ANZCTR - Registration

Registration number

ACTRN12619001544167

Ethics application status

Approved

Date submitted

13/09/2019

Date registered

8/11/2019

Date last updated

8/11/2022

Date data sharing statement initially provided

8/11/2019

Date results provided

8/11/2022

Type of registration

Retrospectively registered

Titles & IDs

Public title

A three-part, double-blind, placebo-controlled, phase I/Ib study of the safety, tolerability and pharmacokinetics of single and multiple ascending doses of IMU-935 in healthy volunteers and Psoriasis Patients.

Scientific title

A three-part, double-blind, placebo-controlled, phase I/Ib study of the safety, tolerability and pharmacokinetics of single and multiple ascending doses of IMU-935 in healthy volunteers and Psoriasis Patients.

Secondary ID [1]

PI/Ib-IMU-935

Universal Trial Number (UTN)

U1111-1240-1937

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Psoriasis

Condition category

Condition code

Skin

Dermatological conditions

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a double-blind, placebo controlled, ascending dose trial. The study will be conducted in three parts: a single ascending dose (SAD) part in healthy volunteers, followed by a multiple ascending dose (MAD) part in healthy volunteers and a repeat dose 2-dose level treatment in moderate-to-severe psoriasis patients.
The study is divided in 3 parts, Part A, Part B and Part C.
Total maximum study duration for participants in Part A Cohorts 1, 3, 4, 5 and 6 or the bridging cohort is 42 days. Total maximum study duration for participants in Cohort 2 is 56 days.
Total maximum study duration for participants in Part B is 56 days.
Total maximum study duration for participants in Part C is 98 days.
In Part A, healthy volunteers will be enrolled to receive single ascending doses of IMU-935 or placebo (oral capsule). In Part B, healthy volunteers will be enrolled to receive multiple ascending doses of IMU-935 or placebo (oral capsule). In Part C, psoriasis patients will be enrolled to receive two different dose levels of IMU-935 or placebo (oral capsule).
For Parts A and B, up to 8 participants are planned to be enrolled in each cohort. A minimum of 6 participants per cohort will be enrolled, with at least one participant randomised to receive placebo.
The decision to escalate between dose levels and proceed to each of study parts (Parts A, B and C) will be based upon review of the available Adverse Event, clinical laboratory and Pharmacokinetic (PK) data by the Safety Monitoring Group (SMG).
The starting dose, dose increments and dose range are based on available pre-clinical data.
Part A: In Part A, IMU-935 dose levels in the range of 25 – 400 mg will be investigated in a total of six cohorts. Each cohort participant receiving a single dose. The 8 participants in each cohort will be randomized to receive either IMU-935 or placebo (ratio 3:1). Cohorts 1, 3, 4, 5 and 6 will receive IMU-935 under fasted conditions only. Cohort 2 participants will receive IMU-935 under fasted and fed conditions (controlled in-house within the Phase I unit through monitoring and controlling meal times). Up to an additional 16 participants may be enrolled in a total of 2 cohorts to assess a second Investigational Product (IP) formulation. Following evaluation of the safety and PK of the first IP formulation, either the first or second IP formulation will be selected for evaluation in the subsequent SAD cohorts. A further 8 participants may be enrolled in a food effect (fasted/fed) cohort for the second formulation. A total of up to 80 participants will be enrolled in Part A.
Dosing in each dose level cohort will start with two sentinel participants with one of the two randomized to receive IMU-935 and the other participant randomized to receive placebo. The safety and tolerability of each sentinel participant will be monitored until Day 4 and will be reviewed prior to dosing the remainder of participants in each cohort. The study PI will review safety/tolerability information available on the sentinel participants on Day 4 and in consultation with a SMR [Sponsor Medical Representative](if necessary), will make the decision to dose the remaining six participants in the cohort.
If the dose level is determined to be safe and tolerated, the next dose cohort will be enrolled and randomized to receive the next dose level of active IMU-935 or placebo. Cohorts will be dosed in an escalating order, each dose level increased by no more than 2-fold over the previous dose level. Following completion of at least 6 out of 8 participants in each cohort in Part A, the SMG will review the data, discuss the findings, and decide to:
a) enroll the next dose cohort at the protocol-defined dose level;
b) enroll the next dose cohort at an intermediate dose level;
c) enrol the next dose cohort in a BID dosing Bridging Cohort; or
d) terminate enrollment in Part A of the study. If the dose level is determined not to be safe and tolerated, the study drug assignment for those participants with a safety concern may be un-blinded.
Evaluation of BID dosing in a Bridging Cohort will be conducted as a way of mitigating potential adverse events and will be conducted following emergence of early signs of potential adverse events attributed to the administration of study treatment (IMU-935 or placebo).
Part A - Bridging Cohort
