Clinical Trials Register

Summary
EudraCT Number:	2016-000850-36
Sponsor's Protocol Code Number:	201600136
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-10-25
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

Netherlands - Competent Authority

A.2

EudraCT number

2016-000850-36

A.3

Full title of the trial

Double-Blind, Randomized, Placebo-Controlled Phase IIa Clinical Trial to Investigate the Safety and Immunogenicity of RUTI® Therapeutic Vaccination in Patients with Multi-Drug Resistant Tuberculosis after successful intensive-phase treatment.

Dubbel-geblindeerde, gerandomiseerde, placebo-gecontroleerde fase IIa klinische studie om de veiligheid en immunogeniciteit van therapeutische vaccinatie met RUTI® te onderzoeken bij patiënten met multidrug-resistente tuberculose na voldoende intensieve-fase behandeling titel:

A.3.1

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

Evaluation of the safety and ability to induce an immune response of RUTI vaccine for patients that have completed the first 12 or 16 weeks of standard therapy for drug-resistant tuberculosis

Evaluatie van de veiligheid en immunogeniciteit van RUTI vaccine voor patienten die de eerste 12 of 16 weken van de standard behandeling voor multiresistente tuberculose afgerond hebbben.

A.3.2

Name or abbreviated title of the trial where available

Safety of RUTI® vaccine in MDR-TB

A.4.1

Sponsor's protocol code number

201600136

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1180-7558

A.5.4

Other Identifiers

Name:

Clinicaltrials.gov

Number:

NCT02711735

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	Archivel Farma S.L.
B.1.3.4	Country	Spain
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	Archivel Farma S.L.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Prof dr Tjip van der Werf
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9700 RB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031503611501
B.5.6	E-mail	t.s.van.der.werf@umcg.nl

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	RUTI® vaccine
D.3.4	Pharmaceutical form	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FCMtb
D.3.9.3	Other descriptive name	Detoxified and pasteurized cellular wall fragments of Mycobacterium tuberculosis prepared as lyophilized powder for liposomal suspension for injection
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	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)	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	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	Powder for suspension for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The medical condition to be investigated is culture-confirmed Multidrug-resistant tuberculosis, i.e. tuberculosis resistant to the two first-line drugs Rifampicin and Isoniazid

E.1.1.1

Medical condition in easily understood language

The disease to be investigated is Multidrug-resistant tuberculosis. This diseases is caused by tubercle bacteria that are resistant to the two most important antibiotics (rifampicin and isoniazid).

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary endpoint:
To evaluate the safety of the novel anti-TB vaccine RUTI® (25μg FCMtb) in patients with MDR-TB favourably responding to second-line, standard MDRTB treatment as evidenced by both clinical and microbiological response criteria.

E.2.2

Secondary objectives of the trial

Secondary endpoint:
To evaluate the immunogenicity of the novel anti-TB vaccine RUTI® (25μg FCMtb) in patients with MDR-TB favourably responding to second-line, standard MDRTB treatment as evidenced by both clinical and microbiological response criteria.

Exploratory endpoint:
To explore the efficacy as the reduction of bacillary load in the sputum of the novel anti-TB vaccine RUTI® (25μg FCMtb) in patients with MDRTB favourably responding to TB treatment as evidenced by an increase in time-to-positivity of liquid culture.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Female or Male patients (aged > 18)
- diagnosed with active MDR-TB
- having successfully completed 16 (Cohort A) or 12 weeks (Cohort B) of MDR-TB treatment fully supervised with beneficial initial response to therapy, evidenced by
i) Clinical response criteria (reduction of weight loss, chronic cough, fever, or night sweats) and
ii) Microbiological response criteria (improvement in at least two measurements at least 4 weeks apart using Mycobacterial Growth Indicator Tube (MGIT, also known as liquid culture)), and
iii) Radiological response criteria (Chest X-Ray)

- The patient must provide written informed consent
- The patient must be willing and able to attend all study visits and comply with all study procedures
- Females of childbearing potential must have a negative pregnancy test at enrolment and must agree to use highly effective methods of birth control during and 30 days after the study

