Clinical Trials Register

Summary
EudraCT Number:	2015-005023-11
Sponsor's Protocol Code Number:	EMR200017-014
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-05-25
Trial results	View 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

2015-005023-11

A.3

Full title of the trial

A Phase II, randomized, double-blind, placebo controlled, parallel-group, multicenter trial to evaluate the efficacy and safety of abituzumab in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD)

A.3.1

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

Abituzumab in SSc-ILD

A.3.2

Name or abbreviated title of the trial where available

STRATUS

A.4.1

Sponsor's protocol code number

EMR200017-014

A.5.4

Other Identifiers

Name:

IND

Number:

122049

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	Merck KGaA
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	Merck KGaA
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	Merck KGaA
B.5.2	Functional name of contact point	Communications Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 6151 72 5200
B.5.5	Fax number	+49 6151 72 2000
B.5.6	E-mail	service@merckgroup.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	No
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	Abituzumab
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	abituzumab
D.3.9.1	CAS number	1105038-73-0
D.3.9.2	Current sponsor code	EMD 525797
D.3.9.3	Other descriptive name	DI-17E6; Anti-CT51 antigen mAb; Anti-integrin alphaV mAb
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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 infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Systemic sclerosis-associated interstitial lung disease (SSc-ILD)

E.1.1.1

Medical condition in easily understood language

Systemic sclerosis is a disease characterized by abnormal and excess fibrosis, a hardening of tissues and organs.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10025109
E.1.2	Term	Lung involvement in systemic sclerosis
E.1.2	System Organ Class	100000004855

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

The primary objective of the trial is to demonstrate efficacy of abituzumab in improving lung function of subjects with SSc-ILD.

E.2.2

Secondary objectives of the trial

•To characterize further the effect of abituzumab on subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To characterize the safety, tolerability, and immunogenicity of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To evaluate the effect of abituzumab on SSc skin disease in subjects with diffuse skin involvement who are treated with a stable mycophenolate regimen;
•To evaluate health-related quality of life (HRQoL) outcomes of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To evaluate pharmacokinetic (PK) parameters of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

* pharmacogenetics substudy
* skin biopsy substudy
* rich PK substudy

E.3

Principal inclusion criteria

Subjects are eligible for this trial if they fulfill all of the following inclusion criteria:
1. Female or male subjects aged between 18 and 75 years of age who provide informed written consent.
2. Subjects fulfilling the 2013 ACR/EULAR criteria for classification of SSc.
3. Disease duration of <7 years from first non-Raynaud’s symptom.
4. According to central readings: DLCO ≥ 30% predicted, FVC 40% to 85% predicted,and ratio of FVC % predicted to DLCO % predicted < 1.8. A ratio of FVC % predicted to DLCO % predicted ≥ 1.8 is acceptable if right heart catheterization within 3 months of Screening revealed no pulmonary hypertension. If these criteria are met, then HRCT of lungs will be performed, and must show at least 5% fibrosis for subjects to be eligible.
5.Use of the same mycophenolate regimen (ie, stable dose) in a range of 1.5 to 3 g/day of MMF or 1080 to 2160 mg/day of MPS, for at least 2 months prior to the Screening Visit and continued through Day 1 of the Treatment Period.
6. For women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two effective methods of contraception, including at least one highly effective method that can achieve a failure rate of < 1% per year, when used consistently and correctly, and one other reliable method during the treatment period and for at least 90 days after the last dose of study treatment.
Examples of contraceptive methods with a failure rate of < 1% per year (highly effective contraceptive methods) include:
• combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
• progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomized partner
• sexual abstinence

