ANZCTR - Registration

Registration number

ACTRN12620000901909

Ethics application status

Approved

Date submitted

13/07/2020

Date registered

11/09/2020

Date last updated

21/09/2023

Date data sharing statement initially provided

11/09/2020

Type of registration

Prospectively 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-856 in healthy volunteers and patients with Celiac disease

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-856 in healthy volunteers and patients with with Celiac disease.

Secondary ID [1]

PI/Ib-IMU-856

Universal Trial Number (UTN)

U1111-1254-7421

Trial acronym

Linked study record

Health condition

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

Diarrhea-predominant irritable bowel syndrome

Celiac disease

Condition category

Condition code

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Oral and Gastrointestinal

Inflammatory bowel disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a double-blind, placebo controlled, ascending dose, multi-cohort trial. The study will be conducted in three parts.

In Part A, healthy volunteers will be enrolled to receive single ascending doses of IMU-856 or placebo (oral tablet). In Part B, healthy volunteers will be enrolled to receive multiple ascending doses of IMU-856 or placebo (oral tablet). In Part C, patients with Celiac disease will be enrolled to receive two different dose levels of IMU-856 or placebo (oral tablet). Each participant will only participate in one of the study groups.

The decision to escalate between dose levels and proceed to each of the study parts (Parts A, B and C) will be based upon review of the available Adverse Event, clinical laboratory and Pharmacokinetic data by the Safety Monitoring Group.

The starting dose, dose increments and dose range are based on available pre-clinical data.
Part A: In Part A, IMU-856 dose levels in the range of 10 – 160 mg will be investigated in a total of six cohorts. Each cohort participant will receive a single (one) dose administered by study nurse at the clinical facility. Compliance will be monitored using mouth check following dosing.

Dosing in each dose level cohort will start with two sentinel participants with one of the two participants randomized to receive IMU-856 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 the Safety Monitoring Group (SMG), 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-856 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 each cohort to Day 7 in Part A, the SMG will review the data, discuss the findings, and decide to:
a) enrol the next dose cohort at the protocol-defined dose level;
b) enrol the next dose cohort at an intermediate dose level;
c) repeat a dose level;
d) determine a starting dose level for Part B;
e) determine whether sentinel dosing at the first dose level in Part B is warranted; or
f) terminate enrolment 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.

Part B:
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. Participants will receive either IMU-856 or placebo once daily for 14 days to be taken in the morning. Doses will be administered by study nurse at the clinical facility during in-clinic visits. Compliance will be monitored using participant diaries during at in-clinic checks (including mouth check and tablet counting).

Sentinel participants are planned for each dose level cohort in Part B. Sentinel dosing may not be used in Part B if considered appropriate by the SMG.

After 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 17) to determine the safety and tolerability of study drug. Following review of the data the SMG will:
a) repeat a dose level;
b) decide to proceed with dosing the next Part B cohort at a higher dose level;
c) decide to proceed with dosing the next Part B cohort at a lower dose level;
d) determine whether use of sentinel dosing at the next dose level is warranted;
e) determine the low and high dose level to be used in Part C;
f) terminate enrolment 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;
g) defer the determination of a Low Dose level for Part C until additional dose level cohorts have been completed in Part B; or
h) decide not to proceed with any treatment of patients in Part C (and fully terminate Part C).

Part C:
Two dose levels will be evaluated in patients with Celiac disease 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=18): Low Dose IMU-856 (n=12) or placebo(n=6)
• Cohort 11 (n=24): High Dose IMU-856 (n=16) or placebo (n=8)

Randomization of patients with Celiac disease to Cohort 10 and Cohort 11 may commence following selection of an IMU-856 low dose level and high dose level by the SMG. Randomization of patients to cohort 11 may commence only once cohort 10 is fully enrolled.

Both cohort 10 and cohort 11 will receive either IMU-856 or placebo once daily for 28 days to be taken in the morning. Doses will be either administered by study nurse at the clinical facility during in-clinic visits or at home by the participant. Compliance will be monitored using participant diaries during at home dosing periods and in-clinic checks (including mouth check and tablet counting).

