PTK0796-CABP-19302

Paratek Pharma, LLC

75 Arlington Street, Suite 500, Boston, United States, 02116

Chief Development and Regulatory, Paratek Pharma, LLC, +1 6172750040, randy.brenner@paratekpharma.com

Chief Development and Regulatory, Paratek Pharma, LLC, +1 6172750040, randy.brenner@paratekpharma.com

No

No

No

Final

17 Sep 2024

Yes

27 Mar 2024

Yes

27 Mar 2024

No

The primary objective of this study was to demonstrate that iv to po omadacycline was non-inferior to iv to po moxifloxacin in the treatment of adults with PORT Risk Class III and IV CABP. The secondary objectives were: • To evaluate the safety of omadacycline in the treatment of adult subjects with CABP in the Safety population. • To evaluate the clinical response according to the identified causative pathogen. • To evaluate the pharmacokinetics (PK) of omadacycline in adult subjects with CABP.

This clinical study was designed and implemented and reported in accordance with the International Council for Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, United States [US] Code of Federal Regulations [CFR] Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. The investigator provided protection of the subjects by following all applicable regulations. These regulations were available upon request from the sponsor. The ICF was reviewed by the sponsor and approved by the IRB/IEC/REB. Before any procedures specified in the protocol were performed, a subject must have: • Been informed of all pertinent aspects of the study and all elements of informed consent. • Been given time to ask questions and time to consider the decision to participate. • Voluntarily agreed to participate in the study. • Signed and dated an IRB/IEC/REB approved ICF.

25 Feb 2021

No

No

Poland: 16

Croatia: 27

Bulgaria: 190

Hungary: 3

Georgia: 246

Russian Federation: 4

Serbia: 91

Ukraine: 93

670

236

0

0

0

0

0

0

334

309

27

Overall trial (overall period)

Randomised - controlled

The iv treatment phase: double-blind, double-dummy design with placebo infusions matched to active omadacycline and moxifloxacin infusions. All iv infusions were administered by qualified blinded personnel. The po treatment phase: double-blind, double-dummy design using omadacycline placebo comparator tablets of matching size and shape to active omadacycline tablets and matching over-encapsulated placebo and active moxifloxacin tablets.

Yes

Omadacycline

Powder for infusion, Tablet

Oral use, Intravenous use

The iv-treatment phase (minimum of 2 days) followed a double-blind, double-dummy design for omadacycline. Infusions of omadacycline or matched placebo were administered continuously, without interruptions, over 30 minutes (± 5 minutes). If once a day (QD) dosing was selected, the 200 mg infusion of omadacycline or matched placebo was administered continuously, without interruptions, over 60 minutes (± 5 minutes). If BID dosing was selected, 100 mg infusion was administered BID on Day 1 followed by 100 mg iv on Day 2. The po treatment phase employed a double-blind, double-dummy design using omadacycline placebo comparator tablets of matching size and shape to active omadacycline tablets. The first po dose was given in the morning 12 to 24 hours after the last iv dose. To maintain investigator and subject blinding, subjects on both arms received 2 tablets and 1 over-encapsulated tablet in the morning.

Moxifloxacin

Solution for infusion, Tablet

Infusion , Oral use

The iv-treatment phase (minimum of 2 days) followed a double-blind, double-dummy design for moxifloxacin 400 mg QD and matched placebo were administered continuously without interruptions over 60 minutes (± 5 minutes). During the first 24 hours of iv treatment, if twice a day dosing (BID) was selected, subjects on the moxifloxacin treatment arm received an additional placebo infusion to match the t=12 hours infusion. Infusions of moxifloxacin or matched placebo were administered continuously, without interruptions, over 60 minutes (± 5 minutes). The first dose of test article was to be administered within 4 hours of randomization. The po treatment phase employed a double-blind, double-dummy design using matching over-encapsulated placebo and active moxifloxacin tablets. When switching from iv to po test article, the recommended interval between doses was maintained. The first po moxifloxacin dose was given in the morning 12 to 24 hours after the last iv dose.

Omadacycline

Moxifloxacin

Intent-to-Treat (ITT) set

The ITT population consisted of all randomized subjects regardless of whether or not the subject received test article.