Following the review of emerging safety and PK data arising from each single dose cohort in Part A, the SMG will consider the option of evaluating BID dosing in a bridging cohort. In the bridging cohort n=8 participants (6 active : 2 placebo) will receive IMU-935 (or placebo) at a dose level previously shown to be safe and tolerated. Intense PK sampling will be performed to clearly delineate the exposure profile of IMU-935 following BID. Doses will be administered 12 hrs apart.
Participants in the bridging cohort will be confined at the clinical facility from Day -1 (day before dosing) through to Day 4, when they will be discharged following completion of safety assessments and sampling for PK. Participants will receive 2 dose administrations of IMU-935 (or placebo) 12 (+/ 0.5) hrs apart on Day 1. The end of study visit for participants in the bridging cohort will be on Day 14 (± 2 days).
Participants who are involved in cohorts evaluating PK under fasted and fed conditions will return to the clinic on Day 14 for a second confinement period. The effect of food on the first formulation will be evaluated in Cohort 2. The effect of food on the second IP formulation may also be evaluated at a dose level lower than the highest dose level demonstrated to be safe in healthy volunteers for that formulation. All assessments and study procedures described in this protocol for Cohort 2 will also apply to the study cohort used to evaluate the effect of food on the second IP formulation.
When available second formulation of IMU-935 will commence evaluation in the study at 1 dose level lower than the dose level shown to be safe for the first formulation. The first or second formulation of IMU-935 will progress to evaluation in study Parts B and C only if deemed appropriate by the SMG following review of safety and PK for either of the 2 formulations in the SAD. It is expected that only one of the two IMU-935 formulations will be selected for evaluation in Parts B and C.
Part B:
A dose level will only be evaluated in Part B if determined to be safe and tolerable in Part A. It is anticipated that three dose levels will be evaluated in Part B, with the starting dose for Part B selected following review of data obtained in Part A. Eight participants will be enrolled at each dose level and randomized to receive either IMU-935 or placebo (ratio 3:1) over a 14 day treatment period. Each Participant will only participate in only one of the study groups. Dosing under fasted or fed conditions in Part B will be determined by the SMG following review of Part A Cohort 2 PK data. However, if the SMG decides to proceed with dosing in the MAD component of the study prior to the availability of PK data from the fed/fasted cohort dosing in Part B will start in fasted conditions. Based on the PK data obtained in Part A, once daily (QD) or twice daily dosing (BID) will be decided for Parts B and C. It may also be allowed to determine a switch between QD and BID dosing for any new cohort in this trial, based on safety data obtained in the previous study cohorts.
Sentinel participants are planned for each dose level cohort in Part B, with the PI to review sentinel safety/tolerability information (in consultation with the SMR, if necessary) on Day 7 before dosing the remaining 6 participants of the cohort. However, prior to commencement of each cohort 8 and 9 of Part B, the SMG will consider the requirement for sentinel dosing. Sentinel dosing may not be used for cohorts 8 and 9 of Part B if considered appropriate by the SMG.
After at least 6 of 8 participants in each dose level cohort in Part B has completed dosing with study drug, the SMG will review available blinded safety data (including study assessments performed on Day 18) to determine the safety and tolerability of study drug. Following review of the data the SMG will:
a) decide to proceed with dosing the next Part B cohort at a higher dose level;
b) determine whether use of sentinel dosing at the next dose level is warranted;
c) determine a low dose level to be used in Part C ; or
d) terminate enrollment in Part B of the study. If the dose level is determined not to be safe and tolerated, the study drug assignment for those participants with a safety concern may be un-blinded.
Part C:
Two dose levels will be evaluated in psoriasis patients in Part C, a Low and a High dose level. Dose levels for Part C will be selected following review of data obtained in Part B.
• Cohort 10 (n=up to 16): Low Dose IMU-935 (n=up to 12) or placebo (n=up to 4)
(ratio 3:1 active: placebo, noting that if the number of participants is less than 16, the ratio may be approximate)
• Cohort 11 (n=up to 24): High Dose IMU-935 (n=up to 18) or placebo (n=up to 6)
(ratio 3:1 active: placebo, noting that if the number of participants is less than 24, the ratio may be approximate)
Both cohort 10 and cohort 11 will have a 28 day repeat dose period (doses to be confirmed by SMG).
After each dose level cohort in Part B has completed dosing with study drug, the SMG will review all available blinded safety data and will:
a) Select a Low Dose level to be used in Part C and proceed with Cohort 10 in psoriasis patients, or
b) defer the determination of a Low Dose level for Part C until additional dose level cohorts have been completed in Part B; or
c) decide not to proceed with any treatment of psoriasis patients in Part C (and fully terminate Part C).
Dose levels will only be selected for evaluation in Part C if they were shown to be safe and well tolerated in Part B.
In each of the 3 parts of this study, cohorts may be added or removed based upon emerging data