In each of the 3 parts of this study, cohorts may be added or removed based upon emerging data.

For both Part A and Part B subsequent cohorts will only commence after the prior cohort safety meeting has been held and an agreement made to escalated. It is estimated that all study cohorts will be separated by at least 8 days.

This Phase 1 is designed to evaluate doses that are expected to show activity (dose to activity approach). The dose levels in Parts B and C will be evaluated on the pharmacokinetic properties that are calculated to be in the active range. Safety and tolerability issues will be included in the consideration of dose levels for Parts B and C with the independent Safety Monitoring Group making the assessment based on all available data.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo Tablet

Microcrystalline Cellulose
Lactose
Croscarmellose Sodium
Magnesium Stearate

Control group

Placebo

Outcomes

Primary outcome [1]

To assess the safety and tolerability of IMU-856 when administered as a single oral dose in healthy adult volunteers.

Timepoint [1]

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

Part A
Physical Exam: Screening, Day -1, Day 1, Pre-dose, Day 1 (3h and 6h), Day 2, Day 3, Day 4, Day 7 and Day 14.
ECGs and Vitals: Day -1, Day 1, Pre-dose, Day 1 (3h, 6h and 14h), Day 2, Day 3, Day 4, Day 7 and Day 14.
Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day -1, Day 1 (6hr), Day 2, Day 4, Day 7 and Day 14.

Primary outcome [2]

To assess the safety and tolerability of IMU-856 when administered as a 14-day repeat oral dose to healthy volunteers.

Timepoint [2]

Clinical observations, safety laboratories, assessments, ECGs and Vitals. Part B Physical Exam: Screening, Day -1, Day 1, Pre-dose, Day 1 (3h and 6h), Day 2, Day 3, Day 4, Day 7, Day 10,Day 13, Day 14, Day 17 and Day 28. ECGs and Vitals: Day -1, Day 1, Pre-dose, Day 1 (3h, 6h and 14h), Day 2, Day 3, Day 4, Day 7, Day 10, Day 13, Day 14, Day 16 (vitals), Day 17 and Day 28. Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day -1, Day 1(6hr), Day 2, Day 4, Day 7, Day 10, Day 13, Day 17 and Day 28.

Primary outcome [3]

To assess the safety and tolerability of IMU-856 when administered as a 28-day repeat dose in patients with CelD.

Timepoint [3]

Clinical observations, safety laboratories, assessments, ECGs and Vitals. Part C Physical Exam: Screening, Day 1, Day 8, Day 14, Day 15, Day 22, Day 29, and Day 56. ECGs and Vitals: Screening, Day 1, Day 8, Day 14, Day 15, Day 22, Day 29, and Day 56. Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day 1, Day 8, Day 14, Day 15, Day 22, Day 29, and Day 56.

Secondary outcome [1]

To assess the pharmacokinetics (PK) of IMU-856 following administration of a single dose in healthy volunteers.

Timepoint [1]

Drug detection assay using a volunteer plasma and urine.

PK plasma collections collected at:
Part A: Pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post-dose.

PK urine collection intervals:
Part A: Pre-dose, 0-24 h, 24-48h and, 48-72h.

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);
• Terminal Elimination Rate Constant (kel);
• Terminal half-life (t1/2);
• Terminal clearance (CL);
• 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.

Secondary outcome [2]

To assess the pharmacokinetics (PK) of IMU-856 following administration of a 14-day repeat dose in healthy volunteers.

Timepoint [2]

Drug detection assay using a volunteer plasma

PK plasma collections collected at:
Part B: Pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post dose Day 1, Day 7, Day 10 and Pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post dose 14.

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);
• Terminal Elimination Rate Constant (kel);
• Terminal half-life (t1/2);
• Terminal clearance (CL);
• Volume of distribution (Vd).
• Area under the drug concentration-time curve from time zero to 24 hours (AUC0-24);
• Area under the drug concentration-time curve from time zero to infinity (AUC0–inf) (Day 1 only)
• Accumulation factor;
• Predose trough drug concentration on Days 2, 3, 4, 7, 10 and 14;

Secondary outcome [3]

To assess the trough plasma concentration levels of IMU-856 in patients with CelD treated in a 28-day repeat dose schedule.