E.4

Principal exclusion criteria

• Inability to provide written informed consent
• Women reported, or detected, or willing to be pregnant during the trial period;
• Severity of illness precluding full evaluation: expected early death, evidenced by respiratory failure, low blood pressure, WHO performance score 3-4; Central Nervous System involvement of TB (TB meningitis, intra-cranial tuberculomas) as there is too little evidence for effective drug penetration for second-line TB drugs;
• Major co-morbid conditions precluding full evaluation, i.e., active lung cancer, acute coronary syndrome, heart failure exceeding NYHA class 2; a diagnosis of metastasized malignancy; renal failure in excess of creatinine clearance < 30 mls/min calculated by the Cockcroft-Gault formula, which would severely complicate administration of aminoglycosides and capreomycin, considered as the major second-line TB drugs; obesity (BMI>30 kg/m2); chronic liver disease – Child-Pugh class C;
• Any of the following laboratory parameters:
o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)
o total bilirubine > 2 x ULN
o Neutrophil count ≤ 500 neutrophils / mm3
o Platelet count < 50,000 cells / mm3
• Receiving or anticipated to receive a daily dose of ≥ 10 mg of systemic prednisone or equivalent within the period starting 14 days prior to enrolment. Note: patients are allowed to receive an acute, short course of methylprednisolone or prednisone or equivalent for management of an acute exacerbation of COPD or reactive airway disease in asthmatics
• Cytotoxic chemotherapy or radiation therapy within the previous 3 months
• HIV co-infection, if CD4 count < 350 copies/mL; those with 350 copies/mL are expected to be able to mount a sufficient cellular immune response and will therefore be eligible
• Blood transfusion in the last three weeks prior to the trial
• Documented allergy to TB vaccines, notably, to the RUTI® vaccine.

E.5 End points

E.5.1

Primary end point(s)

The main endpoint of this study is safety. This will be assessed using standard clinical, routine laboratory, and radiographic data obtained during standard follow-up.
• Local tolerability (limited function, swelling, redness, pain, itch) will be examined daily during the first week and weekly in the remaining 7 weeks of follow up.
• Systemic tolerability (body temperature, generalized pruritus, rashes, arthralgia, myalgia, nausea, malaise, headache) will be assessed daily during the first week and weekly in the remaining 7 weeks of follow up.
• Vital signs (blood pressure, heart rate, respiratory rate, and pulse oxymetry) will be taken at screening, immediately before vaccination and at weeks 1, 2, 3, 4, 6 and 8 during the follow-up.
• Adverse Events raised by patients spontaneously or observed by the study doctor or attending physician during the study
• Chest x-rays will be taken before vaccination and at week 8 follow up for assessment of lung lesions typical of mycobacterial disease (i.e. granulomatous lesions)
• Laboratory tests at screening and at weeks 2 and 8 after vaccination:
o full blood count, haematology;
o serum chemistry (liver and kidney function);
o ESR, CRP;
o Glucose

E.5.1.1

Timepoint(s) of evaluation of this end point

The safety and tolerability will be assessed:
During the first week post-vaccination on every day (Visit 1-7). One visit in week 2, week 3, and week 4 (visit 8, 9, 10), one visit in week 6 (visit 11) and one visit in week 8 (visit 12) post vaccination.

E.5.2

Secondary end point(s)

Immunogenicity is the secondary study endpoint and will be evaluated using

1) IFN-γ responses of stimulated PBMCs comparing placebo and intervention group at three time points (before vaccination, 2 and 8 weeks post-vaccination). The technique used is ELISPOT (Enzyme-linked immunosorbent spot)

Antigens for ex vivo stimulation
Investigations for determining correlates of immune protection to tuberculosis are ongoing and the technical specifications for the ex vivo IFN-y ELISPOT assay are unknown at this time. Decisions on the technical aspects for completing the analysis of correlates of immune protection for this study will be provided when available.

2) a mycobacterial growth inhibition assay (MGIA). This functional immunogenicity assay measures directly the summative ability of the patient derived PBMCs to control the mycobacterial growth in an ex vivo system. Mycobacterial growth inhibition will be assessed using a BACTEC MGIT (mycobacterial growth indicator tube; as used for liquid culture) system as well as plate counting to measure the decrease of bacterial load upon vaccination in the presence of PBMCs. The assessment will be performed after 4 days of PBMC co-culture with Mycobacterium bovis BCG as immune target.

To isolate PBMC, 32 ml of blood will be collected from each study participant at three time points and placed in two BD Vacutainer CPTTM (cell preparation tubes) containing sodium heparin. Blood will be centrifuged for 15 minutes at 1500 RCF at 18°C to separate the different components. PBMCs will be harvested, washed, resuspended in 10ml of RPMI-MGIT (RPMI+10% pooled human serum + L-Glutamine) and frozen at -80°C. Cryopreserved PBMC will be transported to London (London School of Hygiene and Tropical Medicine) where the MGIA assay will be performed.

3) Analyses of other immunological or transcriptional assessments may be performed to further characterize the immune and transcriptional response to study vaccine depending on the current scientific understanding of correlates of protection in tuberculosis research.

E.5.2.1

Timepoint(s) of evaluation of this end point

Blood will be drawn for immunogenicity testing at three time points: Before vaccination (the day before for baseline testing), and in week 2 and week 8 post vaccination.

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

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

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

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 end of the trial will be when the last of the 27 participants has completed the follow-up period.

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

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)

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

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)

Indeed, before, during, and after participation subjects will continue to receive standard treatment for this condition.

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

2016-10-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-01

P. End of Trial
P.	End of Trial Status	Ongoing

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