Clinical Trials Register

Summary
EudraCT Number:	2016-001532-35
Sponsor's Protocol Code Number:	LRP/LNP1955/2016/002
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-06-15
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2016-001532-35

A.3

Full title of the trial

A Phase II, Dose Ranging, Exploratory Clinical Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of LNP1955 in Patients with Moderate to Severe Rheumatoid Arthritis.

II. fázisú, dózistartomány-kereső, feltáró klinikai vizsgálat az LNP1955 hatásosságának, farmakodinámiájának, farmakokinetikájának és biztonságosságának értékelésére mérsékelten súlyos és súlyos, aktív rheumatoid arthritisben szenvedő betegek esetében

A.3.1

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

A Phase II, Clinical Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of LNP1955 in Patients with Moderate to Severe Rheumatoid Arthritis.

A.4.1

Sponsor's protocol code number

LRP/LNP1955/2016/002

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	Lupin Limited
B.1.3.4	Country	India
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	Lupin Limited
B.4.2	Country	India
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Lupin Limited
B.5.2	Functional name of contact point	Project Director
B.5.3	Address:
B.5.3.1	Street Address	Research Park, Survey no. 46A/47A
B.5.3.2	Town/ city	Nande Vilage, Mulshi Taluka, District Pune
B.5.3.3	Post code	412115
B.5.3.4	Country	India
B.5.4	Telephone number	009166749029
B.5.5	Fax number	009166749563
B.5.6	E-mail	rajeshkumawat@lupin.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.3.2	Product code	LNP1955
D.3.4	Pharmaceutical form	Capsule, soft
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.3.9.2	Current sponsor code	LND400111
D.3.9.4	EV Substance Code	SUB177091
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	10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Moderate to Severe Rheumatoid Arthritis.

E.1.1.1

Medical condition in easily understood language

Moderate to Severe Rheumatoid Arthritis.

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

•The primary objective is to assess the proof of efficacy of LNP1955 and find an optimum dose in patients with moderate to severe rheumatoid arthritis (RA).

E.2.2

Secondary objectives of the trial

•To assess the pharmacodynamics (PD) and safety of LNP1955 in comparison to placebo;
•To explore the pharmacokinetics (PK) of LNP1955 and synergy with MTX in patients with moderate to severe RA in an open label study arm.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients will be entered in the study only if they meet all of the following criteria
1.All patients must sign and date an informed consent form consistent with International Council for Harmonisation Good clinical practice (ICH GCP) guidelines and local legislation prior to participation in the trial (i.e., prior to any trial procedures) and be willing to follow the protocol.
2.Ambulatory male or female participants, between 18 and 65 years of age, meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for RA; with at least 6 swollen joints (66 joint count) and at least 6 tender joints (68 joint count).
3.Moderate to severe RA with DAS28 score ≥3.2 (based on swollen joint count (SJC)/TJC using 28 joints).
4.Patients with RA who are treatment naïve or who have failed therapy with at-least 1 DMARD: non-biologic/biologic, due to lack of efficacy or toxicity.
5.Patient should not have received biologic therapy for at least 6 months prior to first dose of IP.
6.Patient has completed washout of minimum 7 days for Azathioprine, Sulfasalazine and Cyclosporine, 4 weeks for hydroxychloroquine and Auranofin (oral gold), and 6 weeks for MTX (except for MTX Add on part) prior to first dose of IP.
7.Patients who have not taken leflunomide within 2 months, unless the patient has completed a Cholestyramine washout at least 4 weeks prior to first dose of IP.
8.Patients who have not taken alkylating agents (e.g., cyclophosphamides) within 6 months prior to first dose of IP.
9.Participants of reproductive potential (males and females), must be willing to use a reliable means of contraception (e.g., combined or progesterone only hormonal contraception, intrauterine devices, surgical sterilization, double barrier methods, or vasectomized partner) throughout trial participation and 2 months after the last dose of IP OR Women if postmenopausal (aged greater than 45 years) must have a history of amenorrhea for at least 1 year from the time of last menstrual cycle and have follicle stimulating hormone (FSH) value indicating menopause with high reliability.
Additional Inclusion Criteria for MTX Add on part:
1.Patients who are MTX naïve and eligible to receive 7.5 mg MTX per week after having tolerated at least one dose; (OR) Patients who are on stable dose of MTX 7.5 mg/week.

E.4

Principal exclusion criteria

Patients will not be entered in the study for any of the following reasons:
1.Patients who are Steinbrocker class IV functional capacity (incapacitated, largely or wholly bed-ridden or confined to a wheelchair, with little or no self-care).
2.Primary or secondary immunodeficiency (e.g., human immunodeficiency virus [HIV]). Evidence of positive serology for hepatitis B (HBsAg) or hepatitis C.
3.Patients with active tuberculosis (TB), prior history of incompletely treated TB, latent TB or evidence of TB as shown positive by QuantiFERON® TB Gold test or appropriate test or those who are at risk of developing TB.
4.Evidence of coronary artery disease or cardiac arrhythmias or severe congestive heart failure (New York Heart Association Classes III and IV), history of stroke, uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg and diastolic BP ≥95 mmHg) or any clinically significant abnormalities in the ECG.
5.Treatment with intra-articular or systemic corticosteroids within 4 weeks prior to the first dose of IP (except oral doses ≤ 10.0 mg prednisolone daily or equivalent.
6.History of malignancy within 5 years prior to the Screening Visit, except curatively treated basal cell carcinoma or squamous cell carcinoma of the skin and Grade 1 cervical cancer.
7.Patient has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, and thrombocytopenia), renal, or liver disease (e.g., fibrosis, cirrhosis, and hepatitis), or gastroenteric ulcer or any other uncontrolled disease or has clinically relevant deviations in laboratory tests at Screening such as the following:
-Serum transaminases, alanine transaminase (ALT) and/or aspartate transaminase (AST) >3 times upper limit of normal (ULN).
-Bilirubin >2 times ULN.
-Alkaline phosphatase (ALP) >3 times ULN.
-Renal insufficiency as defined by creatinine level ≥1.5 mg/dL (132 µmol/L) for females or ≥ 2.0 mg/dL (177 µmol/L) for males.
-Albumin <lower limit of normal.
-Platelets < 100×109/L (<100,000/mm3).
-White blood cell count < 3.5×109/L.
-Neutrophil count < 2000×106/L (<2000/mm3).
-Hemoglobin level ≤ 8 gm/dL.
-Glycosylated hemoglobin level ≥ 8%.
8.Receipt of live/attenuated vaccinations within 30 days prior to the first dose of IP or planned vaccinations throughout the study or 30 days after study completion.
9.History of known and significant drug allergies (such as Steven-Johnson syndrome, anaphylaxis) or any hypersensitivities that can have potential impact on patient’s participation as determined by the Investigator.
10.Have current or recent history of a severe, progressive, or uncontrolled disease, which in the opinion of Investigator makes the patient inappropriate for inclusion in this study.
11.History of, or current, other rheumatic diseases, autoimmune inflammatory joint disease other than RA (e.g., gout, psoriatic arthritis, and Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, or Felty’s syndrome, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome). Secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA is permitted.
12.Any major surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to the Screening visit or planned during the study period or patients with a history of septic arthritis of any joints within 12 months prior to screening.
13.Any neurological (congenital or acquired), vascular or systemic disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinson’s disease, cerebral palsy, and diabetic neuropathy).
14.History or presence of any immunological disease or use of immunosuppressive or any therapy within a period that can have a residual effect as determined by the Investigator.
15.Have any known condition affecting oral absorption of drug (e.g., malabsorption syndrome), or not able to swallow IPs for any reason.
16.History of alcohol abuse or drug addiction within 1 year prior to Screening.
17.Women who are pregnant or lactating or planning pregnancy while enrolled in the study and at least 2 months after last dose of the IP.
18.Participation in other investigational drug study within 30 days prior to Screening.
Additional Exclusion Criteria for MTX Add on part:
1.Intolerance to MTX;
2.Contraindication to MTX (e.g. hypersensitivity to MTX or its excipients, blood dyscrasias etc.);
3.Receiving systemic medicines with antifolate activity (e.g., co trimoxazole).

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 12

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks after treatment

E.5.2

Secondary end point(s)

• The proportion of patients meeting ACR20 response criteria after 4 weeks and 8 weeks of treatment.
• The proportion of patients meeting ACR50 and ACR70 response after 4 weeks, 8 weeks, and 12 weeks of treatment.
• The change from Baseline in DAS28 (CRP) and DAS28 (ESR) at Week 4, Week 8, and Week 12.

E.5.2.1

Timepoint(s) of evaluation of this end point

after 4 and 8 weeks of treatment for ACR 20
4,8 and 12 weeks after treatment for ACR 50 and ACR 70
4, 8 and 12 weeks from baseline for DAS28 (CRP)and DAS 28( ESR)

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

Yes

E.8.1.7.1

Other trial design description

The study has 2 parts. Main part is randomised and MTX addon part is open label

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

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

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.1.1.1

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

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

2016-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-11

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