Timepoint [3]

Drug detection assay using a volunteer plasma PK collections collected at: Part C: Day 1, Day 8, Day 14, Day 15, Day 22, Day 29. and at Early Termination Visit if applicable. Plasma concentration data (predose trough drug concentrations) only will be evaluated for Part C.

Secondary outcome [4]

Exploratory Objective:

To investigate pharmacodynamic (PD) marker changes associated with administration of IMU-856 in healthy volunteers.

Timepoint [4]

Blood (serum and plasma) will be collected for analysis and identification of IMU-856 induced PD marker changes.

• Lactulose/Mannitol levels, plasma
• Antibody titers (including anti-zonulin/occludin, anti-microbials), serum
• Protein markers for gut permeability, serum
• RNA/microRNA expression in blood

For Part A blood samples only will be collected predose, Day 1, Day 2 and at Early Termination Visit if applicable.
For Part B blood samples only will be collected predose,Day 1, Day 2 and at Early Termination Visit if applicable.

Secondary outcome [5]

Exploratory Objective: To investigate pharmacodynamic (PD) marker changes associated with administration of IMU-856 in patients with Celiac Disease

Timepoint [5]

Blood (serum and plasma) and faecal samples will be collected for analysis and identification of IMU-856 induced PD marker changes. • Lactulose/Mannitol levels, plasma • Antibody titers (including anti-zonulin/occludin, anti-microbials), serum • Protein markers for gut permeability, serum • RNA/microRNA expression in blood For Part C blood samples will be collected predose, Day 1, Day 8 (Lactulose/Mannitol levels only), Day 15, Day 22 (Lactulose/Mannitol levels only), Day 29 and at Early Termination Visit if applicable.

Secondary outcome [6]

To assess the safety and tolerability of administrating IMU-856 in a 28-day repeat dose schedule in patients with Celiac Disease during periods of GFD and gluten challenge

Timepoint [6]

Clinical observations, safety laboratories, assessments, ECGs and Vitals. Part C Physical Exam: Screening, Day 1, Day 8, Day 14 pre-dose, Day 15, Day 22, Day 29, and Day 56. ECGs and Vitals: Screening, Day 1, Day 8, Day 14 pre-dose, Day 15, Day 22, Day 29, and Day 56. Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day 1, Day 8, Day 14 pre-dose, Day 15 (blood only), Day 22, Day 29, and Day 56.

Secondary outcome [7]

To investigate the effect of IMU-856 on the gastrointestinal architecture and inflammation in
patients with CelD during periods of GFD and gluten challenge.

These will be analysed together as a composite outcome.

Timepoint [7]

Esophagogastroduodenoscopy (EGD) with biopsy sampling will be performed at Screening Visit 2 (SV2) and Day 29 to perform histological and IHC assessments of gastrointestinal architecture and inflammation. SV2 the endoscopy will only be conducted if all other inclusion criteria are met. The endoscopy must be performed within 2 weeks prior to baseline visit at Day 1.

Secondary outcome [8]

Exploratory Objective: To identify the metabolites of IMU-856 in plasma

Timepoint [8]

Approximately 4 mL per sample of whole blood will be collected for PK analysis of IMU-856 and detection of its metabolites (the latter only in Part B Cohort 9N). Blood samples to
be collected Day 1: pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 14 hours post dose, Day 14: 1, 2, 3,4 5, 6,8, 10, 14, 24, 48 and 72 hours post does, End of Study Visit if applicable

Secondary outcome [9]

Exploratory Objective: To assess treatment satisfaction and safety through patient-reported questionnaires.
These will be analysed together as a composite outcome.

Timepoint [9]

Questionnaires to reviewed Days 1, 8, 14 (-2), 15 (only CDSD), 22; and reviewed and collected on Day 29 (or in the instance of an ETV). The CDSD is a daily patient reported outcome measure assessing the presence or absence of a broad range of CelD symptoms including nausea, diarrhoea, and abdominal pain. The ICDSQ is designed to measure the impact of symptoms on overall quality of life, is assessed weekly and suggested as complement to the CDSD.

