None listed
Conditions
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.
Interventions
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. To
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
Sponsors
Immunic Australia Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
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.
Outcome results
None listed