Phase II study on the safety and efficacy of cysteamine in association with standard tuberculosis therapy for the treatment of patients with pulmonary tuberculosis: a new therapy for tuberculosis directed at the host.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

National Institute For Infectious Diseases Lazzaro Spallanzani

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

16 Oct 2024 → ongoing

Decision date (initial)

2024-10-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516088-10-00

EudraCT number

2019-002514-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Investigate in an off-label phase II study in adult patients with bacilliferous pulmonary TB, the safety and tolerability of using cysteamine as adjunctive therapy to standard TB treatment

Secondary objectives 3

1. Evaluate the effect of cysteamine by molecular assay for bacterial load assessment (MBLA) at different time points (day 0, 7±1, 14±1 and 28±3)
2. Define the immunological and molecular basis of cysteamine activity;
3. Identify biomarkers useful for therapy monitoring in different biological samples (blood, serum, cells, urine, sputum) at different time points [day 0, 7±1, 14±1, 28±3, 60±3, end of therapy (month 6)]

Conditions and MedDRA coding

Pulmonary Tuberculosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age between 18 and 65 years
2. Body Weight ≥50 kg
3. Karnofsky score ≥60 %
4. Ability to provide informed consent
5. Ability to adhere to follow-up visits
6. Consent to be hospitalized for 4 weeks
7. Consent to treatment under direct observation
8. Consent to adhere to contraception requirements for subjects of childbearing age from 2 weeks prior to enrollment to 18 weeks after experimental drug administration
9. Consent to perform a pregnancy test prior to administration of the experimental drug for female subjects of childbearing age
10. Clinical signs and symptoms of pulmonary tuberculosis (new diagnosis)
11. Abnormal chest radiograph compatible with pulmonary tuberculosis
12. At least one positive sputum for alcohol-acid-resistant bacteria (BAAR) (bacterisoscopic examination) and molecular confirmation for M. tuberculosis by DNA detection of M. tuberculosis complex with a cycle threshold (Ct) <40, associated with possible genotypic resistance finding to rifampin and isoniazid
13. Sensitivity to first-line antitubercular drugs by phenotypic pharmacosensitivity test on MGIT liquid medium
14. Infertility status in females. A woman is considered to be potentially fertile, or fertile, after menarche and until she enters postmenopause, unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menses for 12 months without an alternative medical cause. An elevated follicle-stimulating hormone (FSH) level in the postmenopausal range can be used to confirm postmenopausal status in women who are not using hormonal contraceptives or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient. Therefore, for the purposes of this protocol, infertility status in females will be defined as: Premenopausal with: documented bilateral salpingectomy, hysterectomy, documented bilateral oophorectomy. In the post-menopausal phase: with 12 months of spontaneous amenorrhea and confirmation

Exclusion criteria 22

1. Age > 65 years and <18 years
2. Body weight < 50 kg
3. Hemoglobin concentration less than 10 g/dl
4. use of antiretroviral drugs
5. Increasing of creatinine kinase at baseline more than three times the upper limit of normal
6. Abnormal laboratory values at baseline (baseline alanine aminotransferase (ALT) concentration more than three times the upper limit of normal, serum creatinine concentration more than twice the upper limit of normal, serum total bilirubin level more than twice the upper limit of normal, platelet count <100,000/mm3, white blood cell (WBC) <2500 (mcL)
7. Pregnancy or breastfeeding
8. Silico-tuberculosis
9. Previous anti-tubercular treatment or use for more than 5 days of anti-tubercular drugs in the 3 months prior to enrollment
10. Concomitant diseases or conditions for which anti-tubercular drugs are contraindicated. These include severe liver failure, acute arthritis, peripheral neuropathy..
11. Presence of any physical or psychological condition that, in the opinion of the principal investigator, makes participation in the study contraindicated
12. Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine
13. TB with extra-pulmonary localization
14. Therapy with immunosuppressant drugs and/or NSAIDs and/or corticosteroids in the 4 weeks prior at enrollment
15. TB resistant to first- and second-line drugs
16. Inability to understand and sign informed consent
17. Seropositivity for HIV, HCV, HBV (HBsAg positivity)
18. Liver failure (Child B-C), renal failure (creatinine clearance < 50 ml/min), heart failure (NYHA III-IV), decompensated diabetes mellitus, neoplasms (those who have had cycles of chemotherapy including biologic drugs and/or radiation therapy in the past 5 years), ongoing neurological/psychiatric pathology (e.g. depression, psychotic break, suicide attempt), chronic inflammatory bowel disease or gastric/duodenal ulcer under treatment, autoimmune disease
19. Drug/alcohol abuse
20. Hypersensitivity to cysteamine or penicillin
21. Current use of cysteamine
22. Participation in other Clinical Trials.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Acceptability of treatment
2. Adherence: doses taken/expected doses of cysteamine.
3. Tolerability of treatment.
4. Pharmacokinetics of all administered drugs performed on plasma (dedicated test tube with EDTA as anticoagulant).
5. Evaluation of serious adverse events (SAEs) and unexpected events.
6. Correlation of any AEs and SAEs with pharmacokinetic profiles.

Secondary endpoints 3

1. Evaluate the effect of cysteamine on Mtb by molecular assay for bacterial load assessment (MBLA) at different time points (day 0, 7±1 and 28±3).
2. (Additional endpoint). Evaluation of biomarkers useful for therapy monitoring in different biological samples (blood, plasma, serum, cells, urine, sputum) at different time points [day 0, 7±1, 14±1, 28±3,60±3, end of therapy (month 6±3)] ((for example, cytokines/chemokines, cell counts, inflammatory factors, biochemical factors will be evaluated by multiparametric immunohistochemical methods and/or immunometric/enzymatic assays).
3. (Additional Endpoints). Immunological characterization of cysteamine activity. In particular, at different time points [day 0, 7±1, 14±1, 28±3, 60±3, end of therapy (month 6±3)], the following will be evaluated in peripheral blood mononuclear cells (PBMC) stimulated with Mtb-specific stimuli: cellular activation markers, cytokine production and memory profile (e.g. CD3, CD4, CD8, CD19, CD45RA, CD27, CCR7, CD38, CD25, HLA-DR, IFN-γg, TNF-αa,IL-2)by flow cytometry.Transcriptome will be evaluated

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

National Institute For Infectious Diseases Lazzaro Spallanzani

Sponsor organisation

National Institute For Infectious Diseases Lazzaro Spallanzani

Address

Via Portuense 292

City

Rome

Postcode

00149

Country

Italy

Scientific contact point

Organisation

National Institute For Infectious Diseases Lazzaro Spallanzani

Contact name

Fabrizio Palmieri

Public contact point

Organisation

National Institute For Infectious Diseases Lazzaro Spallanzani

Contact name

Fabrizio Palmieri

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications