Clinical Trials Register

Summary
EudraCT Number:	2014-002279-27
Sponsor's Protocol Code Number:	DICL001
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-03
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

Estonia - SAM

A.2

EudraCT number

2014-002279-27

A.3

Full title of the trial

A Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Three-Arm, Multi-Site Study to Evaluate the Clinical Equivalence of Diclofenac Sodium Topical Gel 1% (Hi-Tech Pharmacal Co., Inc.) with Voltaren® Gel (Diclofenac Sodium Topical Gel) 1%(Novartis) in Patients with Osteoarthritis of the Knee.

A.3.1

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

A.4.1

Sponsor's protocol code number

DICL001

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	Hi-Tech Pharmacal Co., Inc.
B.1.3.4	Country	United States
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	Hi-Tech Pharmacal Co., Inc.
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	AS EGeen
B.5.2	Functional name of contact point	Managing Director
B.5.3	Address:
B.5.3.1	Street Address	Sõbra 54
B.5.3.2	Town/ city	Tartu
B.5.3.3	Post code	50106
B.5.3.4	Country	Estonia
B.5.4	Telephone number	+3727309537
B.5.5	Fax number	+3727309534
B.5.6	E-mail	rauno.oja@egeeninc.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	Diclofenac Sodium Topical Gel 1%
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diclofenac Sodium
D.3.9.1	CAS number	15307-79-6
D.3.9.3	Other descriptive name	DICLOFENAC SODIUM
D.3.9.4	EV Substance Code	SUB01674MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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.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	Voltaren® Gel
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Voltaren® Gel
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diclofenac Sodium
D.3.9.1	CAS number	15307-79-6
D.3.9.3	Other descriptive name	DICLOFENAC SODIUM
D.3.9.4	EV Substance Code	SUB01674MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Gel
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

osteoarthritis of the knee

E.1.1.1

Medical condition in easily understood language

Osteoarthritis of the knee

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

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 objectives of the study are to demonstrate clinical bioequivalence of Hi-Tech Pharmacal Co., Inc’s Diclofenac Sodium Topical Gel 1% compared to Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% (Novartis) in the treatment of patients with osteoarthritis of the knee.

E.2.2

Secondary objectives of the trial

not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Ambulatory male and non-pregnant females 35 years and older diagnosed with osteoarthritis according to the American College of Rheumatology Criteria (ACR) (Appendix 2) in target knee. Target knee is the one with higher level of pain.
ACR Criteria includes: Knee Pain and at least 3 of the following:
1) age ≥ 50
2) stiffness lasting < 30 mins
3) bony tenderness
4) crepitus
5) bony enlargement
6) no palpable warmth
2. Symptom onset of > 6 Months prior to Screening for the target knee.
3. If female and of child-bearing potential, prepare to abstain from sexual intercourse or use a reliable method of contraception during the study (e.g., IUD, oral, transdermal, injected, implanted hormonal contraceptives or condom + spermicide).
4. Periarticular knee pain due to osteoarthritis (not bursitis, tendonitis etc) that required the use of oral or topical treatments (e.g, NSAIDs or acetaminophen).
5. Radiograph of the target knee within the previous year with a Grade 1, 2 or 3 disease based upon the Kellgren-Lawrence disease severity scale (Appendix 3).
6. After a minimum of 7-day wash out of all pain medication has baseline pain on movement score of ≥ 50mm on a 0-100-mm Visual Analogue Scale for the target knee.
7. After a minimum of 7-day wash out of all pain medication has baseline WOMAC pain sub scale of ≥ 9 on a 5 question, 5 point (0 to 4) Likert scale for the target knee.
8. Willing and able to use only acetaminophen as rescue medication.
9. Willing and able to comply with the study requirements.

E.4

Principal exclusion criteria

1. Females who are pregnant, breast feeding, or planning a pregnancy.
2. Radiograph of the target knee within the previous year with a Grade 4 score on the Kellgren-Lawrence disease severity scale (Appendix 3).
3. History of osteoarthritis in the contralateral knee requiring medication within 12 months of screening.
4. After a minimum of 7-day wash out of all pain medication has baseline pain on movement score of ≥ 20mm on a 0-100-mm Visual Analogue Scale for the contralateral knee immediately prior to randomization.
5. Known history of secondary osteoarthritis (e.g. congenital, traumatic, gouty arthritis) of the knee or rheumatoid arthritis.
6. Known history of other chronic inflammatory diseases, (e.g., colitis) or fibromyalgia during last 5 years. Patients whose disease was diagnosed at least 5 (five) years prior to screening visit and have had no known disease activity (i.e., no disease related complaints nor disease treatment prescribed) since then may enter into the study.
7. History of asthma, hypertension, myocardial infarction, thrombotic events, stroke, congestive heart failure, impaired renal function or liver disease. Patients who have had high blood pressure measured at least 2 (two) years prior to screening visit and have had no disease activity (i.e., no record of hypertension nor anti-hypertensive treatment prescribed) for at least 2 (two) years prior to screening visit may enter into the study.
8. History of coronary artery bypass graft within 6 months of screening.
9. Concomitant acetylsalicylic acid therapy other than a stable low dose used for cardiac prophylaxis (max. 162 mg daily) taken for at least 3 months prior to enrollment and maintained throughout the duration of the study.
10. Use of warfarin or other anticoagulant therapy within 30 days of screening.
11. Use of ACE inhibitors, cyclosporine, diuretics, lithium or methotrexate, within 30 days of screening or during the study.
12. Known history of gastrointestinal bleeding or peptic ulcer disease.
13. Abnormal screening clinical laboratory evaluations which the Investigator deems clinically significant.
14. Known allergy to aspirin or NSAIDs.
15. Skin lesions or wounds in the affected area.
16. Significant (requiring surgery) injury or major knee surgery to either knee within six months prior to screening.
17. Transaminase levels that are more than two times the upper limit of the normal range at screening.
18. Any other acute or chronic illness that in the opinion of the investigator could compromise the integrity of study data or place the Patient at risk by participating in the study.
19. Concomitant use of corticosteroids (any formulation) or use within 30 days of study randomization.
20. Receipt of any drug as part of a research study within 30 days prior to screening.
21. Previous randomization into this study.
22. Known allergy (hypersensitivity) to acetaminophen.

E.5 End points

E.5.1

Primary end point(s)

Mean Change from Baseline in WOMAC Pain Scale
Time Frame: Baseline and Week 8

Equivalence of Test and Reference Drug in the Mean Change from baseline in the WOMAC pain score.
The analyses will be conducted in the Per-Protocol population using the WOMAC scores at Week 8.

E.5.1.1

Timepoint(s) of evaluation of this end point

at Week 8

E.5.2

Secondary end point(s)

• Superiority of Test and Reference against Placebo in the Mean Change from baseline in the total WOMAC pain score.
Time Frame: Baseline and Week 8

The superiority of Test and Reference treatments over the placebo will be evaluated identically in Intent-to-Treat population using the WOMAC scores at Week 8 in separate ANCOVAs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 8

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

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Clinical Equivalence

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)

Yes

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

Ukraine

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

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:

750

F.1.3

Elderly (>=65 years)

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

650

F.4.2.2

In the whole clinical trial

750

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)

Sponsor does not plan to provide study medication or rescue medication after the subject will end the study. The subject will refer to her/his doctor for receiving the adequate standard of care for her/his disease.

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

2014-10-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-06-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-01

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