E.4

Principal exclusion criteria

1.Any condition that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation or could interfere with trial objectives, conduct, or evaluation
2.Renal impairment (GFR <45 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation) calculated as follows:GFR (mL/min per 1.73 m^2) = 175 x (standardized serum creatinine)^-1.154 x (age)^-0.203 x 1.212 (if black) x 0.742 (if female)
3.Urine dipstick with ≥3+ protein and urine protein:creatinine ratio >2mg/mg
4.Known diagnosis of obstructive lung disease/emphysema (FEV1/FVC ratio <0.65) and/or significant emphysematous change on screening HRCT
5.Other clinically significant abnormalities on HRCT not attributable to scleroderma or emphysema
6.Known diagnosis of other significant respiratory disorders
7.Pulmonary hypertension that fulfills at least 1 of the following:
•Current/planned treatment with therapy targeted to PAH or pulmonary hypertension
•History of transthoracic echocardiography showing at least 1 of the following: tricuspid regurgitation jet >2.8 m/sec, right atrial enlargement (major dimension >53 mm), right ventricular enlargement(mid cavity dimension >35 mm), moderate to severe left ventricular dysfunction
•NT pro-BNP >3xULN
8.Current diagnosis of other inflammatory connective tissue disease (eg,systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, or dermato/polymyositis). Concomitant sclerodermaassociated myopathy, fibromyalgia, and secondary Sjögren's are allowed
9.Suspected/confirmed significant aspiration within the previous 6 mths
10.Active clinically significant viral/bacterial/fungal infection, major episode of infection requiring hospitalization. Treatment with parenteral anti-infectives within 4 wks prior/during Screening Period. Completion of oral anti-infectives within 2 wks of Screening. Use of oral antiinfectives during Screening Period. Vaginal candidiasis, onychomycosis,chronically suppressed oral herpes simplex virus are allowed.Prophylaxis for Pneumocystis jiroveci pneumonia permitted
11.History of/positive HIV, HCV antibody and/or PCR or HBsAg and/or HBV core antibody (total and/or IgM) at screening
12.History of/current diagnosis of active TB, or untreated latent TB infection (LTBI)
13.Presence of uncontrolled or NYHA Class 3 or 4 congestive heart failure
14.History of cancer, except adequately treated (ie, no evidence of recurrence within 5 ys prior screening) basal cell/squamous cell carcinomas of the skin (≤3 total in lifetime) or carcinoma in situ of the cervix
15.Known hypersensitivity to abituzumab DS or DP
16.Current smoker (incl. e-cigarettes)/smoking within 4 wks of screening
17.Use of agents other than mycophenolate considered by the Inv to have immunomodulating, immunosuppressive, or potential scleroderma disease-modifying properties within 2 mths of screening, e.g. pirfenidone, nintedanib, methotrexate, azathioprine, leflunomide, calcineurin inhibitors, D penicillamine, Potaba, and AIMSPRO. Use of cyclophosphamide within 5 months of screening visit is not permitted. Hydroxychloroquine or chloroquine are permitted if dose stable for at least 4 wks before screening.
18.Use of systemic corticosteroids above 10 mg/day prednisone equivalent within 4 wks prior until last dose of study drug. Inhaled and topical corticosteroids are permitted
19.Use of any biologic agent within 12 wks or 5 half-lives, whichever is longer, of screening.
20.History of anti-CD20 B-cell depleting therapy, eg, rituximab or ocrelizumab within 6 months prior to the Screening Visit
21.Use of anticoagulant or antiplatelet agent (aspirin ≤350 mg daily is permitted)
22.Clinically significant or predefined abnormalities in lab tests:
•AST, ALT or AP level >2.5xULN
•Total bilirubin >1.5xULN (other than that due to known Gilbert's disease)
•HB <5.0 mmol/L (9 g/dL), WBC count <2.5x10^9/L, or platelets <100x10^9/L)
•INR or PTT >2.0xULN
•TSH <0.01 or ≥7.1 mIU/L
23.Inability to receive IV infusions
24.History of alcohol/drug abuse for 1 y prior screening
25.Pregnancy/breastfeeding/lactation within 3 mths prior screening.
26.History of thrombotic, thromboembolic, or abnormal bleeding events incl. concomitant antiphospholipid antibody syndrome. Subjects with known lupus anticoagulant and/or anticardiolipin and/or anti-b2 glycoprotein antibodies alone should not be excluded
27.Legal incapacity/limited legal capacity
28.Receipt/planned live/attenuated vaccination within 12 wks prior screening until 3 mths after last dose of study drug. Seasonal influenza vaccination with inactivated vaccine formulation is permitted
29.Major surgery requiring hospitalization within 4 wks prior screening, planned major surgery for the duration of the trial. Subjects with history of lung resection.
30. History of/planned major organ or hematopoietic stem cell/marrow transplant
31. Severe gastrointestinal disease requiring parenteral nutrition

E.5 End points

E.5.1

Primary end point(s)

Annual rate of absolute FVC change in volume (mL)

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 52 or prematurely discontinued from the trial, whichever occur first.

E.5.2

Secondary end point(s)

a) Change in dyspnea from baseline as measured by the Mahler Transition Dyspnea Index (TDI)
b) Absolute change from baseline in St. George Respiratory Questionnaire (SGRQ) total score
c) Absolute change from baseline in Modified Rodnan skin score (mRSS) at Week 52 in subjects with diffuse cutaneous skin involvement at baseline
d) Absolute change from baseline in Quantitative lung fibrosis (QLF) in the region of highest severity
e) Overall survival
f) Proportion of subjects with clinically meaningful progression of Systemic sclerosis (SSc) by meeting Criterion 1 (Interstitial lung disease, ILD)
g) Proportion of subjects with clinically meaningful progression of SSc by meeting Criterion 2 (SSc progression other than ILD)
h) Proportion of subjects with clinically meaningful progression
i) Proportion of subjects with absolute decrease from baseline of FVC % predicted ≥10% on 2 or more consecutive occasions at least 4 weeks apart
j) Time to first clinically meaningful progression
k) Absolute change from baseline in FVC % predicted
m) Absolute change from baseline in Diffusion capacity of the lung for carbon monoxide (DLCO) % predicted
n) Absolute change from baseline in transfer coefficient of the lung for carbon monoxide (KCO)
o) Absolute change from baseline in QLF in the region of highest severity
p) Absolute change from baseline in quantitative High-resolution computed tomography (HRCT) analyses of extent of total ILD

E.5.2.1

Timepoint(s) of evaluation of this end point

a) At Week 52
b) At Week 52
c) At Week 52
d) At Week 52
e) Time from date of randomization until death, assessed up to 5 years
f) By Week 52 and by Week 104
g) By Week 52 and by Week 104
h) By Week 52 and by Week 104
i) By Week 52 and by Week 104
j) not defined
k) Up to Week 104
m) Up to Week 104
n) At Week 104
o) At Week 104
p) Up to Week 104

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

Yes

E.6.7

Pharmacodynamic

Yes

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

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

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

Argentina

Australia

Canada

France

Israel

Italy

Poland

Singapore

Spain

Turkey

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

A clinical trial protocol may not be considered closed as long as:
* Any subject is still receiving any IMP;
* Visits specified by the protocol are still taking place;
* Procedures or interventions according to the protocol are still being undertaken in any subject;
*The post-treatment safety follow up period, defined in the clinical trial protocol as being part of the trial, has not yet been completed for any subject.
The Survival follow up period will end with the end of trial.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1