Tb that fail to return for C Tb reading in 48-72hrs

iv) Delay in starting preventative therapy from testing

v) Proportion of participants completing LTBI treatment

2) Safety
i) Local and systemic reactions

E.5.2.1

Timepoint(s) of evaluation of this end point

i) at the point of prescription dispensing and collection, and at week 24 if applicable

ii) At the point of visit non-attendance, and at week 24

iii) At the scheduled day 2-3 visit

iv) At the point of prescription dispensing and collection.

v) At week 24

2) Safety
i) At each attended visit (day 2-3 for C-Tb arm, and week 4/week 24/any unscheduled visit(s) for all participants)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

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

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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 close when all participants have completed follow-up, after the trial database is locked, which is anticipated to be within 3 months of the last participant reaching the end of the 24-week diagnostic follow up period. It is anticipated that the overall duration of the trial will be approximately 3 years.

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