Clinical Trials Register

Summary
EudraCT Number:	2020-004483-26
Sponsor's Protocol Code Number:	AA2032
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-09-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2020-004483-26

A.3

Full title of the trial

A national prospective study of patients with hepatitis induced by immune checkpoint inhibitors; Characterization of liver injury, outcome of therapy and randomization to either prednisolone or mycophenolate mofetil treatment in case of relapse

Et nationalt, prospektivt studie omhandlende patienter med leverbetændelse induceret af immun checkpoint inhibitorer: Karakterisering af leverbeskadigelse, behandlingseffekt og randomisering til enten prednisolon eller mycophenolat mofetil behandling i tilfælde af tilbagefald

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy of high-dose steroids, mycophenolate mofetil and tacrolimus for treatment of patients with immune related hepatitis induced by cancer immunotherapy

Effekten af højdosis binyrebarkhormon, mycophenolat mofetil og tacrolimus til behandling af patienter med immunrelateret leverbetændelse udløst af cancer immunterapi

A.3.2

Name or abbreviated title of the trial where available

I-HEP

A.4.1

Sponsor's protocol code number

AA2032

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	National Center for Cancer Immune Therapy (CCIT-DK)
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Empowering of cancer immuntherapy in Denmark
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	National Center for Cancer Immune Therapy (CCIT-DK)
B.5.2	Functional name of contact point	Principal investigator
B.5.3	Address:
B.5.3.1	Street Address	Borgmester Ib Juuls Vej 1
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4538682971
B.5.6	E-mail	rikke.boedker.holmstroem@regionh.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mycophenolate mofetil (mycophenolatmofetil)
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	mycophenolatmofetil
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mycophenolatmofetil
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mycophenolate mofetil (mycophenolatmofetil)
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	mycophenolatmofetil
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mycophenolatmofetil
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Prednisolone
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Prednisolone
D.3.9.4	EV Substance Code	SUB10018MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2,5 to 50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cohort A: Immune related hepatitis induced by immune checkpoint inhibitor grade III-IV
Cohort B: Immune related hepatitis induced by immune checkpoint inhibitor grade II-IV (relapse during prednsisolone tapering)

E.1.1.1

Medical condition in easily understood language

Patients who develops severe hepatotoxicity due to their cancer immunotherapy treatment and patients who relapse during treatment

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10019766
E.1.2	Term	Hepatitis drug-induced
E.1.2	System Organ Class	100000004871

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This study is performed to evaluate the crucially important question of which patients with immune related hepatitis will respond to standard treatment with steroids and who needs treatment with a second line immunosuppressive agent in this case steroids plus mycophenolate mofetil or tacrolimus. Treatment efficacy is evaluated as percentage reduction of liver transaminases or bilirubin, and time to peroral prednisolone and discharge in days

E.2.2

Secondary objectives of the trial

Secondary objectives include which patients experience relapse during or after treatment with steroids and mycophenolate mofetil; time to downgrading of Common Terminology Criteria for Adverse Events (CTCAE) grade; changes in blood, liver tissue and phenotypical features during treatment; pre-events before debut of immune related hepatitis; and toxicity related to steroids and mycophenolate mofetil. In addition, the influence of ir-hepatitis and the treatment hereof on the cancer will be explored, including the eligibility for further antineoplastic treatment, and if the event of immune related hepatitis influence progression-free survival and survival rates.
Furthermore, to achieve a deeper understanding of immune related adverse events and find potential biomarkers for the risk of developing immune related adverse events , immune responses in blood and in the affected organ are analyzed in a selected group of patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

4.3.1 Inclusion criteria
Cohort A:
- Abnormal liver parameters equal to ≥ grade 3 ir-hepatitis defined as; AST/ALT/ALP >5 x ULN, INR ≥ 2.5 x ULN, or bilirubin > 3.0 x ULN

Cohort B:
- Patients who recur during or within one months of prednisolone tapering of ≥2 ir-hepatitis equal to AST/ALT ≥3 x ULN, ALP ≥2.5 x ULN, INR ≥ 1.5 x ULN, or bilirubin ≥ 3.0 x ULN

Cohort A and Cohort B:
- Histologically confirmed solid cancer
- Treatment with CTLA-4, PD-1/PD-L1 or LAG3 inhibitor or a combination of CTLA-4 plus PD-1, PD-1 plus LAG3, and PD-1 plus IDO inhibitors within 6 months
- ≥ 18 years of age
- Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives
- Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition, documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
- Signed statement of consent after receiving oral and written study information
- Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.

E.4

Principal exclusion criteria

4.3.2 Exclusion criteria
- Concomitant chemotherapy treatment or tyrosine kinases or angiogenesis inhibitors
- Concomitant immunosuppressive medication except prednisolone
- Patients with hepatocellular carcinoma
- Known hypersensitivity to one of the active drugs or excipients
- Uncontrolled infection
- Acute viral hepatitis
- Any medical condition that will interfere with patient compliance or safety
- Simultaneous treatment with other experimental drugs or other anti-cancer drugs
- Pregnant or breastfeeding females
- Phenylketonuria

E.5 End points

E.5.1

Primary end point(s)

3.3.1 Primary endpoints
• Treatment-assessed hepatitis response rates with steroids, and increased dosis of steroids versus MMF
• Time to response or downgrading of liver injury in patients with ≥ grade 3 ir-hepatitis and patients with relapse of ir-hepatitis (≥2 grade) measured as;
- Days to ≥20% reduction in ALT/AST/ALP or bilirubin
- Days to shift to peroral prednisolone and discharge
- Days for stopping treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

Cohort A: Response rates for steroids is evaluate after minimum 72 hours of treatment, or 7 days if the patient receive an add on of Ursochol.
Cohort B: Response rate for blockrandomization to either increased dose of prednisolone or mycophenolate mofetil is evaluated after seven days

E.5.2

Secondary end point(s)

3.3.2 Secondary endpoints
• Relapse Rate: Percent of patients with relapse to grade ≥2 hepatitis during steroid tapering or MMF
• Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively
• Changes in biochemical, histopathological and phenotypical features during treatment
• Cumulated doses of corticosteroid and MMF respectively
• Toxicity related to steroids and second line immunosuppressive treatment with MMF
• Pre-events before developing ir-hepatitis will be analysed
• Progression free survival and survival rates at 6 and 12 months.
• Proportions of patients eligible for further antineoplastic treatment and re-start of ICI therapy will be studied

E.5.2.1

Timepoint(s) of evaluation of this end point

Cohort A: The evaluation will be performed before, during and after treatment for up to three months after treatment initiation in patients with proper steroid response and minimum for 6 months in patients with a steroid refractory condition
Cohort B: The evaluation will be performed before, during and after treatment for up to six months after treatment initiation in all patients

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

national, multicentre pilot trial using unblinded subgroup block-randomization

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After ended participation the patients will be referred back to their local oncologic department for further treatment or follow-up. Patients with continued symptoms of immune related hepatitis will also be follow at their respective medical gastroenterologic department

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-11-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2024-09-06

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