Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Therapy for Pulmonary Tuberculosis

Tuberculosis, Pulmonary Clinical Trial

Official title:

Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Combination Therapy for Pulmonary Tuberculosis (TB): a Randomized, Double-blind, Placebo-controlled, Proof-of-concept Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01638520
• Other study ID #: DSRB 2012/02212
• Status: Active, not recruiting
• Phase: Phase 2
• First received: July 9, 2012
• Last updated: March 30, 2017
• Start date: June 2012
• Est. completion date: July 2017

Study information

• Verified date: March 2017
• Source: National University Hospital, Singapore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

New approaches are needed to achieve more rapid elimination of dormant mycobacteria and thereby shorten treatment for drug-sensitive and drug-resistant tuberculosis (TB). Dormant mycobacteria are relatively resistant to antibacterial drugs and approaches that enhance immune clearance have the potential to be more effective. Interleukin-4 (IL-4) is a key cytokine in the immune response to TB that may impair the clearance of mycobacteria. We hypothesize that pascolizumab, an anti-IL-4 monoclonal antibody, might be of value as an adjunct to standard treatment.

The aims of this trial are to determine whether administration of pascolizumab as an adjunct to standard combination treatment for drug-sensitive TB produces changes in one or more parameters of bacterial or host response (including bacterial clearance, host clinical status, immune response, bacterial and host transcriptomics, lung imaging) that may indicate potential for enhanced sterilization and to confirm the safety of blocking IL-4 (previously demonstrated in healthy volunteers and patients with asthma) in patients with TB.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 32
• Est. completion date: July 2017
• Est. primary completion date: February 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Aged 21 -75 years of age

2. Male or female: females eligible only if not of childbearing potential or agree to remain abstinent or use an appropriate contraceptive method during the study.

3. Confirmed pulmonary TB by smear microscopy and Gene Xpert™

4. Absence of rifampicin resistance on molecular probe (Gene Xpert™)

5. Estimated to be able to produce at least 5ml of sputum per 24 hour period.

6. No previous history of anti-TB therapy for active disease (treatment for latent disease acceptable).

7. Willing to comply with the study visits and procedures

8. Willing and able to provide written informed consent

Exclusion Criteria:

1. More than 28 days of standard anti-TB chemotherapy at the time of randomization.

2. Disseminated TB (lymphadenopathy is acceptable)

3. Underlying serious chronic diseases such as those of the liver, kidney disease, blood disorders and Type I diabetes (controlled Type II diabetes is acceptable) or any significant organ dysfunction.

4. History of myocardial infarction, congestive heart failure or arrhythmia within 6 months of screening

5. History or evidence of chronic alcohol consumption or drug abuse

6. Current autoimmune disease or history of autoimmune disease.

7. Known or suspected hypersensitivity to any component of the trial medication (sodium phosphate, sodium chloride, glycine, sucrose, polysorbate 80)

8. Chronic use of an immunosuppressant

9. Treatment with any monoclonal antibody within 6 months of randomization

10. Vaccination within the 6 weeks prior to randomization (patients who have received influenza vaccination can enroll at 2 weeks following vaccination).

11. Seropositive for human immunodeficiency virus-1 or 2; hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at screening

12. Creatinine > 1.4 times upper limit of normal or ALT greater than 2.5 times upper limit of normal on screening blood tests

13. QTc >450 msec on ECG performed at screening

14. Women who are currently pregnant or breastfeeding

15. Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.

16. Participation in other clinical intervention trial or research protocol (Participation in other studies that do not involve an intervention may be allowed, but this must be discussed and approved by Chief Investigator )

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Pascolizumab
0.05mg/kg - 10mg/kg Pascolizumab according to dosing cohort
• Placebo
Saline (volume determined based on weight of patient, and cohort of enrollment)

Locations

Country	Name	City	State
Malaysia	Institute of Respiratory Medicine	Kuala Lumpur
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Philippines	Lung Centre Philippines	Manila
Philippines	Philippines Tuberculosis Society Inc.	Manila
Singapore	Changi General Hospital	Singapore
Singapore	National University Hospital, Singapore	Singapore
Singapore	Ng Teng Fong General Hospital	Singapore

Sponsors (2)

Lead Sponsor	Collaborator
National University Hospital, Singapore	National University, Singapore

Countries where clinical trial is conducted

Malaysia,  Philippines,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy - Time to detection on liquid culture of sputum on Week 8		8 weeks post intervention
Primary	Co-primary outcome measure - safety	Adverse events considered at least possibly related to study medication and that are classified by the site investigator as serious and/or grade IV severity	Upto 24 weeks via follow-up visits/assessments and 24-96 weeks via phone assessments
Secondary	Sputum culture status (positive or negative) on liquid culture at week 8		8 weeks
Secondary	Rate of change (area under the curve) from baseline to week 8 in the time to positivity in liquid culture of sputum		8 weeks
Secondary	Rate of change in serial sputum colony counts on solid cultures from baseline to week 8		8 weeks
Secondary	Rate of change of RPF-dependent serial sputum colony counts from baseline to week 8		8 weeks
Secondary	Sputum culture status (positive or negative) on solid culture at week 8		8 weeks
Secondary	Rate of change of sputum smear lipid-body positive mycobacteria from baseline to week 8		8 weeks
Secondary	Serum IL-4 levels (free and drug-bound)		24 weeks
Secondary	Time to resolution of fever		24 weeks
Secondary	Time to resolution of all TB symptoms		24 weeks
Secondary	Resolution of chest X-ray changes at week 24		24 weeks
Secondary	Resolution of PET/MRI changes at week 8 and week 24		24 weeks
Secondary	TB relapse at any time up to week 96		96 weeks
Secondary	Anti-pascolizumab antibodies		24 weeks