TB Host Directed Therapy

Phase 2

• Conditions: Tuberculosis
• Interventions: Drug: Everolimus 0.5 MG; Drug: Auranofin 6 MG; Drug: Vitamin D3; Drug: CC-11050; Drug: 2HRbZE/4HRb

• Registration Number: NCT02968927
• Lead Sponsor: The Aurum Institute NPC

Brief Summary

To examine the safety and preliminary efficacy of multiple adjunctive host directed TB therapies (TB HDT), to assess their potential to shorten TB treatment and/or prevent permanent lung damage.

Detailed Description

OBJECTIVES:

To determine the safety and preliminary efficacy of 4 TB HDT candidates:

1. Safety (treatment emergent serious adverse events and SUSARs)

2. Microbiologic effects in sputum (culture conversion, change in MGIT TTP) and blood (WBA)

3. PET/CT imaging

4. Serum markers of inflammation

5. Effects on Mtb-specific and general immune function

6. Pulmonary effects (spirometry, 6MWT, O2 saturation, and St. George Respiratory Symptom Questionnaire) In each case, TB HDT effects will be determined by comparison to patients treated with standard TB therapy alone with regard to a common set of primary and secondary endpoints.

PRIMARY ENDPOINTS

1. For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs).

2. For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).

Study Timeline

• Study First Submitted: 2016-09-08
• Study Start: 2016-11
• Study First Submitted QC: 2016-11-17
• Study First Posted: 2016-11-21
• Primary Completion: 2018-09
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-09
• Last Update Posted: 2019-01-10
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures.
2. Aged 18 to 65 years, male, or if female, either not of reproductive potential (post-menopause, or status-post surgical sterilization) or with an intrauterine contraceptive device in place.
3. Body weight (in light clothing without shoes) between 40 and 90 kg.
4. First episode of pulmonary tuberculosis diagnosed by positive sputum AFB smear with subsequent culture confirmation OR positive Xpert TB/RIF with Ct <20 [4].
5. RIF susceptibility diagnosed by Xpert TB/RIF OR Hain test
6. Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis [5]
7. HIV-1 seronegative
8. HBsAg negative

Exclusion Criteria

1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments

2. Current or imminent treatment for malaria.

3. Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.

4. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.

5. History of allergy or hypersensitivity to any of the trial therapies or related substances, including known allergy or suspected hypersensitivity to rifampin or rifabutin.

6. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.

7. Subjects with any of the following at screening:

   1. Cardiac arrhythmia requiring medication;
   2. Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;
   3. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
   4. Any clinically significant ECG abnormality, in the opinion of the investigator.
   5. Patients requiring concomitant medications that prolong the QT inter-val.

8. Random blood glucose >140 mg/dL, or history of unstable Diabetes Mellitus which required hospitalization for hyper- or hypoglycaemia within the past year prior to start of screening.

9. Use of systemic corticosteroids within the past 28 days.

10. Subjects with any of the following abnormal laboratory values:

    1. creatinine >2 mg/dL
    2. haemoglobin <8 g/dL
    3. platelets <100x109 cells/L
    4. serum potassium <3.5
    5. aspartate aminotransferase (AST) ≥2.0 x ULN
    6. alkaline phosphatase (AP) >5.0 x ULN
    7. total bilirubin >1.5 mg/dL

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Auranofin	2HRbZE/4HRb	Auranofin 6 MG
Everolimus	Everolimus 0.5 MG	Everolimus 0.5 MG
CC-11050	2HRbZE/4HRb	CC-11050
2HRbEZ/4HRb	2HRbZE/4HRb	2HRbZE
Auranofin	Auranofin 6 MG	Auranofin 6 MG
Vitamin D	2HRbZE/4HRb	Vitamin D3
Everolimus	2HRbZE/4HRb	Everolimus 0.5 MG
Vitamin D	Vitamin D3	Vitamin D3
CC-11050	CC-11050	CC-11050

Primary Outcome Measures

Name	Time	Method
SAEs and SUSARs	through day 180	For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs).; For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).

Secondary Outcome Measures

Name	Time	Method
TEAEs other than SAEs and SUSARs	through day 180	TEAEs other than SAEs, categorized according to severity, drug relatedness, and leading to early withdrawal.
Sputum culture status on day 56	day 56	Proportion of patients with positive sputum cultures on solid culture medium after 8 weeks of treatment

Trial Locations

Locations (1)

The Aurum Institute: Tembisa Clinical Research Centre; 🇿🇦 Tembisa, Gauteng, South Africa