Clinical Trials Register

Summary
EudraCT Number:	2014-005323-27
Sponsor's Protocol Code Number:	IM101-344
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-29
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

UK - MHRA

A.2

EudraCT number

2014-005323-27

A.3

Full title of the trial

A phase II study to evaluate subcutaneous abatacept vs. placebo in diffuse cutaneous systemic sclerosis—a double-blind, placebo-controlled, randomized controlled trial

A.3.1

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

A phase II study to evaluate how safe and effective the study drug abatacept (injected subcutaneously) is compared to placebo in treating diffuse cutaneous systemic sclerosis

A.3.2

Name or abbreviated title of the trial where available

The Abatacept Systemic SclErosis Trial (ASSET)

A.4.1

Sponsor's protocol code number

IM101-344

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02161406

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	University of Michigan
B.1.3.4	Country	United States
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	Bristol Myers Squibb (BMS)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SABER @ University of Michigan
B.5.2	Functional name of contact point	Erica Bush
B.5.3	Address:
B.5.3.1	Street Address	SPH II 1415 Washington Heights
B.5.3.2	Town/ city	Ann Arbor
B.5.3.3	Post code	MI 48109
B.5.3.4	Country	United States
B.5.4	Telephone number	0017348451771
B.5.6	E-mail	ebush@umich.edu

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	ORENCIA
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Company
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Abatacept
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	Abatacept
D.3.9.2	Current sponsor code	IM101-344
D.3.9.3	Other descriptive name	Orencia
D.3.9.4	EV Substance Code	AS1
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	125
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)	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	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	Endotracheopulmonary instillation
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

Diffuse Cutaneous Systemic Sclerosis

E.1.1.1

Medical condition in easily understood language

Scleroderma

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10010759
E.1.2	Term	Connective tissue disorder NOS
E.1.2	System Organ Class	100000004859

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10018124
E.1.2	Term	Generalized scleroderma
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

1.To assess the safety of treatment with abatacept 125 mg subcutaneously (injected under the skin) versus placebo (dummy drug) subcutaneously given every week

2. To assess the effectiveness of treatment with abatacept 125 mg subcutaneously versus placebo subcutaneously given every week on skin fibrosis (thickening and hardening)using the modified Rodnan Skin Score (mRSS)

E.2.2

Secondary objectives of the trial

To assess the effectiveness of treatment with abatacept 125 mg subcutaneously versus placebo subcutaneously given every week on:

i)Joint tenderness as measured by 28-tender joint count
ii) Joint swelling as measured by 28-swollen joint count
iii) Patient’s and physician’s global assessment on a Likert scale
iv)Health-related quality of life (HRQOL) using PROMIS-29 2.0
v) Physical function as assessed by the scleroderma health assessment questionnaire-disability index (SHAQ-DI)
vi)Fatigue as assessed by the PROMIS Fatigue scale
vii)Sleep as assessed by the PROMIS sleep disturbance and impairment scale
viii)Gastrointestinal symptoms as assessed by UCLA SCTC GIT 2.0
ix) Combined Response Index in Systemic Sclerosis (CRISS)
x) Percent Predicted forced vital capacity (FVC)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed Written Informed Consent
2. Diagnosis of SSc, as defined using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc
3. dcSSc as defined by LeRoy and Medsger
4. Disease duration of ≤ 36 months (defined as time from the first non−Raynaud phenomenon manifestation)
For disease duration of ≤ 18 months
 ≥ 10 and ≤ 25 mRSS units at the screening visit
For disease duration of >18-36 months
 ≥ 15 and ≤ 45 mRSS units at the screening visit and one of the following:
1. Increase ≥ 3 in mRSS units compared with the last visit within previous 1–6 months
2. Involvement of one new body area with ≥ 2 mRSS units compared with the last visit within the previous 1–6 months
3. Involvement of two new body areas with ≥ 1 mRSS units compared with the last visit within the previous 1–6 months
4. Presence of 1 or more Tendon Friction Rub
5. Age ≥ 18 years at the screening visit
6. If female of childbearing potential (see 4.2.3), the patient must have a negative pregnancy test at screening and baseline visits
7. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if the patient is on a stable dose regimen for ≥ 2 weeks prior to and including the baseline visit
8. ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are permitted if the patient is on a stable dose for ≥ 2 weeks prior to and including the baseline visit

E.4

Principal exclusion criteria

1. Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and scleroderma-associated myopathy
2. Limited cutaneous SSc or sine scleroderma at the screening visit
3. Major surgery (including joint surgery) within 8 weeks prior to screening visit
4. Any infected ulcer prior to randomization
5. Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the baseline visit
6. Severe (MRSS 3+) skin on the inner aspects of thighs, upper arms, and abdomen
7. Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA
8. Anti-CD20, and cyclophosphamide within 12 months prior to the baseline visit
9. Use of Intravenous Immunoglobulin (IVIG) within12 weeks prior to the baseline visit
10. Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation
11. Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to the baseline visit
12. Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate mofetil rapamycin, colchicine, D-penicillamine, within ≤ 4 weeks prior to the baseline visit
13. Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, ABA or adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to the baseline visit
14. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin) ≤ 40% of predicted at the screening visit
15. Pulmonary arterial hypertension (PAH) as determined by right heart catheterization or on PAH approved medications for PAH. It is acceptable to use PDFE-5 inhibitors for Raynaud’s and digital ulcers.
16. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (≥ 4 weeks).
17. Positive for hepatitis B surface antigen prior to the baseline visit
18. Positive for hepatitis C antigen, if the presence of hepatitis C virus was also shown with polymerase chain reaction or recombinant immunoblot assay prior to baseline visit
19. Any of the following prior to the baseline visit:
 Hemoglobin <8.5 g/dL;
 WBC < 3,000/mm3 (<3 x 109/L);
 platelets < 100,000/mm3 (<3 x 109/L);
 serum creatinine > 2 x ULN; or
 serum ALT or AST > 2 x ULN
20. Any other laboratory test results that, in the opinion of the investigator, might place a participant at unacceptable risk for participation in the study.
21. The following medical history and concurrent diseases:
Subjects who are impaired, incapacitated, or incapable of completing study-related assessments.
 Subjects with active vasculitis of a major organ system.
 Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether or not related to SSc and which, in the opinion of the investigator, might place a participant at unacceptable risk for participation in the study.
 Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ. Existing non-melanoma skin cell cancers should be removed, the lesion site healed, and residual cancer ruled out before administration of the study drug.
 Subjects who currently abuse drugs or alcohol.
 Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including participants with evidence of human immunodeficiency virus (HIV) detected during screening.
 Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months prior to screening.
 Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, osteomyelitis, or bronchiectasis).
22. Patients with a history of anaphylaxis to abatacept

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the change from baseline to month 12 in mRSS( Modified Rodnan Skin Score)

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

To assess the efficacy of treatment with abatacept 125 mg SC versus
placebo SC given every week on:
 Joint swelling and tenderness as measured by 28 joint count
 Patient’s and physician’s global assessment on a Likert scale
 Health-related quality of life (HRQOL) using PROMIS-29 2.0
 Physical function as assessed by the scleroderma health
assessment questionnaire-disability index (SHAQ-DI)
 Fatigue as assessed by PROMIS fatigue scale
 Sleep as assessed by PROMIS sleep disturbances and impairment scales
Gastrointestinal symptoms as assessed by UCLA SCTC GIT2.0
 Combined Response Index in Systemic Sclerosis (CRISS)
 Percent predicted forced vital capacity (FVC)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

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)

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

Yes

E.8.1.5

Parallel group

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Italy

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1