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo composition (for IP Formulation 1):
Glyceryl monocaprylate (Capmul MCM C8 EP)
Lauroyl macrogol 6 glycerides (Labrafil M2130)
Polyoxyl 40 hydrogenated castor oil (Cremophor RH40)
Diethylene glycol monoethyl ether (Transcutol HP)
Macrogol 12-hydroxystearate (Solutol HS15)
HMPC (Hypromellose) capsules (plant origin)

Placebo composition (for IP Formulation 2):
Eudragit L100

Control group

Placebo

Outcomes

Primary outcome [1]

To assess the safety and tolerability of IMU-935 when administered as a single oral dose in healthy adult volunteers, as a 14-day repeat oral dose to healthy volunteers and as a 28-day oral dose in psoriasis patients.

Timepoint [1]

Clinical observations, safety laboratories, assessments, ECGs and Vitals.

Part A - Physical Exam: Screening, Day -1, Day 1 (Pre-dose, 3h and 6h), Day 2, Day 3, Day 4 and End of Study. ECGs and Vitals: Screening, Day -1, Day 1(Pre-dose, 3h, 6h and 14h), Day 2, Day 3 and Day 4, End of Study. Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day -1, Day 1 (6h), Day 2, Day 4 and End of Study.

Part B - Physical Exam: Screening, Day -1, Day 1 (Pre-dose, 3h, 6h), Day 2, Day 3, Day 4, Day 7, Day 14 Pre-dose, Day 18, End of Study. ECGs and Vitals: Screening, Day -1, Day 1 (Pre-dose, 3h, 6h, 14h), Day 2, Day 3, Day 4, Day 7, Day 14 Pre-dose, Day 18, End of Study. (Additional timepoints for vitals - Day 14: 6h, 14 h; Day 15, Day 16, Day 17). Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day -1, Day 1 (6h), Day 2, Day 4, Day 7, Day 14 (Pre-dose), Day 18 and End of Study.

Part C – Physical Exam: Screening, Day 1, Day 8, Day 15, Day 22, Day 28, End of Study. ECGs and Vitals: Screening, Day 1, Day 8, Day 15, Day 22, Day 28, End of Study. Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day 1, Day 8, Day 15, Day 22, Day 28, End of Study.

Secondary outcome [1]

To assess the pharmacokinetics of IMU-935 following administration of a single dose and a 14-day repeat dose in healthy volunteers.

Timepoint [1]

Drug detection assay using a volunteer plasma. PK collections collected at: Part A Cohorts 1, 3, 4, 5, 6 = Pre-dose, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48 and 72h post-dose. Part A Cohort 2 = Pre-dose, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48 and 72h post-dose (collected at Fed and Fasted Periods), Part B: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48 and 72h post dose Day 1, Day 13 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16h (Day 14), 24, 36h (Day15), 48h (Day 16), 72h (Day 17), 96h (Day 18). The following pharmacokinetic parameters will be determined: Time to maximum concentration (Tmax); Maximum concentration (Cmax); Area under the concentration-time curve from time 0 to last measurable time-point (AUC0–t); Area under the concentration-time curve from time 0 to infinity (AUC0–inf); Apparent terminal Elimination Rate Constant (kel); Terminal half-life (t1/2); Apparent terminal clearance (CL); Apparent volume of distribution (Vd). For Part A (SAD): Area under the concentration-time curve from time 0 to 24 hours following dose administration (AUC0-24h); Amount of drug excreted in urine in each collection interval. The food effect of the capsule: AUC capsule fed/ AUC capsule fasted; Cmax capsule fed/ Cmax capsule fasted.
For Part B (MAD): Area under the concentration-time curve over the dosing interval (AUCtau) on Day 1 and following the last dose on Day 14; Accumulation factor; Pre-dose trough on Days 2, 3, 4, 7, and 14.
Relative bioavailability for each of the two IMU-935 formulations will be evaluated at each common dose level administered.

Secondary outcome [2]

To assess the trough plasma concentration levels of IMU-935 in psoriasis patients treated in a 28-day dose schedule.

Timepoint [2]

Drug detection assay using a volunteer plasma.

PK collections collected at:
Part C: Day 1, Day 8, Day 15, Day 22 and Day 28. Early Termination Visit if Applicable.

Secondary outcome [3]

To assess the effects of IMU-935 on skin symptoms in moderate-to-severe plaque psoriasis patients.

