Clinical Trials Register

Summary
EudraCT Number:	2020-001611-24
Sponsor's Protocol Code Number:	CAIN457ADE16
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-10-26
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

Germany - PEI

A.2

EudraCT number

2020-001611-24

A.3

Full title of the trial

A two-year multi-center Phase 3 study to investigate the efficacy and safety of secukinumab in adult patients with active, moderate to severe thyroid eye disease (ORBIT), with a randomized, parallel-group, double-blind, placebo-controlled, 16-week treatment period, and a follow-up/retreatment period

A.3.1

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

Study of efficacy and safety of secukinumab in adult patients with active, moderate to severe thyroid eye disease

A.3.2

Name or abbreviated title of the trial where available

ORBIT

A.4.1

Sponsor's protocol code number

CAIN457ADE16

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	Novartis Pharma GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice
B.5.3	Address:
B.5.3.1	Street Address	Roonstr. 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90419
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49911273 12100
B.5.5	Fax number	+49911 273 12160
B.5.6	E-mail	infoservice.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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	Cosentyx
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Secukinumab
D.3.2	Product code	AIN457
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	secukinumab
D.3.9.1	CAS number	1229022-83-6
D.3.9.2	Current sponsor code	AIN457
D.3.9.3	Other descriptive name	SECUKINUMAB
D.3.9.4	EV Substance Code	SUB33242
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Active, moderate to severe thyroid eye disease

E.1.1.1

Medical condition in easily understood language

Thyroid eye disease

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10060742
E.1.2	Term	Endocrine ophthalmopathy
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate that secukinumab is superior to placebo with regard to the overall responder rate after 16 weeks of treatment.

E.2.2

Secondary objectives of the trial

- To demonstrate that secukinumab is superior to placebo with regard to the CAS responder rate after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to the proptosis responder rate after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to reduction in diplopia after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to reduction in CAS after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to reduction in proptosis after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to improvement in disease severity after 16 weeks of treatment.
- To demonstrate that secukinumab is superior to placebo with regard to improvement in GO-QoL after 16 weeks of treatment.
- To evaluate the safety of secukinumab compared to placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must give a written, signed and dated informed consent before any study assessment is performed.
2. Male or non-pregnant, non-lactating female patients ≥ 18 years of age.
3. Clinical diagnosis of active, moderate-to-severe TED (not sight-threatening) in the study eye at Baseline associated with 2 or more of the following:
- Lid retraction ≥ 2 mm
- Moderate or severe soft tissue involvement
- Exophthalmos ≥ 3 mm above normal
- Inconstant or constant diplopia
4. Onset of TED symptoms fewer than 12 months prior to Baseline.
5. CAS ≥ 4 (on a 7-point scale, with a score of ≥ 3 indicating active TED) in the more severely affected (study) eye at Screening and Baseline. Note: Proptosis is the primary qualifier for selection of the study eye. In case both eyes show a similar degree of proptosis, other inflammatory signs and symptoms (CAS) should be taken into account by the investigator for the selection of the study eye.
6. Peripheral euthyroidism or mild hypo-/hyperthyroidism defined as free T3 (fT3) and free T4 (fT4) < 30% above/below normal limits at Screening. Every effort should be made to correct the mild hypo-/hyperthyroidism promptly and to maintain the euthyroid state until the end of this study.
7. Orbital MRI assessment available confirming the diagnosis of TED for patients initially presenting with hypo- or euthyroidism (without treatment for hyperthyroidism) before or at the time of TED diagnosis (to rule out other potential causes of orbital signs and symptoms).

E.4

Principal exclusion criteria

1. Improvement in CAS of ≥ 2 points and/or improvement in proptosis of ≥ 2 mm in the study eye between Screening and Baseline.
2. Signs of sight-threatening TED defined by optic neuropathy or severe corneal injury.
3. Patients, in the opinion of the investigator, requiring immediate or urgent medical treatment with glucocorticoids for TED.
4. Patients requiring immediate surgical ophthalmological intervention or planning corrective surgery/irradiation during the course of the study.
5. Decreased best corrected visual acuity (BCVA) as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect within the last 6 months.
6. Any other ophthalmic and/or orbital disease or condition that might interfere with the assessment of TED.
7. Previous orbital radiotherapy.
8. Previous ophthalmological/orbital surgery for TED (e.g. orbital decompression).
9. Previous use of biological agents for the treatment of TED.
10. Previous use of systemic, non-biologic, immunomodulatory agents for the treatment of TED (e.g., mycophenolate or cyclosporine).
11. Previous exposure to secukinumab or other biologic drugs directly targeting IL-17A or the IL-17 receptor (e.g., ixekizumab, brodalumab).
12. Previous treatment with rituximab, tocilizumab or teprotumumab.
13. Previous use of systemic corticosteroids for the treatment of TED, except for oral corticosteroids with a cumulative dose equivalent to < 1 g oral prednisone/prednisolone if the corticosteroid was discontinued at least 4 weeks prior to Baseline.
14. Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19).
15. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer.
16. Previous or ongoing use of prohibited treatments. Respective washout periods have to be adhered to.
17. History of hypersensitivity to any of the study drug constituents.

Other protocol-defined exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients achieving overall response defined as follows: ≥ 2 point reduction in CAS AND ≥ 2 mm reduction in proptosis from Baseline in the study eye, provided there is no corresponding deterioration in CAS or proptosis (≥ 2 point or 2 mm increase, respectively) in the fellow eye after 16 weeks of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16

E.5.2

Secondary end point(s)

- Proportion of patients achieving response in reduction of CAS at Week 16 defined as follows: reduction of ≥ 2 points from Baseline in the study eye without deterioration (≥ 2 point increase) of CAS in the fellow eye.
- Proportion of patients achieving response in reduction of proptosis at Week 16 defined as follows: reduction of ≥ 2 mm from Baseline in the study eye without deterioration (≥ 2 mm increase) of proptosis in the fellow eye.
- Proportion of patients achieving response in diplopia at Week 16 defined as follows: Baseline diplopia > 0 and a reduction of ≥ 1 grade with no corresponding deterioration (≥ 1 grade worsening) in the fellow eye at Week 16.
- Mean change from Baseline to Week 16 in CAS in the study eye.
- Mean change from Baseline to Week 16 in proptosis in the study eye.
- Proportion of patients with improvement in EUGOGO disease severity between Baseline and Week 16.
- Mean change from Baseline to Week 16 in GO QoL score.
- Frequency of AEs, TEAEs, AEs resulting in treatment discontinuation, SAEs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 16

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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)

None (subjects who have ended the participation in the trial will be treated according to the physicians discretion)

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

2021-02-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-16

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