Single Dose and Multiple Dose Study to Assess Safety and Tolerability of LOU064

NCT03918980 | Completed Phase 1

• 1 other identifier: CLOU064X2101
• Study Type: interventional
• Target: 185
• Locations: 2 countries
• Sites: 2

Brief Summary

This is a 6-part first-in-human study in up to approximately 184 participants. Parts 1 to 5 is in health volunteers and part 6 is in subjects with atopic dermatitis. The purpose of this first-in-human study is to assess the safety and tolerability and pharmacokinetics (PK) of single and multiple doses of LOU064 both as once and twice daily oral administration in healthy volunteers and those with atopic diathesis or atopic dermatitis. This study will also explore the effect of food intake and different drug substance particle sizes on the in vivo disposition of LOU064 in healthy volunteers to guide dosing and formulation development for future clinical trials. The study is registered on CT.Gov with the initiation of part 6 in patients (FPFV in April 2019).

Conditions

Healthy Volunteers, Atopic Diathesis and Atopic Dermatitis

Outcome Measures

Primary Outcomes (1)

• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Clinically significant changes in physical examination and anamnesis, vital signs, ECG, safety laboratory will be reported under (S)AEs.

  Part 1: 22 days, Part 2: 33 days, Part 3: 40 days, Part 4: 33 days, Part 5: 26 days, Part 6: 50 days

Secondary Outcomes (7)

• LOU064 pharmacokinetics Cmax

  Part 1: Day 1, 2, 3, 4, 5 and 8, Part 2: Day 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 3: Day 1, 2, 3, 4 and 5, Part 4: Day 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 5: Day 1, 2, 3, 5 and 8 Part 6: Day 1, 2, 8, 15, 22, 29, and day 30

• LOU064 pharmacokinetics Tmax

  Part 1: Day 1, 2, 3, 4, 5 and 8, Part 2: Day 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 3: Day 1, 2, 3, 4 and 5, Part 4: Day 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 5: Day 1, 2, 3, 5 and 8 Part 6: Day 1, 2, 8, 15, 22, 29, and day 30

• LOU064 pharmacokinetics AUCinf

  Part 1: Day 1, 2, 3, 4, 5 and 8, Part 2: Day 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 3: Day 1, 2, 3, 4 and 5, Part 4: Day 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 5: Day 1, 2, 3, 5 and 8 Part 6: Day 1, 2, 8, 15, 22, 29, and day 30

• LOU064 pharmacokinetics AUClast

  Part 1: Day 1, 2, 3, 4, 5 and 8, Part 2: Day 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 3: Day 1, 2, 3, 4 and 5, Part 4: Day 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 5: Day 1, 2, 3, 5 and 8 Part 6: Day 1, 2, 8, 15, 22, 29, and day 30

• LOU064 pharmacokinetics AUCtau

  Part 1: Day 1, 2, 3, 4, 5 and 8, Part 2: Day 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 3: Day 1, 2, 3, 4 and 5, Part 4: Day 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16 and 19, Part 5: Day 1, 2, 3, 5 and 8 Part 6: Day 1, 2, 8, 15, 22, 29, and day 30

Study Arms (27)

Part 1 Dose A

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose B

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose C

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose D

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose E

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose F

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose G

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose H

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose I

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Dose J

EXPERIMENTAL

(Single Ascending Dose) Healthy volunteers will receive a single dose of LOU064.

Drug: LOU064

Part 1 Placebo

PLACEBO COMPARATOR

(Single Ascending Dose) Healthy volunteers will receive a single dose of placebo.

Drug: Placebo

Part 2 Dose K

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Dose L

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Dose M

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Dose N

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Dose O

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Dose P

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 once daily for 12 days

Drug: LOU064

Part 2 Placebo

PLACEBO COMPARATOR

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take placebo once daily for 12 days

Drug: Placebo

Part 3 Dose Fasted

EXPERIMENTAL

Healthy volunteers will receive a single dose of LOU064 given under fasting conditions followed by a single dose of LOU064 given after a high fat meal (cross-over design).

Drug: LOU064

Part 3 Dose Fed

EXPERIMENTAL

Healthy volunteers will receive a single dose of LOU064 given after a high fat meal followed by a single dose of LOU064 given under fasting conditions (cross-over design).

Drug: LOU064

Part 4 Dose R

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 twice daily for 12 days

Drug: LOU064

Part 4 Dose S

EXPERIMENTAL

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take LOU064 twice daily for 12 days

Drug: LOU064

Part 4 Placebo

PLACEBO COMPARATOR

(Multiple Ascending Dose) Healthy Volunteers with asymptomatic atopic diathesis will take placebo twice daily for 12 days

Drug: Placebo

Part 5 Formulation A

EXPERIMENTAL

Healthy Volunteers will receive a single dose of LOU064 formulation A followed by a single dose of LOU064 formulation B (cross-over design).

Drug: LOU064

Part 5 Formulation B

EXPERIMENTAL

Healthy Volunteers will receive a single dose of LOU064 formulation B followed by a single dose of LOU064 formulation A (cross-over design).