Omadacycline

Moxifloxacin

Intent-to-Treat (ITT) set

The ITT population consisted of all randomized subjects regardless of whether or not the subject received test article.

The primary efficacy outcome measure was ECR at 72 to 120 hours after administration of the first dose of test article in the ITT population. Overall, omadacycline was found to be non-inferior to moxifloxacin for the ECR assessment in the ITT population. Clinical success rates were high (89.6% omadacycline, 87.7% moxifloxacin) and comparable between both treatment groups (difference [95% CI]: 1.9 [-3.0, 6.8]). Given that the lower limit of the 95% CI for the treatment difference (omadacycline – moxifloxacin) was greater than -10%, omadacycline was considered non-inferior to moxifloxacin.

Primary

72-120 hours after first infusion of test article

The primary efficacy analyses were based on the ITT population. The non-inferiority (NI) test was a 1-sided hypothesis test performed at the 2.5% level of significance. This NI test was based on the lower limit of the 2-sided 95% confidence interval (CI) (Miettinen & Nurminen method). The primary efficacy outcome was the percentage of subjects with a clinical success at the ECR Assessment (72-120 hours after the first infusion of test article).

Omadacycline v Moxifloxacin

670

Pre-specified

1.9

2-sided

The number and percentage of subjects classified as clinical success, clinical failure, and indeterminate by the investigator’s assessment at PTE in the ITT and CE populations calculated for each treatment group was summarized. Clinical success rates were high and similar between the treatment groups at the overall PTE visit. In the ITT population, clinical success at PTE was 86.0% for omadacycline and 87.7% for moxifloxacin (difference [95% CI]: -1.7 [-6.9, 3.4]). Similar results were observed in the CE-PTE population (clinical success was observed in 94.1% of omadacycline subjects and 95.9% of moxifloxacin subjects; difference [95% CI]: -1.8 [-5.7, 2.0]).

Secondary

The PTE visit occurred at 5-10 days after the last day of therapy

Difference was observed difference in overall clinical success rate at PTE between the omadacycline and moxifloxacin groups. Overall clinical response at the PTE was based on the investigator assessment at the EOT and PTE visits. Percentages were based on the number of subjects in each treatment group. 95% CI was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

-1.7

2-sided

Within 15 days after the first dose of test article, 4 subjects in each treatment group died, and 1 subject in each treatment group was lost to follow-up. Within 30 days after the first dose of test article, 5 subjects in the omadacycline group and 6 subjects in the moxifloxacin group died. In addition, 2 subjects in the omadacycline group and 3 subjects in the moxifloxacin group were lost to follow-up in this time period.

Secondary

15 and 30 days after first dose of test article

Of the subjects who did not have complete resolution of symptoms at the PTE visit, a majority (83.1% omadacycline, 82.9% moxifloxacin) were determined to be clinical successes by the investigators at PTE; such subjects had residual or minimal clinical symptoms of CABP at PTE that did not require further systemic antimicrobial therapy.

Other pre-specified

Post therapy evaluation (PTE; 5-10 days after the last day of therapy)

Difference was observed difference in overall clinical success rate at PTE between the omadacycline and moxifloxacin groups. Clinical symptoms for CABP: cough, sputum production, pleuritic chest pain, and dyspnea. Resolution was defined as the absence of all baseline symptoms. Overall clinical response at the PTE was based on the investigator assessment at the EOT and PTE visits. 95% CI was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

0.1

2-sided

Subjects classified as a clinical success, clinical failure, or indeterminate by the investigator’s assessment at EOT in the ITT population. The percentage of subjects in the ITT population with clinical success was similar in the omadacycline group compared to the moxifloxacin group (90.2% and 91.3%, respectively.

Other pre-specified

From the first dose of test article to the EOT visit.

