C22-109-08

Pharma Holdings AS

Killengreensgate 8, postbox 1288, Tromsø, Norway, NO-9263

Johnny Ryvoll, VP projects, Pharma Holdings AS, ryvoll@pharmaholdings.no

Johnny Ryvoll, VP projects, Pharma Holdings AS, ryvoll@pharmaholdings.no

No

No

No

Final

24 Oct 2022

Yes

24 Oct 2022

Yes

24 Oct 2022

No

To evaluate the efficacy of LTX-109 (3%) gel in an intensive dosing regimen to anterior nares in healthy volunteers who have persistent carriage of S. aureus.

The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are compliant with the ICH GCP E6 (R2) guidance, the EU Clinical Trials Directive 2001/20/EC, and applicable local regulatory requirements. It was the responsibility of the Investigator/authorised associate to give each potential study subject adequate verbal and written information before any study specific assessments were performed. The information included the objectives and the procedures of the study as well as any risks or inconvenience involved. It was emphasised that participation in the study was voluntary and that the subject could withdraw from participation at any time and for any reason, without any prejudice. All subjects were given the opportunity to ask questions about the study and were given sufficient time to consider participation before signing the Informed consent form (ICF). Before performing any study-related procedures, the ICF had to be signed by the subject and by the person who conducted the informed consent discussion. A copy of the subject information including the signed ICF was provided to the subject. The ICF process was carried out in 2 steps. At the first screening visit (Visit 1), the subject was provided with the written study information and was informed about the study. The subjects signed an ICF for nasal swab for the first MSSA verification. At Visit 1 the first nasal swab was performed in line with Inclusion criterion No 3 but no other criteria were checked. A positive result of the first nasal swab at Visit 1 had to be available prior to Visit 2. Subjects who tested positive for S. aureus at Visit 1 were asked to come back for comprehensive information about the study and subsequent signing of the full ICF covering their participation in the remaining part of the study. Following the subjects’ signing of second ICF, all eligibility criteria were checked at Visit 2 and verified at Visit 3 prior to dosing.

30 Aug 2022

No

No

Sweden: 27

27

27

0

0

0

0

0

0

27

0

0

Overall trial (overall period)

Randomised - controlled

This was a double-blind study. The allocation of treatments was not disclosed until clean file had been declared and the database had been locked. LTX-109 and the placebo were identical in appearance.

Yes

LTX-109 3%

Gel

Topical use

Day 1: all subjects were dosed 4 times, during an intensive dosing regimen for 4 ½-hours (every 1 ½ hours at 0, 1 ½, 3 and 4 ½hours). Before the first application of IMP, the nose was cleansed with sodium chloride (0.9 % NaCl). On each dosing occasion, a large drop (diameter approx., 8 to 9 mm corresponding to approx. 250 μL) of the assigned treatment (LTX-109 or placebo) was applied into each nostril and distributed to cover the whole area of the nostril by a qualified healthcare professional. It was important that the volume was large enough to cover the whole inner area of the nose. A nasal bandage was used to prevent the liquid from leaking. The subjects lied in an approximately 30-degree supine position during the application. After application of the IMP to both nostrils, the nostrils were gently squeezed together and were gently massaged. Subjects had to remain in the 30-degree supine position for 5 minutes after each IMP application.

Placebo

Gel

Topical use

Day 1: all subjects were dosed 4 times, during an intensive dosing regimen for 4 ½-hours (every 1 ½ hours at 0, 1 ½, 3 and 4 ½hours). Before the first application of IMP, the nose was cleansed with sodium chloride (0.9 % NaCl). On each dosing occasion, a large drop (diameter approx., 8 to 9 mm corresponding to approx. 250 μL) of the assigned treatment (LTX-109 or placebo) was applied into each nostril and distributed to cover the whole area of the nostril by a qualified healthcare professional. It was important that the volume was large enough to cover the whole inner area of the nose. A nasal bandage was used to prevent the liquid from leaking. The subjects lied in an approximately 30-degree supine position during the application. After application of the IMP to both nostrils, the nostrils were gently squeezed together and were gently massaged. Subjects had to remain in the 30-degree supine position for 5 minutes after each IMP application.