Secondary outcome [10]

To assess the PK of IMU-856 following administration of a 28-day repeat dose in patients with CelD.

Timepoint [10]

Plasma concentrations of IMU-856 at timepoints 30, 60, 120, 240 and 360 minutes post dose on on Day 8 will be used to calculate PK parameters for patients with CelD. The following PK parameters will be evaluated at Day 8: Tmax, Cmax; AUC0–tlast, AUC0-24h, AUC0–inf; kel; t1/2; CL/f; Vd/f.

Also, plasma concentration data (predose trough study drug concentrations) will be evaluated at Days 1, 8, 14, 15, and 22.

Eligibility

Key inclusion criteria

Part A and Part B: Healthy Volunteers
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 and females, 18 to 55 years of age (inclusive) at the screening visit;
3. Body Mass Index greater 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 the screening visit and on Day -1, prior to dosing;
4. Be non-smokers (including tobacco, e-cigarettes and marijuana) for at least 1 month prior to the first scheduled dosing in the study;
5. Medically healthy without clinically significant abnormalities during the screening, period 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 the screening visit;
c. Heart rate in the range of 45 to 100 beats/min (inclusive) after 5 minutes rest in supine position at the screening visit;
d. Body temperature, between 35.5°C and 37.7°C (inclusive);
e. The Screening 12-lead electrocardiogram (ECG) must be within normal range (corrected QT interval [QTc] males less than or equal to 450 msec; females less than or equal to 470 msec) or with abnormalities, which are not hazardous to the volunteer according to the opinion of the Investigator at the screening visit;
f. No clinically relevant findings in serum chemistry, 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 the Screening visit) 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; OR
• 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:
i. Female diaphragm
ii. Condom usage for male partner
c. Women of child bearing potential with same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their preferred and usual lifestyle.
7. Male volunteers must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree 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.

Inclusion Criteria- Part C- Patients with CelD
1. Adult male or female patients, 18 to 65 years of age (inclusive) at the screening visit 1(SV1);
2. Patients who have been diagnosed with CelD at least 12 months prior to randomization with initial diagnosis proven by duodenal biopsy.
3. Successful adherence to a GFD for at least 612 months prior to randomization confirmed through a negative immunoglobulin A (IgA)-transglutaminase 2 (TG2) serology at SV1.
4. Negative urine gluten immunogenic peptide (GIP) test at SV1.
In case of a positive GIP test at SV1, participants shall remain an additional 14 days on a very strict GFD and repeat the GIP test at SV2.
5. 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.
6. Body Mass Index greater or equal to 18.0 and less than or equal to 35.0 kg/m2 at SV1.
7. No clinically significant abnormalities at SV1 in the following:
a. Systolic blood pressure in the range of 90 to 160 mm Hg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes in supine position (measurements may be repeated once if the first measurement showed values outside the reference range); and/or
b. Heart rate in the range of 45 to 100 beats/min (inclusive) after 5 minutes rest in supine position; and/or
c. Body temperature between 35.5°C and 37.7°C (inclusive); and/or
d. The screening 12-lead ECG must be within normal range (PR interval: 120 ms–220 ms
(inclusive), QRS-Duration < 120 ms, males less than or equal to 450 ms; females less than or equal to 470 ms) and/or
e. No clinically relevant findings in serum chemistry, haematology, coagulation and urinalysis examinations as judged by the Investigator.
8. Willingness to comply with a strict GFD and willingness to consume a defined amount of gluten as part of the study
9. Have suitable venous access for blood sampling.
10. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
11. Female patients must:
a. Be of non-child-bearing potential i.e., surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before SV1) 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 SV1 (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; OR
• 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:
i. Female diaphragm
ii. Condom usage for male partner
c. Women of child-bearing potential with same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their preferred and usual lifestyle.
12. Male patients must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree 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, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological or psychiatric 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 oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications, or the use of these medication within 4 weeks of randomization
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. interferon) during the study or less than or equal to 4 months prior to the first Investigational Product administration;
6. Liver function test results (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transferase [GGT]) and total bilirubin elevated greater than 1.2 fold above the normal limits at the screening visit;
7. Positive testing for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or Quantiferon tuberculosis (TB) infection (Quantiferon test);
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, known malabsorption or short bowel syndrome;
9. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or more than 4 standard drinks on any one day; where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) during less than or equal to 12 months prior to the screening visit;
10. Positive urine drug and alcohol breath 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;
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 (for women of childbearing potential [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 the first scheduled dosing in the study;
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.
23. Clinically diagnosed lactose intolerance;
24. Subjects with known or suspected hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltose insufficiency;
25. Consumption of grapefruit or grapefruit-containing products within 72 hours prior to study drug administration.