Timepoint [3]

1. Absolute and relative change of PASI at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose);
2. Proportion of patients to achieve:
• PASI 90 (i.e., 90% reduction from baseline PASI);
• PASI 75 (i.e., 75% reduction from baseline PASI);
• PASI 50 (i.e., 50% reduction from baseline PASI);
3. Change from baseline in DLQI at Day 28 compared to baseline (Day 1 pre-dose);
4. Absolute and relative change of psoriasis involved body surface area (BSA) at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose);
5. Absolute and relative change of itch Numeric Rating Scale (NRS) at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose);
6. Absolute and relative change of Physician Global Assessment (PGA) score at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose);
7. Absolute and relative change of local target lesion assessment score at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose);
8. Absolute and relative change of local target lesion size estimation at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre-dose).

Secondary outcome [4]

To compare the pharmacokinetic profile of IMU-935 capsule administered under fasted and fed conditions.

Timepoint [4]

Drug detection assay using plasma. Part A Cohort 2 = Pre-dose, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48 and 72h post-dose (collected at Fed and Fasted Periods)

Secondary outcome [5]

Exploratory Objective: To investigate pharmacodynamic biomarker changes associated with administration of IMU-935 in healthy volunteers and psoriasis patients

Timepoint [5]

Part B, Cohort 8 only (healthy volunteers):
Exploratory analyses will be performed to evaluate how the CYP3A activity (measured by endogenous concentrations of 4ß-hydroxycholesterol in plasma) impacts the IMU-935 PK, which may include investigating correlation of 4ß-hydroxycholesterol with PK concentrations, and comparisons of active with placebo
Collections will be Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48 and 72h post dose Day 1, Day 13 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16h (Day 14), 24, 36h (Day15), 48h (Day 16), 72h (Day 17), 96h (Day 18).

Part C (psoriasis patients):
1. Change in serum cytokine and biomarker levels (including but not restricted to: IL-17A, IL-17F, IL-12, IL-22, IL-23, TNF-alpha) at Day 28 (or Early Termination Visit (ETV)) compared to baseline (Day 1 pre-dose);
2. Change in skin immune cells and other relevant biomarker levels (including but not restricted to: Th17, Th1, T-reg cells, granulocytes, B cells) from skin biopsy samples collected at baseline (Day 1 pre-dose) and Day 28;
3. Change in gene expression markers from whole blood at Day 15 and Day 28 compared to baseline (Day 1 pre-dose).

Secondary outcome [6]

To identify the major metabolites of IMU-935 in plasma

Timepoint [6]

Part B Cohort 8: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48 and 72h post dose Day 1, Day 13 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16h (Day 14), 24, 36h (Day15), 48h (Day 16), 72h (Day 17), 96h (Day 18).

Secondary outcome [7]

To determine 4ß-hydroxycholesterol levels in plasma in order to evaluate endogenous CYP3A activity following multiple doses of IMU-935 in healthy volunteers

Timepoint [7]

Part B Cohort 8: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48 and 72h post dose Day 1, Day 13 and 0.5, 1, 1.5,2, 3, 4, 5, 6, 8, 10, 12, 16h (Day 14), 24, 36h (Day15), 48h (Day 16), 72h (Day 17), 96h (Day 18).

