Clinical Trials Register

Summary
EudraCT Number:	2010-022271-59
Sponsor's Protocol Code Number:	242-09-213
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-27
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

Latvia - SAM

A.2

EudraCT number

2010-022271-59

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group
Trial to Evaluate the Safety and Efficacy of Delamanid (OPC-67683) Administered
Orally as 200 mg Total Daily Dose for Six Months in Patients With Pulmonary Sputum
Culture-positive, Multidrug-resistant Tuberculosis

A.3.1

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

A.4.1

Sponsor's protocol code number

242-09-213

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	Otsuka Pharmaceutical Development & Commercialization, 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	Otsuka Pharmaceutical Development & Commercialization, 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	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	2440 Research Blvd.
B.5.3.2	Town/ city	Rockville, MD
B.5.3.3	Post code	20850
B.5.3.4	Country	United States
B.5.4	Telephone number	+13019056710
B.5.5	Fax number	+13017217243
B.5.6	E-mail	Carolyn.Petersen@otsuka-us.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/524
D.3 Description of the IMP
D.3.1	Product name	Delamanid
D.3.2	Product code	OPC-67683
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	Delamanid
D.3.9.1	CAS number	681492-22-8
D.3.9.2	Current sponsor code	OPC-67683
D.3.9.3	Other descriptive name	Delamanid
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	50
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	Tablet
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

Pulmonary Multidrug-resistant Tuberculosis (MDR TB)

E.1.1.1

Medical condition in easily understood language

Pulmonary Multidrug-resistant Tuberculosis (MDR TB)

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10037443
E.1.2	Term	Pulmonary tuberculosis, unspecified
E.1.2	System Organ Class	100000004862

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

The primary objective of this trial is to evaluate the efficacy of delamanid administered orally as 100 mg twice daily (BID) for 2 months followed by 200 mg once daily (QD) for 4 months in combination with an optimized background regimen (OBR) versus placebo with OBR during the 6-month intensive phase of MDR TB treatment. Efficacy will be assessed by comparing the proportion of patients achieving sputum culture conversion (SCC) from growth of Mycobacterium tuberculosis (MTB) to no growth of MTB after 2 months of treatment as well as distribution of time to SCC between the two treatment groups during the 6-month Intensive Treatment Period of MDR TB treatment.

E.2.2

Secondary objectives of the trial

• To evaluate the safety of delamanid administered orally as 100 mg BID for 2 months followed by 200 mg QD for 4 months in combination with OBR versus placebo with OBR during the 6-month Intensive Treatment Period
• To evaluate pharmacokinetics (PK) of delamanid administered orally as 100 mg BID for 2 months followed by 200 mg QD for 4 months during the 6-month Intensive Treatment Period as part of a population PK analysis.
• To evaluate the durability of SCC achieved by patients from the two treatment groups during the 6-month Intensive Treatment Period, through the 12 to 18-month Continuation Treatment Period, and until the end of the Post-Treatment Follow-up Period at Month 30.
• To evaluate final treatment outcomes as defined by WHO for patients at the end of the 18 to 24-month full treatment period for MDR TB

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

Same title as given in Section 1. Version number is "6.1". Sub-trial will only be applicable for South Africa only.
Only sites in South Africa will be eligible and qualified for conducting this clinical trial with HIV co-infected patients.

E.3

Principal inclusion criteria

Provide written, informed consent prior to all trial-related procedures.
Male or female patients aged between 18 and 69 years, inclusive.
Current Diagnosis of MDR TB from one of the following methods:
• From a single sputum specimen collected no more than 60 days prior to the date of trial enrollment (defined as the date the ICF is signed and screening begins), mycobacterial culture positive for growth of MTB with documented resistance to isoniazid and rifampicin, OR
• From a single sputum specimen collected no more than 60 days prior to date of trial enrollment (defined as the date the ICF is signed and screening begins), sputum smear positive for acid fast bacilli (AFB) with positive rapid tests for isoniazid and rifampicin resistance.
Findings on screening chest radiograph consistent with TB.
Able to produce sputum for mycobacterial culture.
Female patients of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, IUD, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).
Male patients must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose (to cover duration of spermatogenesis).

E.4

Principal exclusion criteria

A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
Use of the medications in Section 4.1 including: use of amiodarone at any time during the previous 12 months or use of other anti-arrhthymics for the previous 30 days.
Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels greater or equal 1.5 mg/dL or hepatic impairment characterized by ALT and/or AST levels 3 times the upper limit of the laboratory reference range.
Current clinically relevant abnormalities in the screening ECG including conduction abnormalities (AV block or hemiblock) or QTcF interval over 450 msec in male patients and 470 msec in female patients.
Current clinically relevant/significant cardiovascular disorder such as congestive heart failure, ventricular hypertrophy, coronary artery disease, arrhythmia, or poorly controlled hypertension.
BMI < 16 kg/m2.
Karnofsky score < 50%.
Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
Evidence of currently active clinically significant metabolic, gastrointestinal, neurological, psychiatric, or endocrine diseases (eg, poorly controlled diabetes mellitus), currently active malignancy, or other abnormalities (other than those related to the indication being studied).
Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the patient in the opinion of the investigator.
Administered an IMP within 1 month prior to Visit 1 (Screening [Days −21 to −2]).
Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the ICF.
Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications prescribed by a physician for a nonabuse-related indication.
Any disorder that in the judgment of the investigator makes the patient not a good candidate for the trial or may prevent the patient from reliably participating in the entire course of the trial.
Previous exposure to delamanid.
Evidence of XDR TB based on the definition from WHO as TB with demonstrated resistance to isoniazid and rifampicin as well to any one of the fluoroquinolones and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin).
HIV co-infection for patients screened at sites not participating in the HIV subtrial.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoints are (1) proportion of patients achieving SCC at 2 months (8 weeks) using MGIT, and (2) distribution of the time to SCC using the MGIT system during the 6-month Intensive Treatment Period. SCC is defined as a sputum specimen from a patient negative for growth of MTB using the MGIT culture system, followed by at least one confirmatory negative sputum culture at least 27 days after the first negative sputum and not followed by any sputum cultures positive for growth in the MGIT system at any point through Month 7. Time to SCC is defined as the time elapsed between the date of the first dose of delamanid and the date of collection of the first sputum specimen negative for growth of MTB eligible for SCC using the MGIT culture system.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time to SCC is defined as the time elapsed between the date of the first dose of delamanid and the date of collection of the first sputum specimen negative for growth of MTB eligible for SCC using the MGIT culture system.

E.5.2

Secondary end point(s)

Efficacy:
Intensive Treatment Period (Weeks 1 through 26):
• Proportion of patients with SCC at 2 months using solid culture media
• Distribution of time to SCC (using the same definition as for the primary endpoint) using solid culture media
• Proportion of patients with SCC at 6 months using MGIT.
• Proportion of patients with SCC at 6 months using solid culture media

Continuation Treatment Period (Months 7 through 18 to 24) and Post-treatment follow up period (Months 19 to 24 through Month 30):
• Durability of SCC with the MGIT system during the Continuation Treatment and Post-treatment Follow-up periods at Month 18.
• Durability of SCC with the MGIT system during the Continuation Treatment and Post-treatment Follow-up periods at Month 30.

E.5.2.1

Timepoint(s) of evaluation of this end point

see section E.5.2

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

India

Moldova, Republic of

Peru

Philippines

South Africa

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 End of Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up CRF page for the last patient completing or withdrawing from 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.1.1.1

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:

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

150

F.4.2.2

In the whole clinical trial

390

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)

none

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

2011-07-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-04

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