Part C (Patients with Celiac Disease (CelD))
1. Selective IgA deficiency as measured by serum IgA levels being less than 0.07g/L during SV1.
2. Wheat or gluten allergy separate from Celiac disease.
3. Signs of malabsorption as measured at SV1 by:
a. Anaemia with a haemoglobin less than 110g/L in women and less than 120g/L in men, and/or
b. Deficiency of albumin as defined by albumin less than 35 g/L, and/or
c. Deficiency of folic acid as defined by folic acid < 6.1nmol/L
4. History or presence of refractory CelD defined as persistent or recurrent malabsorptive
symptoms and villous atrophy shown in a most recent biopsy despite strict adherence to a
GFD for more than 12 months.
5. History or presence of severe complications of CelD (e.g., enteropathy associated T cell
lymphoma (EATL), ulcerative jejunitis, perforation).
6. History or presence of skin manifestations of CelD like dermatitis herpetiformis at any
time.
7. History or presence of neurological manifestations of CelD like ataxia or neuropathy at
any time.
8. Any clinically significant concomitant disease of the intestinal tract in addition to CelD
(e.g., Crohn´s disease, ulcerative colitis, other form of inflammatory bowel disease, severe
and therapeutically uncontrolled irritable bowel syndrome, microscopic colitis, primary
sclerosing cholangitis)
9. History or presence of significant cardiovascular, pulmonary, hepatic, renal,
haematological, gastrointestinal (in addition to CelD), endocrine, immunologic,
dermatologic, neurological or psychiatric disease, including any acute illness or surgery
within the past 3 months determined by the Investigator to be clinically relevant.
10. Known history of diabetes mellitus type 1 or type 2.
11. Known history of clinically significant liver disease (including liver cirrhosis, portal
hypertension), and/or increased ALT and AST (greater than 1.5 x ULN) at SV1.
12. Known history of clinically significant kidney disease and/or renal function impairment,
assessed as Glomerular Filtration Rate less than or equal to 60 mL/min/1.73m2 at SV1.
13. Presence of an ileostomy or colostomy or total proctocolectomy, short bowel syndrome, signs of malnutrition following gastrointestinal surgery or other major gastrointestinal surgery.
14. Current infection that requires oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications, the use of oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications within 4 weeks of randomization;
or infections that reoccur on a regular basis, if assessed by the Investigator to be
clinically significant.
15. History of chronic systemic infections including but not limited to HIV, hepatitis B or C,
within 6 months before SV1.
16. Positive HBsAg, HBcAb (hepatitis B core antibody), positive HCV and/or HIV-antigen antibody (HIV-Ag/Ab) test at SV1.
17. Have or had an infection typical of an immunocompromised host and/or an infection that occurs with increased incidence in an immunocompromised host (including, but not
limited to, pneumocystis jirovecii pneumonia, histoplasmosis, or coccidioidomycosis); or
have a known immunodeficiency ongoing.
18. Clinically diagnosed small intestinal bacterial overgrowth, other than simple bacterial
overgrowth present at initial diagnosis of CelD;
19. Receive or plan to receive probiotics during the study or less than or equal to 7 days prior to the first IMP administration (foods such as yogurt or kefir are acceptable);
20. History of malignant disease within the last 10 years with the following exceptions: a) Curatively treated cervical carcinoma in situ, with no evidence of recurrence within 5 years prior to baseline may
participate in the study b) Curatively treated non melanoma skin cancer with no evidence of recurrence (i.e. surgically removed basal-cell carcinoma or squamous-cell carcinoma)
21. Known, or at SV1 experienced, intolerance to lactulose/mannitol testing.
22. Any other condition or prior therapy, which, in the opinion of the Investigator, 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.
23. Intake of corticosteroids or immunomodulators (e.g., oral or systemic glucocorticoids
including oral budesonide, cyclosporine, methotrexate, anti-tumour necrosis factor-alpha
therapy, anti-integrin therapy, Janus kinase inhibitors) during the past 3 months before
screening biopsy sampling at SV2.
24. Intake (at least 3 times/week) of non-steroidal anti-inflammatory drugs (NSAIDs; except
acetylsalicylic acid if daily dose is less than or equal to 350 mg) during the past 2 months before screening biopsy sampling at SV2.
25. Patients receiving antiplatelet therapy (i.e. acetylsalicylic acid ± combination with
thienopyridines [clopidogrel, prasugrel, ticlopidine, or ticagrelor] or oral anticoagulants
(i.e. warfarin, dabigatran, etexilate, rivaroxaban, apixaban).
26. Patients with known bleeding disorder or clinically relevant prolonged bleeding time as
judged by the Investigator at the SV1.
27. Unwillingness to undergo upper endoscopy with biopsy during screening and during the Study.
28. Known intolerance/hypersensitivity/resistance to IMP and excipients or drugs of similar chemical structure or pharmacological profile.
29. Doubt about the patient’s cooperation, e.g., because of known or suspected addiction to alcohol or drugs (Cannabis excluded).
30. Positive urine drug and alcohol breath testing at SV1 or positive alcohol breath test on Day 1, prior to study drug administration.
31. Any live vaccinations within 30 days prior to study drug administration (mRNA-based
vaccinations and adenovirus vector vaccines are not considered live vaccinations);
32. Concurrent participation in any other clinical trial using an IMP or medical device, or use
of any IMP within 60 days or 5 x the respective half-life prior to the first study drug
administration, whatever is longer.
33. 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 the first scheduled dosing in the study.
34. Mental handicaps or disorders leading to inability to give informed consent.
35. An employee of an Investigator or Sponsor or an immediate relative of an Investigator.
36. Patients institutionalized due to judicial or administrative order.