Eligibility

Key inclusion criteria

Part A and Part B: Healthy Volunteers

1. Participants must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects;
2. Adult males and females, 18 to 55 years of age (inclusive) at screening;
3. Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than or equal to 55 kg at screening;
4. Be non-smokers (including tobacco, e-cigarettes and marijuana) for at least 1 month prior to participation in the study;
5. Medically healthy without clinically significant abnormalities at the screening, including:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 90 to 160 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes in supine position at screening;
c. Heart rate in the range of 40 to 100 beats/min (inclusive) after 5 minutes rest in supine position at screening;
d. Body temperature, between 35.0°C and 37.5°C (inclusive);
e. The Screening 12-lead ECG must be within normal range (QTc males equal to or less than 450 msec; females equal to or less than 470 msec) or with abnormalities, which are not hazardous to the participant according to the opinion of the Investigator at screening;
f. No clinically relevant findings in biochemistry, haematology, coagulation and urinalysis examinations as judged by the Investigator at screening;
6. Female participants must:
a. Be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of child-bearing potential, must have a negative pregnancy test at Screening (blood test) and before the first study drug administration (Day -1 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must agree to use 2 forms of highly effective contraceptive method between signing consent, during the study, and at least 30 days after the last dose of study therapy.
7. Male participants must be willing not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective contraceptive method between signing consent, during the study, and at least 64 days after the last dose of study therapy;
8. Have suitable venous access for blood sampling;
9. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Part C: Psoriasis patients
1. Patients must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects;
2. Adult males or females, 18 to 65 years of age (inclusive) at screening;
3. Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 40.0 kg/m2, with a body weight greater than or equal to 55 kg at screening;
4. Diagnosis of chronic plaque-type psoriasis diagnosed at least 6 months prior to screening, meeting the following criteria:
a. Psoriasis Area and Severity Index (PASI) score greater than or equal to 10, or PASI score less than 10 and Dermatology Quality of Life Index (DLQI) score greater than 10, plus
b. Psoriasis BSA involvement greater than or equal to 10%, plus
c. PGA score greater than or equal to 3.
5. Presence of at least one evaluable target lesion meeting the following criteria:
a. Minimum size of approximately 10 cm2 and (at the discretion of the Investigator), amenable to skin biopsies.
6. Failed to fully respond to or is intolerant and/or has a contraindication to at least one topical therapy for psoriasis;
7. Have suitable venous access for blood sampling;
8. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions;
9. Patients must agree to avoid prolonged sun exposure and avoid use of tanning booths or other ultraviolet light sources during the study;
10. Female patients must:
a. Be of non-child-bearing potential i.e. surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of child-bearing potential, must have a negative pregnancy test at Screening (blood test) and before the first study drug administration (Day 1 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must agree to:
i. Use 2 forms of highly effective contraceptive method between signing consent, during the study, and at least 30 days after the last dose of study therapy; OR
ii. Use 1 form of highly effective contraceptive method plus an additional barrier method of contraception between signing consent, during the study, and at least 30 days after the last dose of study therapy. Acceptable barrier methods include:
• Female diaphragm
• Condom usage for male partner
11. Male patients must be willing not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective contraceptive method between signing consent, during the study, and at least 64 days after the last dose of study therapy.

Minimum age

18 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Part A and Part B: Healthy Volunteers

1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past three months determined by the PI to be clinically relevant;
2. Current infection that requires antibiotic, antifungal, anti-parasitic or anti-viral medications;
3. Any history of malignant disease in the last 10 years;
4. Has clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
5. Receives or plans to receive systemic immunosuppressive (e.g. corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g. IFN) during the study or less than or equal to 4 months prior to the first investigational product administration;
6. Liver function test results (ie, AST, ALT, and GGT) and total bilirubin must not be elevated greater than 1.2 fold above the normal limits at screening;
7. Positive testing for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C antibodies (HCV), Quantiferon (Tuberculosis (TBC) infection);
8. Any major surgery within 3 months of screening; any previous gastrointestinal surgery or recent (within 3 months) history of gastrointestinal disease that could impact the absorption of the study drug;
9. History of substance abuse or alcohol abuse during less than or equal to 12 months prior to screening;
10. Positive urine drug/alcohol testing at screening or check-in (Day -1);
11. Use of any medication, including multi-vitamin preparations, received within 10 days prior to the drug administration, or within six times the elimination half-life, whichever is longest, except occasional use of paracetamol or ibuprofen;
12. Volunteers who have demonstrated clinically significant (required intervention, e.g. emergency room visit, epinephrine administration) allergic reactions (e.g. food, drug, atopic reactions, asthmatic episodes) which, in the opinion of the investigator and sponsor, interfere with their ability to participate in the trial;
13. Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine;
14. Positive serum pregnancy test (WOCBP) at the Screening or positive urine pregnancy test with confirmatory serum pregnancy test on Day -1;
15. Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of study enrollment;
16. Participation in another investigational clinical trial within 60 days prior to the first drug administration;
17. Volunteers participating in Part A of this study are excluded from participation in Part B;
18. Any other condition or prior therapy, which, in the opinion of the PI, would make the volunteer unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements;
19. Volunteers have legal incapacity or limited legal capacity;
20. An employee of an investigator or sponsor or an immediate relative of an investigator;
21. Volunteers institutionalized due to judicial or administrative order cannot participate;
22. Mental handicaps or disorders leading to inability to give informed consent.