LTX-109 3%

Gel

Topical use

Day 1: all subjects were dosed 4 times, during an intensive dosing regimen for 4 ½-hours (every 1 ½ hours at 0, 1 ½, 3 and 4 ½hours). Before the first application of IMP, the nose was cleansed with sodium chloride (0.9 % NaCl). On each dosing occasion, a large drop (diameter approx., 8 to 9 mm corresponding to approx. 250 μL) of the assigned treatment (LTX-109 or placebo) was applied into each nostril and distributed to cover the whole area of the nostril by a qualified healthcare professional. It was important that the volume was large enough to cover the whole inner area of the nose. A nasal bandage was used to prevent the liquid from leaking. The subjects lied in an approximately 30-degree supine position during the application. After application of the IMP to both nostrils, the nostrils were gently squeezed together and were gently massaged. Subjects had to remain in the 30-degree supine position for 5 minutes after each IMP application.

Placebo

Gel

Topical use

Day 1: all subjects were dosed 4 times, during an intensive dosing regimen for 4 ½-hours (every 1 ½ hours at 0, 1 ½, 3 and 4 ½hours). Before the first application of IMP, the nose was cleansed with sodium chloride (0.9 % NaCl). On each dosing occasion, a large drop (diameter approx., 8 to 9 mm corresponding to approx. 250 μL) of the assigned treatment (LTX-109 or placebo) was applied into each nostril and distributed to cover the whole area of the nostril by a qualified healthcare professional. It was important that the volume was large enough to cover the whole inner area of the nose. A nasal bandage was used to prevent the liquid from leaking. The subjects lied in an approximately 30-degree supine position during the application. After application of the IMP to both nostrils, the nostrils were gently squeezed together and were gently massaged. Subjects had to remain in the 30-degree supine position for 5 minutes after each IMP application.

LTX-109 3% Cohort 1

Placebo Cohort 1

LTX-109 3% Cohort 2

Placebo Cohort 2

LTX-109 3% Cohort 1

Placebo Cohort 1

LTX-109 3% Cohort 2

Placebo Cohort 2

LTX-109 3%

Subjects were randomised in a 2:1 ratio to receive either LTX-109 (n=18) or placebo (n=9). Cohort (1 [8 doses] or 2 [6 doses]) was used as a stratification variable to preserve the 2:1 treatment randomisation ratio in each cohort (LTX-109 n=9 or placebo n=5/4). This subject analysis set represents the active treatment groups receiving LTX-109.

Placebo

Subjects were randomised in a 2:1 ratio to receive either LTX-109 (n=18) or placebo (n=9). Cohort (1 [8 doses] or 2 [6 doses]) was used as a stratification variable to preserve the 2:1 treatment randomisation ratio in each cohort (LTX-109 n=9 or placebo n=5/4). This subject analysis set represents the groups receiving placebo treatment.

Eradication of bacteria is defined as non-presence of S. aureus (MSSA) in quantitative cultures (<5 CFU/mL). Non persistent MSSA carriers are not included in the analysis (e.g., subjects with no growth of S.aureus at time 0 are omitted from the analysis). Subjects need to be eradicated at both 6 and 12 hours to be defined as “Yes”.

Primary

From 6 to 12 hours after start of treatment, corresponding to the “Operation Window”.

The number of subjects on LTX-109 versus placebo with bacterial eradication period lasting for 6 hours, from 6 to 12 hours after start of treatment (the OW) was analysed using Fisher’s exact test. The significance level of the test was targeted at 0.0500. There was no statistically significant difference in the number of subjects with complete eradication during the Operation Window between the treatment groups.

LTX-109 3% v Placebo

25

Pre-specified

Eradication of bacteria is defined as non-presence of S. aureus (MSSA) in quantitative cultures (<5 CFU/mL). Non persistent MSSA carriers are not included in the analysis (e.g., subjects with no growth of S.aureus at time 0 are omitted from the analysis).

