Clinical trial NCT01638520: Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Therapy for Pulmonary Tuberculosis
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Keywords: Immune Therapy
Interleukin 4
monoclonal antibody
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: National University of Singapore
First posted: 2012-07-11
Enrollment: 32
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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 )

Primary outcomes:
measure: Efficacy - Time to detection on liquid culture of sputum on Week 8
timeFrame: 8 weeks post intervention
measure: Co-primary outcome measure - safety
timeFrame: Upto 24 weeks via follow-up visits/assessments and 24-96 weeks via phone assessments
Secondary outcomes:
measure: Sputum culture status (positive or negative) on liquid culture at week 8
timeFrame: 8 weeks
measure: Rate of change (area under the curve) from baseline to week 8 in the time to positivity in liquid culture of sputum
timeFrame: 8 weeks
measure: Rate of change in serial sputum colony counts on solid cultures from baseline to week 8
timeFrame: 8 weeks
measure: Rate of change of RPF-dependent serial sputum colony counts from baseline to week 8
timeFrame: 8 weeks
measure: Sputum culture status (positive or negative) on solid culture at week 8
timeFrame: 8 weeks
measure: Rate of change of sputum smear lipid-body positive mycobacteria from baseline to week 8
timeFrame: 8 weeks
measure: Serum IL-4 levels (free and drug-bound)
timeFrame: 24 weeks
measure: Time to resolution of fever
timeFrame: 24 weeks
measure: Time to resolution of all TB symptoms
timeFrame: 24 weeks
measure: Resolution of chest X-ray changes at week 24
timeFrame: 24 weeks
measure: Resolution of PET/MRI changes at week 8 and week 24
timeFrame: 24 weeks
measure: TB relapse at any time up to week 96
timeFrame: 96 weeks
measure: Anti-pascolizumab antibodies
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Kuala Lumpur
country: Malaysia
facility: Institute of Respiratory Medicine
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Manila
country: Philippines
facility: Lung Centre Philippines
city: Manila
country: Philippines
facility: Philippines Tuberculosis Society Inc.
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Singapore
country: Singapore
facility: National University Hospital, Singapore
city: Singapore
country: Singapore
facility: Ng Teng Fong General Hospital
Study officials:
affiliation: National Univesity, Singapore
name: Nick Paton
role: PRINCIPAL_INVESTIGATOR
References: