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CompletedNCT03456102StAT-TBUpdated Jun 28, 2023Results posted

Statin Adjunctive Therapy for TB

A Phase 2 interventional study of Pravastatin in Tuberculosis, sponsored by Johns Hopkins University. Completed at 1 site in South Africa. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2023-06-28.

Sponsored by Johns Hopkins University · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
16
Allocation
Non-randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

There is an urgent need for novel therapies to shorten TB treatment and improve long-term lung function outcomes. Host-directed therapies (HDT) have received significant attention recently given the ability of M. tuberculosis to subvert host immune responses and cause destructive lung pathology. Statins are among the most promising HDT agents for TB. In addition to having a highly favorable safety profile, statins have been shown to have anti-TB activity in macrophages, to synergize with anti-TB drugs, and to shorten the duration of TB treatment in the standard mouse model.

The StAT-TB trial will comprise two different stages. In the 14-day Stage 1 study, investigators will test the safety and tolerability, as well as Pharmacokinetics (PK), of two different doses of pravastatin co-administered with standard anti-TB treatment. In Stage 2, investigators will test the ability of pravastatin adjunctive therapy (dose to be determined in Stage 1) to shorten the mean time to sputum culture conversion (primary endpoint) and improve lung function outcomes (secondary endpoints) relative to the standard regimen. In addition, investigators will continue to investigate the anti-TB mechanism of action of pravastatin in order to further improve HDT options for TB in the future.

02

Conditions studied

  • Tuberculosis

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03

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • 18 years of age or older
  • Clinical signs and symptoms of pulmonary tuberculosis
  • Abnormal chest radiograph consistent with pulmonary tuberculosis
  • At least one sputum positive for M. tuberculosis by Xpert Mycobacterium tuberculosis (MTB)/resistance to rifampicin (RIF) with a cycle threshold (Ct) \<28.
  • Documentation of HIV status
  • Weight ≥45 kg
  • Karnofsky score of at least 60
  • Ability to provide informed consent
  • Ability to adhere to study follow-up visits
  • Ability to adhere to contraceptive requirements and willing to use two forms of contraception.
  • Five days or fewer of anti-tuberculosis treatment within the previous 3 months

Exclusion criteria

Exclusion Criteria:

  • A history of severe adverse reactions to any statin or any other study agent or contraindications to use of statins.
  • Current use of statins or other lipid-lower agents;
  • Clinical indication for statin therapy based on cardiovascular risk (Familial hypercholesterolemia, Previous history of myocardial infarction or stroke)
  • For HIV-positive individuals, a cluster of differentiation 4 (CD4+) T-cell count \<100/mm3
  • Use of antiretroviral drugs
  • Hemoglobin concentration less than 7 g/dL;
  • Baseline creatinine kinase elevation more than three times the upper limit of normal
  • Abnormal baseline laboratory values (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 greater than twice the upper limit of normal, Platelet count \< 100,000/mm3, White Blood Cell (WBC) \< 2500 (mcL))
  • Pregnant or breastfeeding;
  • Silico-tuberculosis.
  • Currently receiving TB treatment
  • Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include sever hepatic damage, acute liver disease of any cause, acute uncontrolled gouty arthritis and peripheral neuropathy.
  • Any medical or psychological condition which, in the view of the study investigator, makes study participation inadvisable.
  • Infection with an isolate known to be resistant to a first -line TB drug; for example rifampin.
  • More than five days of anti-tuberculosis treatment within the previous 3 months
  • Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine
  • Central nervous system (CNS) TB
  • Extra-pulmonary TB only, not in combination with pulmonary TB
  • History of TB
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
16 participants (actual)

Study arms

  • Other
    Pravastatin 80 mg

    Pravastatin 80 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 2 will only be recruited if pravastatin 40 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

    Drug: Pravastatin

  • Other
    Pravastatin 120 mg

    Pravastatin 120 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 3 will only be recruited if pravastatin 80 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

    Drug: Pravastatin

  • Other
    Pravastatin 160 mg

    Pravastatin 160 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 4 will only be recruited if pravastatin 120 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

    Drug: Pravastatin

  • Other
    Pravastatin 40 mg

    Pravastatin 40 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days

    Drug: Pravastatin

Interventions

  • DrugPravastatin

    Phase IIB clinical trial: A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated. A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated.

05

What researchers measure

Primary outcomes

  1. Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events

    Safety of escalating doses of pravastatin (40 mg - 160 mg) when co-administered with rifampin, as evidenced by number of Grade 3 or higher adverse events.

    Time frame: Up to 30 days

06

Results

Posted Jun 28, 2023

Participant flow

Study participants were recruited from clinics in Soweto, South Africa by the study team at the PHRU, Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. Participants were recruited based on having a sputum specimen that is positive for TB by GeneXpert MTB/RIF.

Participant flow — Overall Study
MilestonePravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mg
Started10600
Completed10600
Not completed0000

Outcome measures

PrimarySafety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events

Safety of escalating doses of pravastatin (40 mg - 160 mg) when co-administered with rifampin, as evidenced by number of Grade 3 or higher adverse events.

Time frame:
Up to 30 days
Reported as:
Number · AEs Grade 3 or Higher
Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events
AEs Grade 3 or HigherPravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mg
Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events84——

Adverse events

Collected over Up to 5 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Pravastatin 40 mg0/10 (0%)4/10 (40%)5/10 (50%)
Pravastatin 80 mg0/6 (0%)1/6 (16.7%)3/6 (50%)
Pravastatin 120 mg———
Pravastatin 160 mg———
Most frequent serious events
Most frequent serious events
EventPravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mg
Elevated Uric AcidInvestigations3/101/6——
Elevated liver enzymes (ALT/AST)Investigations1/100/6——
Most frequent other events
Most frequent other events
EventPravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mg
Elevated uric acidInvestigations2/103/6——
Elevated liver enzymes (ALT/AST)Investigations1/100/6——
Elevated creatinine kinaseInvestigations1/100/6——
Decreased hemoglobin levelInvestigations1/100/6——

Baseline characteristics

No participants were enrolled and no data was collected in the 120mg and 160mg pravastatin arms due to early termination.

Age, Continuous
Age, Continuous(years)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
Mean26.70 ± 5.3526.83 ± 7.03——26.75 ± 5.80
Sex: Female, Male
Sex: Female, Male(Participants)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
Female32——5
Male74——11
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
African/Black106——16
Coloured00——0
Indian/Asian00——0
White00——0
Other00——0
Region of Enrollment
Region of Enrollment(Participants)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
South Africa106——16
Weight at Baseline (kg)
Weight at Baseline (kg)(Participants)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
45-49kg10——1
50-59kg74——11
60-69kg22——4
HIV Status
HIV Status(Participants)Pravastatin 40 mgPravastatin 80 mgPravastatin 120 mgPravastatin 160 mgTotal
Negative106——16
Positive00——0
07

Study locations

1 site
  • Chris Hani Baragwanath Hospital
    Johannesburg, South Africa
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Jun 1, 2019

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03456102
Lead sponsor
Johns Hopkins University
Responsible party
Sponsor
First posted
Mar 7, 2018
Start date
Mar 9, 2020
Primary completion
Aug 31, 2022
Completion
Aug 31, 2022
Results posted
Jun 28, 2023
Last update
Jun 28, 2023

Study contacts

Richard Chaisson
principal investigator · Johns Hopkins University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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