Clinical Trials Register

Summary
EudraCT Number:	2020-004295-18
Sponsor's Protocol Code Number:	DRTB-HDT
National Competent Authority:	Romania - National Agency for Medicines and Medical Devices
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2025-01-31
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

Romania - National Agency for Medicines and Medical Devices

A.2

EudraCT number

2020-004295-18

A.3

Full title of the trial

A randomized controlled trial of two adjunctive host-directed therapies in rifampin-resistant tuberculosis (DRTB-HDT)

A.3.1

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

A trial of two host-directed therapies in patients with drug-resistant tuberculosis (DRTB-HDT)

A.3.2

Name or abbreviated title of the trial where available

DRTB-HDT

A.4.1

Sponsor's protocol code number

DRTB-HDT

A.5.4

Other Identifiers

Name:	SANCTR	Number:	DOH-27-042021-8345
Name:	SAHPRA	Number:	20210330
Name:	WHREC	Number:	210109

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	The Aurum Institute
B.1.3.4	Country	South Africa
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	Horizon 2020 / EC
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Aurum Institute
B.5.2	Functional name of contact point	Chief Science Officer
B.5.3	Address:
B.5.3.1	Street Address	29 Queens Rd, Parktown
B.5.3.2	Town/ city	Johannesburg
B.5.3.3	Post code	2193
B.5.3.4	Country	South Africa
B.5.6	E-mail	rwallis@auruminstitute.org

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	CC-11050
D.3.2	Product code	CC-11050
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	CC-11050
D.3.9.2	Current sponsor code	CC-11050
D.3.9.3	Other descriptive name	N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl]cyclopropanecarboxamide
D.3.9.4	EV Substance Code	SUB233088
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Accord ratiopharm
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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	metformin ratiopharm
D.3.4	Pharmaceutical form	Tablet
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	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	657-24-9
D.3.9.4	EV Substance Code	SUB03200MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rifampin-resistant pulmonary tuberculosis

E.1.1.1

Medical condition in easily understood language

Drug-resistant tuberculosis

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

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	10037440
E.1.2	Term	Pulmonary tuberculosis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To examine the safety, tolerability, and preliminary efficacy of two adjunctive TB-HDTs (one anti-inflammatory, and one antimicrobial) in patients with rifampin-resistant pulmonary tuberculosis. Efficacy endpoints will include measures of recovery of lung function and eradication of M tuberculosis infection.

E.2.2

Secondary objectives of the trial

Not applicable

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

CT sub-study: This sub-study will examine treatment effects at baseline and at 16 weeks using CT scan. The CT sub-study is described in the main protocol.

E.3

Principal inclusion criteria

1. Aged 16 to 65 years
2. Able and willing to provide signed written consent or witnessed oral con-sent in the case of illiteracy, prior to undertaking any trial-related procedures. In the case of children 16 or 17 years of age, consent of at least one parent or guardian plus assent of the child will be required.
3. Body weight (in light clothing without shoes) between 30 and 90 kg.
4. Positive sputum Xpert (TB/RIF or Ultra) with Ct ≤22, with subsequent culture confirmation.
5. RIF resistance diagnosed by Xpert OR Hain test OR phenotypic drug susceptibility test
6. Chest radiograph meeting National TB Association criteria for moderate or far advanced pulmonary tuberculosis1
7. If sexually active, willing to use an effective contraceptive method for the duration of TB treatment
8. HIV-1 seronegative, OR if HIV-1 seropositive, presenting to an African study site with a CD4 T cell count >100/µl, and either currently receiving ART or willing to start ART during study participation as specified
NB: HIV+ patients will only be enrolled at African sites

E.4

Principal exclusion criteria

1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
2. Current or imminent (within 24 hr) treatment for malaria.
3. Pregnancy or breastfeeding
4. Is critically ill, such that in the judgment of the investigator, death is likely during the trial.
5. TB meningitis or other forms of severe TB with high risk of a poor outcome as judged by the investigator.
6. History of allergy or hypersensitivity to any of the trial therapies or related substances
7. Having participated in other clinical trials with investigational agents within 8 wks prior to trial start or currently enrolled in an investigational trial.
8. Prior RIF-R-TB treatment in the preceding 12 months
9. Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
10. Patients requiring treatment with drugs that are strong CYP3A4 inducers or inhibitors (eg, ketoconazole, lopinavir, or cobicistat), carbonic anhydrase inhibitors (eg, acetazolamide), or OCT2 or MATE inhibitors (eg, cimetidine, pyrimethamine).
11. Use of systemic corticosteroids within the past 28 days.
12. History of unstable diabetes mellitus that required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening, or requiring treatment with metformin.
13. Subjects with any of the following abnormal laboratory values:
a. creatinine >2 mg/dL
b. haemoglobin <8 g/dL
c. platelets <100x10^9 cells/L
d. serum potassium <3.5
e. alanine aminotransferase (ALT) ≥2.0 x ULN
f. alkaline phosphatase (AP) >5.0 x ULN
g. total bilirubin >1.5 mg/dL
h. Hepatitis B surface antigen positive
i. random blood glucose >140 mg/dL (7.8 mmol/L)
j. SARS-CoV-2 PCR or antigen test positive
NB: All of the inclusion and none of the exclusion criteria must be met
NB: Enrolled patients whose baseline sputum cultures subsequently fail to show growth of RIF-R-TB will be excluded from the mITT and PP populations. They may be removed from further study participation based on their individual benefit-risk balance, as assessed by the site and study PIs and the DMC.

E.5 End points

E.5.1

Primary end point(s)

There are two co-primary endpoints:
1. FEV1 at month 6
2. Likelihood of stable culture conversion through month 6
Both co-primary endpoints must be met for a treatment to be considered successful. The CC-11050 and metformin arms will each be compared to the control arm.

E.5.1.1

Timepoint(s) of evaluation of this end point

month 6 (nominal 4-week months)

E.5.2

Secondary end point(s)

Secondary endpoints:
1. FEV1 and FVC at additional time points (2, 6, and 18 months)
2. FEV1 and FVC slope over time
3. Proportions of patients with negative sputum cultures after 2 and 6 months of treatment
4. The proportion of patients with new TB drug resistance
5. Proportions of patients whose treatment is considered unsuccessful due to failure, relapse, or death, individually and in total
6. TE-SAEs, categorized according to severity, treatment relatedness, and leading to early withdrawal
7. Quantitative and qualitative clinical and laboratory safety measurements, including observed and change from baseline
8. Proportion of patients with disease exacerbation (paradoxical reactions or IRIS)
Exploratory endpoints:
1. Lung radiodensity by chest CT, measured at baseline and month 4
2. PK/PD analysis based on sparse sampling

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 18 months after study entry

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard RIF-R-TB treatment alone

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

Mozambique

Moldova, Republic of

Georgia

South Africa

Romania

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

Yes

F.1.1

Number of subjects for this age range:

330

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

310

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

F.4.2.2

In the whole clinical trial

330

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)

Study treatments will end at month 6. Patient participation will end at month 18. Patients whose RIF-R-TB treatment has not yet finished by month 18 will continue under care of the local TB treatment program.
Please also note that the trial protocol does not specify the number of patients age 16-17 or 65.

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

2022-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-08

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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