Clinical Trials Register

Summary
EudraCT Number:	2012-002682-36
Sponsor's Protocol Code Number:	DGEL-12058
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:	2012-07-19
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

2012-002682-36

A.3

Full title of the trial

Comparison of the Efficacy of Diclofenac Sodium Topical Gel, 1% (Mylan) to Voltaren® Gel, 1% (Novartis US) and Placebo in Adult Subjects with Knee Osteoarthritis

A.3.1

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

Comparison of the Efficacy of Diclofenac Sodium Topical Gel, 1% (Mylan) to Voltaren® Gel, 1% (Novartis US) and Placebo in Adult Subjects with Knee Osteoarthritis

A.4.1

Sponsor's protocol code number

DGEL-12058

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	Mylan Pharmaceuticals 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	Mylan Pharmaceuticals 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	Mylan Pharmaceuticals Inc
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	3711 Collins Ferry Road
B.5.3.2	Town/ city	Morgantown
B.5.3.3	Post code	WV 26505
B.5.3.4	Country	United States
B.5.4	Telephone number	001304554-6693

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	1% Diclofenac Sodium Topical Gel
D.3.4	Pharmaceutical form	Transdermal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diclofenac
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, 1%
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, 1%
D.3.4	Pharmaceutical form	Transdermal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diclofenac
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	Transdermal gel
D.8.4	Route of administration of the placebo	Topical use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Osteoarthritis of joints amenable to topical treatment, such as the knees.

E.1.1.1

Medical condition in easily understood language

Osteoarthritis of joints amenable to topical treatment, such as the knees.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis
E.1.2	System Organ Class	100000004859

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 objective of this study is to investigate the clinical endpoint bioequivalence of
Mylan's Diclofenac Sodium Topical Gel, 1% compared to Novartis US’ Voltaren® Gel,
1% and placebo (vehicle, Mylan) following multiple topical applications of 4 g to a
single osteoarthritic knee (4 g four times daily for 4 weeks).

E.2.2

Secondary objectives of the trial

No secondary objectives of the trial have been established.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and Female subjects aged 35 years or older with a clinical diagnosis of
osteoarthritis of the knee according to the American College of Rheumatology (ACR)
criteria:
1. knee pain plus 3 of the following:
a. 50 years of age or older
b. stiffness lasting less than 30 minutes,
c. crepitus,
d. bony tenderness,
e. bony enlargement,
f. no warmth to the touch,
and including:
2. Symptoms for at least 6 months prior to screening; AND
3. Knee pain (not referred) for at least 15 days of the preceding month (30 days)
(periarticular knee pain due to osteoarthritis and not due to other conditions such
as bursitis, tendonitis, etc); AND
4. the pain in the target knee required the daily use of non-steroidal antiinflammatory
drugs (NSAIDS) or acetaminophen/paracetamol (topical or oral
treatments);
5. Had an X-ray of the target knee, taken no more than 1 year before the initiation of
the study, demonstrating evidence of osteoarthritis with Kellgren-Lawrence grade
1-3 disease;
6. After discontinuing their current regimen of analgesic(s) for a period of at least 7 days or ≥ 5 half-lives of the mean half-life of their previous analgesic, which ever is longer,had at least moderate pain on movement (POM) in the target knee, defined as a baseline score of ≥ 50 mm on a 0-100 mm Visual Analog Scale (VAS) immediately prior to randomization, AND a baseline Western Ontario McMaster Osteoarthritis (WOMAC®) pain subscale of at least 9 immediately prior to randomization; and
7. Willing to use and able to tolerate the rescue medication
(acetaminophen/paracetamol)
- Males and non-pregnant, non-lactating females weighing at least 50 kg and 48 kg,
respectively
- Subjects judged by Principal Investigator or Medical Sub-investigator as otherwise
normal and healthy during a pre-study medical evaluation including physical
examination, vital signs (respiration rate, blood pressure, temperature, and heart rate),
within normal limits or not clinically significant laboratory results for serum
chemistries, hematology and urinalysis.
- Negative Hepatitis B, Hepatitis C, and HIV test
- Negative urine drugs of abuse screen
- Normal or not clinically significant electrocardiogram (EKG/ECG).