Study design

Statistical methods / analysis

Sample Size Considerations
This study is the first in human study with IMU-856 and as such no formal sample size calculation was performed. Results from this study will be utilized 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, body mass index, 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 weight, 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 treatment-emergent AEs will be summarized for each treatment.
Participants who have discontinued treatment due to an adverse event or who experienced a severe or a serious adverse event will be followed.
Laboratory data will be summarized 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 summarized using descriptive statistics. A listing of participants with any laboratory results outside the reference ranges will be provided.

Pharmacokinetic Data

Plasma concentrations of IMU-856 collected at specified time points post-dose from all participants at different dose levels will be used to calculate pharmacokinetic parameters.
Reasons for exclusion of a participant or a sample from the analysis include, but are not limited, to the following:
• Vomiting within 6 hours after investigational product administration;
• Too few data (greater than 10% missing values for a participant);
• Noncompliance with study procedures affecting pharmacokinetics (e.g., concomitant medication).
All participants and samples excluded from the analysis will be clearly documented in the study report.
The pharmacokinetic parameters will be determined using non-compartmental method(s). Descriptive statistics of pharmacokinetic parameters will include mean, standard deviation (SD), and coefficient of variation (CV), minimum and maximum. Dose-related trends in pharmacokinetic parameters will be assessed.
Interim pharmacokinetic data analysis will be performed for each cohort using nominal times.
Mean and individual IMU-856 plasma concentration-time curves will be tabulated for each dose cohort and presented graphically with concentration displayed on a linear and logarithmic scale. Pharmacokinetic parameters, including amount excreted in urine, will be determined for each participant and summarized by cohort (dose level) using descriptive statistics (arithmetic means, standard deviations [SD], coefficients of variation [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).

Mean and Analyses will be performed to assess time dependence and accumulation (multiple dose), and attainment of steady state (multiple dose).
Statistical analysis will be performed on the pharmacokinetic parameters using validated statistical software.