Part C: Psoriasis Patients
1. Serious or unstable illnesses including cardiovascular, respiratory, renal, hepatic, gastrointestinal, endocrinologic ophthalmologic, hematologic, psychiatric, or neurological diseases. Well controlled diseases including but not limited to hypertension, hyperlipidemia, diabetes or hypothyroidism are permitted;
2. Liver function test results (ie, AST, ALT, and GGT) and total bilirubin must not be elevated greater than 2 fold above the normal limits at screening. In addition, patients must not have a diagnosis of, or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial;
3. Presence of increased metabolic risk, as evidenced by the presence of any of the following criteria:
a. Triglycerides greater than 2.5 mmol/L.
b. HDL cholesterol less than 0.8 mmol/L.
c. Fasting blood glucose greater than 6.5 mmol/L
4. Have uncontrolled arterial hypertension characterised by a systolic blood pressure (BP) greater than 160 mm Hg or diastolic BP greater than 95 mm Hg
5. Have electrocardiogram (ECG) abnormalities that are considered clinically significant and would pose an unacceptable risk to the patient if participating in the study;
6. History of clinically significant severe drug allergies or severe post treatment hypersensitivity reactions;
7. Any previous gastrointestinal disease or surgery that (in the opinion of the PI) could impact the absorption of the study drug;
8. Positive testing for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C antibodies (HCV), Quantiferon (Tuberculosis (TBC) infection);
9. Current infection that requires systemic antibiotic, antifungal, anti-parasitic or anti-viral medications, or the use of these medication within 4 weeks of randomisation;
10. History of chronic systemic infections including but not limited to tuberculosis, human immunodeficiency virus (HIV), hepatitis B or C, within 6 months before Screening
11. History of latent or active Mycobacterium tuberculosis infection or signs or symptoms suggestive of active Mycobacterium tuberculosis infection upon medical history and/or physical examination;
12. History of clinically significant opportunistic infection;
13. Active systemic infections during the last two weeks (exception: common cold) prior to initiation of study drug and any infections that reoccur on a regular basis, if assessed by the investigator to be significant;
14. Has clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
15. History of malignant disease, with the following exceptions:
a. Curatively treated non melanoma skin cancer (i.e. surgically removed basal-cell carcinoma or squamous-cell carcinoma).
b. Curatively treated carcinoma in situ (CIS) of the cervix.
c. Curatively treated CIS of the breast.
d. Curatively treated CIS of the bladder.
e. Other solid tumours curatively treated with no evidence of disease for greater than or equal to 5 years.
f. Prostate cancer qualifying for active surveillance.
16. Any other condition or prior therapy, which, in the opinion of the PI, would make the patient unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements;
17. Current forms of psoriasis other than chronic plaque-type;
18. Drug-induced psoriasis (including but not limited to new onset or current exacerbation from e.g. anti-TNF-alpha antibodies, beta-blockers, calcium channel inhibitors or lithium);
19. Patients with eczema or other significant skin conditions, that, according to the investigator, could interfere with the psoriasis clinical evaluation;
20. Use of:
a. any biologic agent within 24 weeks prior to the start of study treatment
b. any systemic anti-psoriasis medications or phototherapy within 4 weeks prior to start of study treatment
c. any topical anti-psoriasis medications within 2 weeks prior to the start of study treatment
d. any non-medicated emollient within 24 hours prior to start of study treatment on Day 1.
21. Exposure to:
a. immunosuppressive or immunomodulator drugs within 4 weeks prior to start of study treatment, or five half-lives of that drug (whichever is longer).
b. investigational drugs within 4 weeks prior to start of study treatment, or five half-lives of that investigational drug (whichever is longer).
22. Has received (or plans to receive) any live or live-attenuated vaccinations within 30 days prior to study drug administration and during the study (with the exception of post-exposure rabies vaccination);
23. Use of grapefruit juice or St. John’s wort, or any concomitant medications that are strong to moderate inhibitors of CYP3A (such as cimetidine, diltiazem, dronedarone, verapamil, fluvoxamine, nefazodone or tofisopam) or strong or moderate inducers of CYP3A (such as carbamazepine, phenytoin or modafinil);
24. Donation of blood or plasma within 30 days prior to randomisation, or loss of whole blood of more than 500 mL within 30 days prior to randomisation, or receipt of a blood transfusion within 1 year of study enrollment;
25. Positive serum pregnancy test (WOCBP) at the screening or positive urine pregnancy test with confirmatory serum pregnancy test on Day 1;
26. Known or suspected Gilbert syndrome;
27. History of substance abuse or alcohol abuse during less than or equal to 12 months prior to screening;
28. Positive urine drug/alcohol testing at screening or check-in (Day 1);
29. Mental handicaps or disorders leading to inability to give informed consent;
30. An employee of an investigator or sponsor or an immediate relative of an investigator;
31. Patients institutionalised due to judicial or administrative order cannot participate;
32. Patients have legal incapacity or limited legal capacity.

Study design

Statistical methods / analysis

Sample Size Considerations
This study is the FIHS with IMU-935 and as such no formal sample size calculation was
performed. Results from this study will be utilised for sample size calculations of subsequent studies.

Demographic Data
For all participants who received at least 1 dose of investigational product, descriptive statistics (mean, standard deviation, median, minimum, maximum) will be performed for age, gender, BMI, weight, and height.