Drug: LOU064

Part 6 Dose T

EXPERIMENTAL

Subjects with atopic dermatitis will receive a twice daily dose of LOU064 for 4 weeks

Drug: LOU064

Part 6 Placebo

PLACEBO COMPARATOR

Subjects with atopic dermatitis will receive a twice daily dose of placebo for 4 weeks

Drug: LOU064; Drug: Placebo

Interventions

LOU064 DRUG

LOU064 will be administered as oral capsules in parts 1 to 6.

Part 1 Dose A; Part 1 Dose B; Part 1 Dose C; Part 1 Dose D; Part 1 Dose E; Part 1 Dose F; Part 1 Dose G; Part 1 Dose H; Part 1 Dose I; Part 1 Dose J; Part 2 Dose K; Part 2 Dose L; Part 2 Dose M; Part 2 Dose N; Part 2 Dose O; Part 2 Dose P; Part 3 Dose Fasted; Part 3 Dose Fed; Part 4 Dose R; Part 4 Dose S; Part 5 Formulation A; Part 5 Formulation B; Part 6 Dose T; Part 6 Placebo

Placebo DRUG

Matching placebo capsules will be administered in parts 1,2, 4 and 6.

Part 1 Placebo; Part 2 Placebo; Part 4 Placebo; Part 6 Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be obtained before any assessment is performed.
• Male and female healthy subjects with an age range between 18 and 65 years (inclusive), and in good general health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening. Healthy subjects to participate in Part 2 or Part 4 must additionally have an atopic diathesis to be eligible for these specific study portions. Atopic healthy volunteers must have a positive skin prick test to a known allergen at screening (atopic diathesis) but must be clinically asymptomatic and not requiring any systemic medication. To participate in Part 6, subjects must additionally have chronic atopic dermatitis (AD) according to American Academy of Dermatology Consensus Criteria (Eichenfield et al 2014), that has been present for at least 1 year before the baseline visit and defined as:
• Eczema Area and Severity Index (EASI) ≥ 12 at screening and baseline
• IGA (Investigator's Global Assessment) ≥ 3 on a 5-point scale at screening and baseline
• BSA (Body Surface Area) involvement ≥ 8% at screening and baseline
• Subjects have applied a stable dose of bland topical emollient at least twice daily for at least 7 consecutive days immediately before the baseline visit
• Able to communicate well with the Investigator, to understand and comply with the requirements of the study.
• Subjects must weigh at least 50 kg and must have a body mass index (BMI) within the range of 18 -30 kg/m2 (inclusive) (parts 1-5) / 18-35 kg/m2 inclusive (part 6). BMI = body weight (kg) / \[Height (m)\]2.
• At screening, and first baseline, vital signs (body temperature, systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes and again (when required) after three minutes in the standing position. Sitting vital signs should be within the following ranges (inclusive):
• Oral body temperature between 35.0-37.5 °C
• Systolic blood pressure 90-139 mm Hg; for subjects ≥ 55 years, systolic blood pressure up to 149 mm Hg is accepted (part 6)
• Diastolic blood pressure 50-89 mm Hg
• Pulse rate 50 - 90

You may not qualify if:

• Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
• History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
• Known family history or known presence of long QT syndrome.
• A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening and/or pre-treatment: PR \> 200 msec QRS complex \> 120 msec QTcF \> 450 msec (males) QTcF \> 460 msec (females)
• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
• Known history of or current clinically significant arrhythmias.
• Use of any systemic prescription drugs (including CYP3A inducers and inhibitors, and drugs with arrhythmogenic potential) other than hormonal contraceptives for women of childbearing potential, herbal supplements, within four (4) weeks prior to initial dosing or within 3 months for biologics (like dupilumab), and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing. If needed, (i.e. an incidental and limited need) paracetamol is acceptable, but must be documented in the Concomitant medications / Significant non-drug therapies page of the eCRF.
• For topical treatments in Part 6, the following rules apply:
• Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) must be stopped
• week prior to randomization to allow an adequate washout-period.
• Other topical treatments for AD such as crisaborole, tar etc. and prescription moisturizers or moisturizers containing ingredients such as ceramides, lactic acid, urea, α-hydroxy- or fruit acids, vitamins A, D or E must be discontinued during the 4-week treatment period.
• Phototherapy or tanning booth treatment must have stopped 4 weeks prior to baseline.
• Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days after stopping LOU064. Highly effective contraception methods include:

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (2)

Novartis Investigative Site

Berlin, 14050, Germany

Location

Novartis Investigative Site

Leiden, 2333 CL, Netherlands

Location

Related Links

• Results for CLOU064X2101 from the Novartis Clinical Trials Website
• A Plain Language Trial Summary is available on novartisclinicaltrials.com

MeSH Terms

Conditions

Dermatitis, Atopic

Interventions

remibrutinib

Condition Hierarchy (Ancestors)

Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: April 18, 2019
• Study Start: August 18, 2016
• Primary Completion: January 27, 2020
• Study Completion: January 27, 2020
• Last Updated: October 12, 2021

Record last verified: 2021-10

Locations

NL (1); DE (1)