E.4

Principal exclusion criteria

1. Institutionalized subjects will not be used.
2. History of drug and/or alcohol abuse.
3. Women who are pregnant, lactating, or planning to become pregnant during the
study period.ALT (SGPT) and AST (SGOT) values higher than 3.0 times the upper limit of normal.
4. Social Habits:
a. Alcohol consumption greater than 15 units of alcohol per week with 1 unit equivalent to 12 oz of beer (350 mL), 4 oz of wine (120 mL), or 1.5 oz (45mL) of 80 proof (40% alcohol) distilled spirits,
b. Caffeine ingestion greater than 5 cups (180 mL/cup) of coffee or its equivalent of caffeine- or xanthine-containing foods or beverages per day.
c. Ingestion of any vitamin or herbal supplement known to induce or inhibit hepatic enzyme activity within 7 days prior to the initial dose of study medication. (see Sec 18. Hepatic Enzyme Inducers and Inhibitors List).
d. Any recent, significant change in dietary or exercise habits.
5. Medications:
a. All concomitant medications will be documented. Individuals receiving
medications with clinically significant drug-drug interactions with diclofenac
or other non-steroidal anti-inflammatory drugs (NSAIDs) will be excluded
unless the drug can be safely discontinued.
b. Use of anticoagulants, ACE-inhibitors, cyclosporine, tacrolimus, sirolimus, diuretics, lithium, methotrexate within 30 days prior to the first dose of study medication. Stable doses of ACE-inhibitors and diuretics will be allowed if taken for at least 3 months prior to enrollment and maintained throughout the study.
c. Use of intra-articular hyaluronic acid injections with in 6 months of study start.
d. Use of pain medication (e.g. NSAIDs, opioids, muscle relaxants) within the last 7 days prior to the first dose of study medication.
e. Use of acetaminophen (paracetamol) during the 24 hours prior to the
randomization visit.
f. Use of aspirin (acetylsalicylic acid) therapy other than a stable low dose used for cardiac prophylaxis (≤ 162 mg/day) taken for at least 3 months prior to enrollment and maintained throughout the duration of the study.
g. Use of glucosamine, chondroitin, systemic or topical corticosteroids within 30 days of the first dose of study medication.
h. Diacerein (also known as Diacetylrhein), and ASU (Avocado-Soybean
Unsaponificable) within 30 days of the first dose of study medication.
i. Use of occlusive bandages, ultrasound, transcutaneous electrical stimulation or any alternative therapies such as acupuncture, homeopathy, or mesotherapy for the treatment of osteoarthritis within 7 days of the first dose of study medication.
j. Use of any medication known to induce or inhibit hepatic enzyme activity
within 30 days prior to the first dose of study medication except for those agents expressly allowed. (see Sec 18. Hepatic Enzyme and Inhibitors List).
6. Diseases:
a. History of osteoarthritic (OA) pain in the contralateral knee requiring
medication within 1 year prior to screening.
b. After discontinuing all pain medication for at least 7 days, had a baseline score
of ≥ 20 mm on 0-100 mm Visual Analog Scale (VAS) for POM in the
contralateral knee immediately prior to randomization.
c. History of secondary osteoarthritis (e.g. congenital, traumatic, gouty arthritis),
rheumatoid arthritis, chronic inflammatory disease (e.g. colitis) or
fibromyalgia.
d. History of gastrointestinal bleeding or peptic ulcer disease.
e. X-ray showing evidence of osteoarthritis with Kellgren-Lawrence grade 4 disease.
f. History of any significant or unstable cardiovascular disease, including "sick sinus syndrome" or other supraventricular cardiac conduction disorder, or a history of a known accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine), paroxysmal supraventricular tachycardia, atrial flutter, and recurring symptomatic hypotension.

Due to limited space for exclusion critria, for g.,h., i. and for following 7,8,9,10,11,12,13,14 points please refer to the study protocol.

E.5 End points

E.5.1

Primary end point(s)

The primary bioequivalence endpoint will be the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) pain
score.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit number 6.

E.5.2

Secondary end point(s)

No secondary endpoints have beed established.

E.5.2.1

Timepoint(s) of evaluation of this end point

N/A

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

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

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

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

LPLV

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 months

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:

1200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

400

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

400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1600

F.4.2.2

In the whole clinical trial

1600

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)

Patients will be given standard treatment after completing the study.

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

2012-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-30

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