HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the PRETOMANID Package Insert for complete information.
Mylan Laboratories Limited
Approval date: August 14, 2019
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
PRETOMANID is a drug used for the treatment of lung tuberculosis (TB) in adults. It is to be used only when other drugs for the treatment of lung TB do not work (drug-resistant TB) or are not tolerated.
How is this drug used?
PRETOMANID is a tablet taken once a day for 26 weeks. It must be used in combination with two other antimicrobial drugs (bedaquiline and linezolid).
What are the benefits of this drug?
The trial showed that 95 out of 107 patients (89%) had no TB bacteria in the sputum six months after completing the treatment.
PRETOMANID is approved under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, which provides approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need.
What are the benefits of this drug (results of trials used to assess efficacy)?
The following table presents efficacy results from the trial based on the treatment failure, defined as the incidence of bacteriologic failure, bacteriologic relapse, or clinical failure 6 months after the end of treatment.
Table 2. Outcomes Six Months After the End of Treatment
|Favorable||Total favorable (culture negative status at 6 months post treatment)||95 (89%)||63 (89%)||32
|Relapse post treatment (not culture confirmed)||1||0||1|
|Withdrawal, loss to follow-up, or contaminated cultures||3||1||2|
|Total unfavorable||12 (11%)||8 (11%)||4(11%)|
TI/NR MDR-TB = treatment-intolerant or nonresponsive multidrug-resistant tuberculosis; XDR-TB = extensively drug resistant tuberculosis
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: PRETOMANID was similarly effective in men and women.
- Race: Most patients were Black. Differences in response to PRETOMANID among various race could not be determined.
- Age: PRETOMANID was similarly effective in adult patients below and above 30 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
The following table presents demographic information for the efficacy population.
Table 3. Subgroup Analysis of Favorable Outcomes (Six Months After End of Treatment in ITT Population)
(N = 107)
|Men (N = 56)||50 (89)|
|Women (N = 51)||45 (88)|
|Black (N = 81)||74 (91)|
|Other* (N=26)||21 (81)|
|<30 (N=34)||30 (88)|
|>30 (N=73)||65 (89)|
|US (N = 0)||N/A|
|Non-US (N = 107)||95 (89)|
*Includes mixed race
Adapted from FDA Review
What are the possible side effects?
PRETOMANID taken together with bedaquiline and linezolid can cause serious side effects including:
- liver problems,
- bone marrow suppression (resulting in low blood counts),
- nerve damage,
- vision problems,
- changes in heart rhythm due to prolongation of heart electrical activity, and
- an acid build-up in the blood.
The most common side effects of PRETOMANID taken together with bedaquiline and linezolid include nerve damage, acne, anemia, nausea, vomiting, headache, and abnormal liver tests.
What are the possible side effects (results of trials used to assess safety)?
The following table summarizes the incidence of select adverse reactions occurring in ≥5% of subjects.
Table 4. Select Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving the PRETOMANID, Bedaquiline, and Linezolid Regimen
|Adverse Reactions||PRETONAMID, Bedaquiline and Linezolid Combination Regimen
(N = 109)
|All Grades n (%)|
|Peripheral neuropathy*||88 (81)|
|Musculoskeletal Pain*||32 (29)|
|Transaminases increased*||30 (28)|
|Decreased appetite||24 (22)|
|Abdominal pain*||21 (19)|
|Pleuritic pain||21 (19)|
|Gamma-glutamyltransferase increased||19 (17)|
|Lower respiratory tract infection*||16 (15)|
|Visual impairment*||13 (12)|
|Abnormal loss of weight||11 (10)|
|Dry skin||8 (7)|
|Electrocardiogram QT prolonged||6 (6)|
*Select terms are collapsed, as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); acne (acne, dermatitis acneiform); anemia (anemia); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); transaminases increased (alanine aminotransferase [ALT]) increased, aspartate aminotransferase [AST] increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); lower respiratory tract infection (bronchitis, influenza, lower respiratory tract infection, pneumonia); hyperamylasemia (amylase increased, hyperamylasemia);cough (cough, productive cough); visual impairment (vision blurred, visual acuity reduced, visual impairment); neutropenia (neutropenia); hypertension (blood pressure increased, hypertension); hyperlipasemia (hyperlipasemia, lipase increased); thrombocytopenia (thrombocytopenia).
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was similar in men and women.
- Race: Most patients were Black. Differences in side effects among various race could not be determined.
- Age: The occurrence of side effects was similar in patients below and above 30 years of age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
The following table presents treatment emergent adverse events by sex.
Table 5. Adverse Events by Sex
|Peripheral Sensory Neuropathy||39||68%||37||71%|
|Upper Respiratory Tract Infection||8||14%||12||23%|
Adapted from FDA Review
The following table presents adverse events (regardless of whether treatment emergent) by age <30 years versus ≥30 years.
Table 6. Adverse Events by Age, occuring in ≥ 20 patients (Safety Population)
|Adverse Event||Age <30 years
|%||Age >30 years (n=75)||%|
|Peripheral Sensory Neuropathy||23||68%||53||71%|
|Upper Respiratory Tract Infection||10||29%||10||13%|
Clinical Trial Data
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved PRETOMANID based on evidence from one clinical trial (NCT02333799) of 109 patients 17-60 years old for whom other drugs for the treatment of lung TB did not work (drug-resistant) or were not tolerated. The trial was conducted at 3 sites in South Africa. All 109 patients that provided data for evaluation of side effects (called the safety population) are presented in the charts below.
Figure 1 summarizes how many men and women were in the clinical trial.
Figure 1. Baseline Demographics by Sex (Safety Population)
Figure 2 summarizes the percentage of patients by race in the clinical trials.
Figure 2. Baseline Demographics by Race (Safety Population)
Table 1. Demographics of Efficacy Trials by Race
|Race||Number of Patients||Percentage|
|Black or African American||83||76|
Figure 3 summarizes the percentage of patients by age group in the clinical trial.
Figure 3. Baseline Demographics by Age
Who participated in the trials?
The FDA approved PRETOMANID based on evidence from one clinical trial of 109 adult patients 17-60 years old with either pulmonary extensively drug-resistant (XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDR) tuberculosis. The demographics of the safety population are presented in the following table.
Table 7. Trial Demographics (Safety population)
|Variable||N = 109|
|<30 years||34 (%)|
|>30 years||75 (%)|
|South Africa||109 (100%)|
Adapted from FDA Review
How were the trials designed?
PRETOMANID was evaluated in one trial. Only adult patients for whom other drugs for the treatment of lung TB did not work (drug-resistant) or were not tolerated were included in the trial.
All patients in the trial received PRETOMANID together with bedaquiline and linezolid. All three drugs were taken by mouth, once daily for 6 months.
The benefit of this regimen was measured by the proportion of patients achieving a favorable response (no TB bacteria in the sputum) at 6 months after the end of treatment.
How were the trials designed?
The FDA approved PRETOMANID based on a single, uncontrolled, multicenter trial which enrolled adult patients with either pulmonary extensively drug-resistant tuberculosis (XDR-TB) or pulmonary treatment-intolerant/nonresponsive multidrug-resistant tuberculosis (TI/NR MDR-TB). PRETOMANID was given orally as part of a three-drug combination regimen with bedaquiline and linezolid for 6 months. The primary endpoint of the trial was treatment failure, defined as the incidence of bacteriologic failure, bacteriologic relapse, or clinical failure 6 months after the end of treatment. The results of the trial were compared to results of subjects with drug-resistant TB treated with drugs other than those used in the trial.
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.