Safety/Tolerability Data
All participants who are randomly assigned to a study cohort or treatment and receive at least one dose of the investigational product will be included in the safety and tolerability analysis. Baseline for physical examination, all vital signs, 12-lead ECG measurements, and clinical laboratory assessments will be defined as the last evaluation done before the first administration of investigational product in each dose cohort or treatment arm on Day 1.

Safety evaluations will be based on the incidence, intensity and type of AE and clinically
significant changes in the participant’s physical examination findings, vital signs, 12-lead ECGs, and clinical laboratory results. Safety variables will be tabulated and presented for all study participants who receive investigational product, i.e., the safety population.

Abnormalities in clinical laboratory, vital signs, and ECG will be based on pre-defined normal ranges and will be tabulated by treatment group showing participant counts and percentages.

The original terms used in the eCRF by investigators to identify AEs will be coded using the current version of the Medical Dictionary of Regulatory Activities (MedDRA). The percentage of participants with TEAEs will be summarised for each treatment and formulation. Any TEAEs in placebo participants will not be pooled and will be presented separately for each formulation.

Participants who have discontinued treatment due to an AE or who experienced a severe or a SAE will be followed.

Laboratory data will be summarised by the type of laboratory test. Normal reference ranges and markedly abnormal results will be used in the summary of laboratory data. Raw data and change from baseline in clinical laboratory parameters will be summarised using descriptive statistics. A listing of participants with any laboratory results outside the reference ranges will be provided.

Pharmacokinetic Data
Plasma concentrations of IMU-935 collected at specified time points post-dose from all
participants at different dose levels will be used to calculate PK parameters.

Reasons for exclusion of a participant or a sample from the analysis include, but are not limited to the following:
• Pre-dose IMU-935 plasma concentrations higher than 5% of Cmax;
• Vomiting within 6 hours after investigational product administration;
• Too few data (greater than 10% missing values for a participant);
• Noncompliance with study procedures affecting PK parameters (e.g., concomitant
medication).

All participants and samples excluded from the analysis will be clearly documented in the study report.

The PK parameters will be determined using non-compartmental method(s). Descriptive statisticsof PK parameters will include mean, standard deviation (SD), and coefficient of variation (CV), minimum and maximum. Dose-related trends in PK parameters will be assessed.

Interim PK data analysis will be performed for each cohort using nominal times.

Mean and individual IMU-935 plasma concentration-time curves will be tabulated for each dose cohort and presented graphically with concentration displayed on a linear and logarithmic scale. All PK parameters, including amount excreted in urine, will be determined for each participant and summarised by cohort (dose level) using descriptive statistics (arithmetic means, (SD), (CV), sample size (N), minimum, maximum and median). In addition, geometric means will be calculated for AUC and Cmax. Analyses using linear models will be performed to assess dose proportionality (both single dose and multiple dose), time dependence, accumulation, and attainment of steady state (multiple dose). In the event that treatments are assessed at only 2 dose levels, comparisons of exposure will be evaluated using dose-normalised parameters.

Point estimates and 95% Confidence Interval (CI) for the food effect of the capsule will be
calculated as capsule fed/capsule fasted ratios for AUC and Cmax.

Relative bioavailability for each of the two formulations will be evaluated at each common dose level administered.

For Cohort 8, the following exploratory analyses will be performed:
• Exploratory IMU-935 metabolite profiling
• Exploratory analyses to evaluate how the CYP3A activity (measured by endogenous
concentrations of 4ß-hydroxycholesterol) impacts the IMU-935 PK, which may include
investigating correlation of 4ß-hydroxycholesterol with PK concentrations, and
comparisons of active with placebo.

Statistical analysis will be performed on the PK parameters using validated statistical software.

Pharmacodynamic and Disease-Related Data
All PD marker parameters – observed data and change from baseline – will be summarised using descriptive statistics and graphs (mean ± Standard Error of the Mean (SEM)) per dose cohort, treatment arm, formulation and time interval as appropriate.

For Part C, PASI scores will be summarised at each protocol scheduled time point, by treatment group at each time point. Actual values and actual changes from baseline will be presented.

The number and percentage of patients with greater than or equal to 90% reduction from baseline PASI score (PASI 90) will be presented by treatment group at each time point. Reduction is defined as the relative change from the baseline value. Similarly, the number of participants with greater than or equal to 75% reduction and greater than or equal to 50% reduction from baseline PASI score (PASI 75 and PASI 50, respectively) will be
presented. A logistic regression (response: reduction (yes/no)) will be performed to compare IMU-935 with placebo statistically. The model will include fixed effects for treatment group and the participant’s baseline PASI score as covariate. In this model the repeated measures structure will be taken into account. From this model, the IMU-935 to placebo odds ratio of reduction and its 95% CI will be calculated.