Pharmacodynamic Data
Pharmacodynamic marker parameters – observed data and change from baseline – will be summarized using descriptive statistics and graphs (mean ± SEM) per dose cohort, treatment arm and time interval as appropriate.

For Part C, the CDSD and ICDSQ scores will be summarised at each protocol scheduled timepoint, by treatment group for each parameter.

The change from baseline in the CDSD and ICDSQ severity score as determined by the CDSD and ICDS questionnaire will be analysed by means of an analysis of covariance (ANCOVA) to statistically compare IMU-856 with placebo. The model will include fixed effects for treatment group (low dose of IMU-856, high dose of IMU-856, placebo) and the patient’s baseline CDSD and ICDSQ severity score as covariate. From this model, the estimated difference between IMU-856 to placebo and its 95% CI will be calculated for low dose vs. placebo and high dose vs. placebo.

Interim Analysis (Part C)

A 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 development of IMU-856 by the Sponsor. These may occur at the following timepoints:
1. Following the completion of the Day 29 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 29 visit for all patients in Cohort 11.

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

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

7/07/2022

Date of last participant enrolment

Anticipated

30/11/2022

Actual

10/11/2022

Date of last data collection

Anticipated

31/01/2023

Actual

16/01/2023

Sample size

Target

120

Accrual to date

Final

114

Recruitment in Australia

Recruitment state(s)

QLD,SA,VIC

Recruitment hospital [1]

CMAX Clinical Research Pty Ltd - Adelaide

Recruitment hospital [2]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [3]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [4]

The Alfred - Melbourne

Recruitment hospital [5]

Coral Sea Clinical Research Unit - North Mackay

Recruitment hospital [6]

Wesley Medical Research - Auchenflower

Recruitment hospital [7]

Eastern Health - Box Hill

Recruitment postcode(s) [1]

5000 - Adelaide

Recruitment postcode(s) [2]

3050 - Parkville

Recruitment postcode(s) [3]

3004 - Melbourne

Recruitment postcode(s) [4]

4740 - North Mackay

Recruitment postcode(s) [5]

4066 - Auchenflower

Recruitment postcode(s) [6]

3128 - Box Hill

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland 1010, Wellington 6021, Palmerston North 4414 and Havelock North, 4130

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 Human Research Ethics Committee

Ethics committee address [1]

123 Glen Osmond Road Eastwood Adelaide
South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

17/06/2020

Approval date [1]

14/07/2020

Ethics approval number [1]

2020-04-396

Ethics committee name [2]

Northern A 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]

26/01/2022

Approval date [2]

12/04/2022

Ethics approval number [2]

2022 FULL 12019

Ethics committee name [3]

Royal Melbourne Hospital Human Research Ethics Committee

Ethics committee address [3]

Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

22/02/2022

Approval date [3]

04/05/2022

Ethics approval number [3]

HREC/84342/MH-2022

Ethics committee name [4]

Central Adelaide Local Health Network Human Research Ethics Committee

Ethics committee address [4]

North Terrace
Adelaide, SA, 5000

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

11/04/2022

Approval date [4]

26/04/2022

Ethics approval number [4]

2022/HRE00026

Summary

Brief summary

The research project is testing a potential new treatment for Celiac disease called IMU-856. 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.

To purpose of this study is to assess the safety and tolerability of IMU-856 when administered as a single oral dose as a 14-day repeat oral dose to healthy volunteers and as a 28-day repeat dose in patients with CelD.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Dr James Daveson

Address

Wesley Medical Research
Level 8 East Wing, The Wesley Hospital
451 Coronation Dr
Auchenflower QLD 4066

Country

Australia

Phone

+61 737211708

Email

[email protected]

Contact person for public queries

Name

Jolanta Airey

Address

5 Portobello Place
Melbourne VIC 3150

Country

Australia

Phone

+61 409 020209

Email

[email protected]

Contact person for scientific queries

Name

Andreas Muehler

Address

Immunic AG
Lochhamer Schlag 21 ,
82166 Gräfelfing

Country

Germany

Phone

+498920804771902

Email

[email protected]

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