Secondary

At 4 ½, 6 and 12 hours after start of treatment.

Eradication of bacteria is defined as non-presence of S. aureus (MSSA) in quantitative cultures (<5 CFU/mL). Non persistent MSSA carriers are not included in the analysis (e.g., subjects with no growth of S.aureus at time 0 are omitted from the analysis).

Secondary

At pre-dose (baseline) and at 4 1/2, 6 and 12 hours after start of treatment.

Eradication of bacteria is defined as non-presence of S. aureus (MSSA) in quantitative cultures (<5 CFU/mL). Non persistent MSSA carriers are not included in the analysis (e.g., subjects with no growth of S.aureus at time 0 are omitted from the analysis). Subjects need to be eradicated at all timepoints from 6 to 54 hours to be defined as “Yes”.

Secondary

From 6 to 54 hours after start of treatment (the “48 hours Eradication Window”).

The grading of the severity/intensity of AEs followed the common terminology criteria for AEs (CTCAE) v5.0. AEs were assessed as unlikely, possibly or probably related to the IMP.

Secondary

AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.

Safety laboratory values were specified and documented as normal, abnormal not clinically significant, or abnormal clinically significant. Abnormal values assessed as clinically significant were reported as AEs. If an abnormal value was associated with corresponding clinical signs or symptoms, the sign/symptom had to be reported as the AE.

Secondary

Blood samples for the analysis of clinical chemistry and haematology were collected through venepuncture or an indwelling venous catheter at screening, pre-dose Day 1 (baseline), 54 hours after first dose and at the end-of-study visit Day 7.

Systolic and diastolic blood pressure and pulse were measured in supine position after 10 minutes of rest. Any vital signs outside of normal ranges were specified and documented as clinically significant or not clinically significant. Abnormal post-IMP administration findings assessed as clinically significant were reported as AEs.

Secondary

Vital signs (blood pressure and pulse) were measured at screening, pre-dose Day 1 (baseline) at 24 hours and 54 hours after first dose and at the end-of-study visit on Day 7.

A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Any abnormalities were specified and documented as clinically significant or not clinically significant. Abnormal post-IMP administration findings assessed by the Investigator as clinically significant were reported as AEs.

Secondary

A physical examination was performed at screening and at the end-of-study visit on Day 7 (Visit 5).

Local erythema was assessed in left and right nostril and graded using a 4-graded scale (1 none/2 mild/3 moderate/4 severe).

Secondary

Day 1 (pre-dose and at 1 ½ h, 4 ½ h, 6 h, 12 h post first dose), Day 3 (54 h post first dose) and at end-of-study visit Day 7.

Local swelling was assessed in left and right nostril and graded using a 4-graded scale (1 none/2 mild/3 moderate/4 severe).

Secondary

Day 1 (pre-dose and at 1 ½ h, 4 ½ h, 6 h, 12 h post first dose), Day 3 (54 h post first dose) and at end-of-study visit Day 7.

Local lesions were assessed in left and right nostril and graded using a 4-graded scale (1 none/2 mild/3 moderate/4 severe).

Secondary

Day 1 (pre-dose and at 1 ½ h, 4 ½ h, 6 h, 12 h post first dose), Day 3 (54 h post first dose) and at end-of-study visit Day 7.

Each nostril was evaluated separately using a Visual analogue scale (VAS).

Secondary

Day 1 (pre-dose and at 1 ½ hours, 4 ½ hours, 6 hours and 12 hours post first dose), Day 3 (54 hours post first dose) and at the end-of-study visit Day 7.

Each nostril was evaluated separately using a VAS.

Secondary

Day 1 (pre-dose and at 1 ½ hours, 4 ½ hours, 6 hours and 12 hours post first dose), Day 3 (54 hours post first dose) and at the end-of-study visit Day 7.

AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.

25.0

LTX-109 3% Cohort 1

Placebo Cohort 1

LTX-109 3% Cohort 2

Placebo Cohort 2