For Part C, DLQI, itch NRS, PGA, BSA and local target lesion assessment values will be
summarised by treatment group at each time point. Actual values and actual changes from baseline will be presented.

Interim Analysis
Two optional group-level unblinded interim analyses of selected safety and disease assessment data are planned during this study, for the purposes of planning further steps in the product development of IMU-935 by the Sponsor. These may occur at the following timepoints:
1. Following the completion of the Day 28 visit for all patients in Cohort 10. No study
enrollment decisions will be made based on this information (screening, enrollment and
dosing of Cohort 11 may occur in parallel with the interim analysis).
2. Following completion of the Day 28 visit for all patients in Cohort 11.

Full details of these optional interim analyses, including details of assessments, will be described in the statistical analysis plan.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

17/09/2019

Date of last participant enrolment

Anticipated

31/08/2022

Actual

2/09/2022

Date of last data collection

Anticipated

26/10/2022

Actual

31/10/2022

Sample size

Target

144

Accrual to date

Final

135

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

CMAX Clinical Research Pty Ltd - Adelaide

Recruitment hospital [2]

University of the Sunshine Coast Clinical Trials Centre - Health Hub Morayfield - Morayfield

Recruitment hospital [3]

University of the Sunshine Coast Clinical Trials Centre - Sippy Downs - Sippy Downs

Recruitment hospital [4]

Sinclair Dermatology - East Melbourne

Recruitment hospital [5]

Fremantle Dermatology - Fremantle

Recruitment hospital [6]

Emeritus Research - Botany - Botany

Recruitment hospital [7]

Emeritus Research - Camberwell

Recruitment hospital [8]

Veracity Clinical Research - Woolloongabba

Recruitment hospital [9]

Holdsworth House Medical Practice - Sydney

Recruitment postcode(s) [1]

5000 - Adelaide

Recruitment postcode(s) [2]

4506 - Morayfield

Recruitment postcode(s) [3]

4556 - Sippy Downs

Recruitment postcode(s) [4]

3002 - East Melbourne

Recruitment postcode(s) [5]

6160 - Fremantle

Recruitment postcode(s) [6]

2019 - Botany

Recruitment postcode(s) [7]

3124 - Camberwell

Recruitment postcode(s) [8]

4102 - Woolloongabba

Recruitment postcode(s) [9]

2010 - Sydney

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Country [2]

New Zealand

State/province [2]

Bay of Plenty

Country [3]

New Zealand

State/province [3]

Wellington

Country [4]

New Zealand

State/province [4]

Hawke's Bay

Country [5]

New Zealand

State/province [5]

Manawatu-Wanganui

Country [6]

Bulgaria

State/province [6]

Country [7]

Macedonia, The Former Yugoslav Republic Of

State/province [7]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Immunic Australia Pty Ltd

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Immunic Australia Pty Ltd

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Avance Clinical

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry HREC

Ethics committee address [1]

123 Glen Osmond Road Eastwood Adelaide
South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

10/07/2019

Approval date [1]

02/09/2019

Ethics approval number [1]

2019-07-575

Ethics committee name [2]

Central Health and Disability Ethics Committee

Ethics committee address [2]

Ministry of Health
133 Molesworth Street
Wellington 6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

05/08/2021

Approval date [2]

10/09/2021

Ethics approval number [2]

21/CEN/218

Summary

Brief summary

The research project is testing a potential new treatment for psoriasis (an inflammatory skin condition) called IMU-935. Before a new medicine can be approved for use in humans, it is necessary to confirm that it is safe and effective. This is done by carrying out clinical research studies such as this one.

The purpose of this study is to evaluate the safety and tolerability of single and multiple doses of IMU-935. The pharmacokinetics (PK) of IMU-935 in humans will also be determined. PK testing involves taking blood and urine samples to measure how much of the drug gets into the blood stream, and how long the body takes to get rid of it. When testing for PK, the sample will also be tested for metabolites (breakdown products) of IMU-935.

Trial website

Public notes

Contacts

Principal investigator

Name

Prof Kurt Gebauer

Address

Fremantle Dermatology
299 High Street Fremantle
Western Australia 6160

Country

Australia

Phone

+61 08 9340 4488

Email

[email protected]

Contact person for public queries

Name

Kurt Gebauer

Address

Fremantle Dermatology
299 High Street Fremantle
Western Australia 6160

Country

Australia

Phone

+61 08 9340 4488

Email

[email protected]

Contact person for scientific queries

Name

Jolanta Airey

Address

SJA Consultancy Services Pty Ltd
5 Portobello Place
Melbourne, VIC
Australia 3150

Country

Australia

Phone

+61 409 020 209

Email

[email protected]

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