Efficacy

EVOLVE clinical trial improvement in Lung function vs Placebo

EVOLVE Study

TOBI PODHALER improved lung function vs placebo1

Chart showing mean relative change in FEV as between patients on TOBI PODHALER (12.54%) versus placebo (0.09%) in EVOLVE study

Mean absolute changes in FEV1 predicted: TOBI PODHALER, +6.38%; placebo, -0.52%; difference of 6.90% (95% CI: 2.40, 11.40)1

*Each cycle consisted of 28 days on treatment followed by 28 days off treatment.1

Study design: EVOLVE was a 24-week, randomized, double-blind (during Cycle 1) trial in patients aged 6 to 21 years with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa), and FEV1 ≥25% and ≤80% predicted at screening. The first cycle was double-blind and placebo-controlled with eligible patients randomized 1:1 to TOBI PODHALER (four 28-mg capsules twice daily) or placebo. For Cycles 2 and 3, patients who were initially randomized to placebo received TOBI PODHALER. Of the 79 patients included in the prespecified interim analysis, 18 were excluded due to a failure to meet spirometry quality review criteria, which resulted in a total of 61 patients included in the primary analysis.1,2

EVOLVE, Evaluate tobramycin inhaled dry powder efficacy versus placebo in cystic fibrosis patients.

Patients who switched from placebo to TOBI PODHALER after Cycle 1 demonstrated improvements in lung function1

Line graph comparing mean relative change in FEV in patients randomized to TOBI PODHALER or placebo

Improvements in lung function were achieved during the subsequent cycles of treatment with TOBI PODHALER, although the magnitude of improvement was reduced1

Patients taking TOBI PODHALER experienced fewer respiratory-related hospitalizations and needed fewer intravenous (IV) antipseudomonal antibiotics when compared with placebo treated patients in clinical study

64% reduction in the
percentage of patients with
respiratory-related
hospitalizations

Hospital icon

Secondary endpoint in EVOLVE (Study 2, Cycle 1)1,2

4.4% in the TOBI PODHALER treatment
group vs 12.2% in the placebo group

15% reduction in the
percentage of patients
needing IV antipseudomonal
antibiotics

IV bag Icon

Secondary endpoint in EVOLVE (Study 2, Cycle 1)1,2

8.7% in the TOBI PODHALER treatment group
vs 10.2% in the placebo group

EVOLVE was a 24-week, randomized, double-blind (during Cycle 1) trial in patients aged 6 to 21 years with CF, Pa, and FEV1 ≥25% and ≤80% predicted at screening. The first cycle was double-blind and placebo-controlled with eligible patients randomized 1:1 to TOBI PODHALER (four 28-mg capsules twice daily) or placebo. For Cycles 2 and 3, patients who were initially randomized to placebo received TOBI PODHALER. Of the 79 patients included in the prespecified interim analysis, 18 were excluded due to a failure to meet spirometry quality review criteria, which resulted in a total of 61 patients included in the primary analysis.1,2

EDIT Study

Lung function in patients treated with TOBI PODHALER vs placebo was also evaluated in a separate 8-week study1

Chart showing mean relative change in FEV versus primary endpoint in EDIT study

Results not statistically significant1
Mean absolute change in FEV1% predicted was 4.86% for TOBI PODHALER and 0.48% for placebo, with a difference of 4.38% (95% CI: -0.17, 8.94)1

EDIT Study Design

  • EDIT was an 8-week, randomized, double-blind, placebo-controlled study in patients aged 6 to 21 years with CF, Pa, and FEV1 ≥25% and ≤80% predicted at screening
  • Patients with any use of inhaled antipseudomonal antibiotics within 4 months prior to screening were excluded1
  • Eligible patients were randomized 1:1 to receive TOBI PODHALER (4 times 28-mg capsules twice daily; n=32) or placebo (n=30) for one cycle (28 days on treatment and 28 days off treatment)1
  • The EDIT Study was underpowered due to an inability to recruit the prespecified number of TOBI-naïve patients into each arm3
EDIT, Establish tobramycin dry powder efficacy in cystic fibrosis. Decreased susceptibility of Pa to tobramycin has been seen with use of TOBI PODHALER. The relationship between in vitro susceptibility test results and clinical outcome with TOBI PODHALER therapy is not clear. Occurrence of decreased susceptibility on treatment should be monitored, and treatment with an alternative therapy should be considered if clinical worsening is observed.1

References

  1. TOBI® PODHALER® [Prescribing Information, 2023]
  2. Konstan MW, Geller DE, Minic P, Brockhaus F, Zhang J, Angyalosi G. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol. 2011;46(3):230-238.
  3. Galeva I, Konstan MW, Higgins M, et al. Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial. Curr Med Res Opin. 2013;29(8):947-956.
MORE + LESS –

INDICATION

TOBI® PODHALER® (Tobramycin Inhalation Powder) 28 mg per capsule is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.

Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or >80% predicted, or patients colonized with Burkholderia cepacia.

IMPORTANT SAFETY INFORMATION

TOBI PODHALER is contraindicated in patients with known hypersensitivity to any aminoglycoside.

Bronchospasm can occur with inhalation of TOBI PODHALER. Bronchospasm should be treated as medically appropriate.

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction.

Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI PODHALER clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia, or dizziness.

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected renal dysfunction. Nephrotoxicity was not observed during TOBI PODHALER clinical studies but has been associated with aminoglycosides as a class.

TOBI PODHALER should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Patients who use TOBI PODHALER during pregnancy, or who become pregnant while taking TOBI PODHALER, should be apprised of the potential hazard to the fetus. The amount of tobramycin excreted in human breast milk is unknown. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal. A decision should be made whether to discontinue nursing or TOBI PODHALER. TOBI may cause intestinal flora alteration. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis.

Patients receiving concomitant TOBI and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

Concurrent and/or sequential use of TOBI PODHALER with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI PODHALER should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol.

In a clinical trial, the most commonly observed adverse events with TOBI PODHALER occurring at a frequency of at least 10%, were cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache.

Please see Full Prescribing Information

INDICATION

TOBI® PODHALER® (Tobramycin Inhalation Powder) 28 mg per capsule is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.

Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or >80% predicted, or patients colonized with Burkholderia cepacia.

IMPORTANT SAFETY INFORMATION

TOBI PODHALER is contraindicated in patients with known hypersensitivity to any aminoglycoside.

Bronchospasm can occur with inhalation of TOBI PODHALER. Bronchospasm should be treated as medically appropriate.

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction.

Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI PODHALER clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia, or dizziness.

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected renal dysfunction. Nephrotoxicity was not observed during TOBI PODHALER clinical studies but has been associated with aminoglycosides as a class.

TOBI PODHALER should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Patients who use TOBI PODHALER during pregnancy, or who become pregnant while taking TOBI PODHALER, should be apprised of the potential hazard to the fetus. The amount of tobramycin excreted in human breast milk is unknown. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal. A decision should be made whether to discontinue nursing or TOBI PODHALER. TOBI may cause intestinal flora alteration. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis.

Patients receiving concomitant TOBI and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

Concurrent and/or sequential use of TOBI PODHALER with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI PODHALER should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol.

In a clinical trial, the most commonly observed adverse events with TOBI PODHALER occurring at a frequency of at least 10%, were cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache.

Please see Full Prescribing Information