Difference was observed difference in investigator assessment of clinical success rate at EOT between the omadacycline and moxifloxacin groups. Two-sided unadjusted 95% CI was constructed for the observed difference in the clinical success rate based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

-1.1

2-sided

Analyses of shifts from Baseline to each visit (Day 2 through the PTE visit) in the clinical symptoms of CABP were performed by treatment group for the ITT population. In general, most subjects who had cough, pleuritic chest pain, dyspnea, and phlegm/sputum considered severe at Baseline were reported to have mild to no symptoms at the EOT and PTE visits. Shifts to less severe categories were also observed in the mild and moderate categories. At the PTE visit the percentage of subjects who had resolution of all clinical symptoms in the omadacycline and moxifloxacin groups were 81.0% and 86.8%, respectively. A vast majority of subjects in either treatment group did not have a new or worsening symptom (99.7% omadacycline, 99.7% moxifloxacin). Of the subjects who did not have complete resolution of symptoms at the PTE visit, a majority (83.1% omadacycline, 82.9% moxifloxacin) were determined to be clinical successes by the investigators at PTE.

Other pre-specified

From baseline (Day 2) to PTE visit

Difference was observed difference in overall clinical success rate at PTE between the omadacycline and moxifloxacin groups. Clinical symptoms for CABP: cough, sputum production, pleuritic chest pain, and dyspnea. Resolution was defined as the absence of all baseline symptoms. Overall clinical response at the PTE was based on the investigator assessment at the EOT and PTE visits. 95% CI was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

100

Pre-specified

0.1

2-sided

Among subjects with definitive assessments (ie, not indeterminate), there was generally good concordance (≥ 80%) between ECR and the later clinical assessment in each treatment group. Overall, the incidences of subjects who were programmatically determined as non-responders at ECR and later deemed clinical cures at PTE by the investigators were 5.4% for omadacycline subjects and 4.5% for moxifloxacin subjects. The incidences of subjects who were responders at ECR and later deemed clinical failures at PTE were 5.7% for omadacycline subjects and 2.4% for moxifloxacin subjects. The difference between treatment groups was driven mainly by the greater number of subjects in the omadacycline group who did not complete the PTE visit.

Other pre-specified

72 to 120 hours to PTE visit

ECR (at 72 to 120 hours after the first infusion of test article) and overall assessment of clinical response (based on the investigator’s assessment) at the PTE visit across PORT Risk Class in the ITT population. In general, comparable results were observed between PORT Risk Class III and Class IV scores for both the ECR and PTE assessments.

Other pre-specified

ECR (72-120 hours after first infusion of test article) to PTE visit

Difference was observed difference in early clinical success rate or overall clinical response rate at PTE between the omadacycline and moxifloxacin groups. 95% CI within each type of PORT Risk Class was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

1.1

2-sided

ECR (at 72 to 120 hours after the first infusion of test article) and overall assessment of clinical response (based on the investigator’s assessment) at the PTE visit across prior antibiotic use in the ITT population. Comparable results were observed between those who did and did not receive a prior antibiotic (ie, a single dose short-acting antibiotic within 72 hours prior to the first dose of test article) for both the ECR and PTE assessments.

Other pre-specified

ECR (72-120 hours after first infusion of test article) to PTE visit

Difference was observed difference in early clinical success rate or overall clinical response rate at the PTE between the omadacycline and moxifloxacin groups. 95% CI within each type of prior antibiotics use (yes/no) was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

0.8

2-sided

In subjects with SIRS, the ECR assessment of clinical success was reported in 90.3% omadacycline subjects and 88.0% moxifloxacin subjects. At PTE, the corresponding clinical success rates were 85.2% and 87.6%. In addition, generally comparable results were observed between different CURB-65 scores, although there were relatively few subjects with CURB-65 scores of 3 or 4.

Other pre-specified

From ECR (72-120 after first infusion of test article) to PTE visit

Difference was observed difference in early clinical success rate or overall clinical response rate at the PTE between the omadacycline and moxifloxacin groups. 95% CI within each subgroup was constructed based on the Miettinen and Nurminen method without stratification.

Omadacycline v Moxifloxacin

670

Pre-specified

2.3

2-sided

A treatment-emergent AE was defined as any AE that newly appeared, increased in frequency, or worsened in severity on or after the initiation of active test article.

The Safety population consisted of all randomized subjects who received test article. An AE was considered treatment-emergent if the AE start date and time was on or after the start date and time of the first infusion of active test article.

27.0

Omadacycline

Moxifloxacin