Clinical Trials Register

Summary
EudraCT Number:	2011-002768-25
Sponsor's Protocol Code Number:	191622-102
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-11-07
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

Denmark - DHMA

A.2

EudraCT number

2011-002768-25

A.3

Full title of the trial

A Single Center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex as Treatment for Osteoarthritis Knee Pain

A.3.1

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

Study of BOTOX® in the treatment of Osteoarthritis Knee Pain

A.3.2

Name or abbreviated title of the trial where available

Study of BOTOX® in the treatment of Osteoarthritis Knee Pain

A.4.1

Sponsor's protocol code number

191622-102

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	Allergan Limited
B.1.3.4	Country	United Kingdom
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	Allergan Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Allergan Limited
B.5.2	Functional name of contact point	Allergan Ltd, EU Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Marlow International, Parkway
B.5.3.2	Town/ city	Marlow, Buckinghamshire
B.5.3.3	Post code	SL6 1YL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441628494444
B.5.5	Fax number	+441628494449
B.5.6	E-mail	ml-eu_reg_affairs@allergan.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	Yes
D.2.1.1.1	Trade name	BOTOX®
D.2.1.1.2	Name of the Marketing Authorisation holder	Allergan Pharmaceuticals Ireland
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	BOTOX®
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BOTULINUM TOXIN TYPE A
D.3.9.1	CAS number	93384-43-1
D.3.9.2	Current sponsor code	AGN 191622
D.3.9.3	Other descriptive name	Botox purified neurotoxin complex
D.3.9.4	EV Substance Code	SUB13117MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200 to Allergan Units
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	Yes
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	Powder for solution for injection
D.8.4	Route of administration of the placebo	Intraarticular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of Osteoarthritis Knee Pain

E.1.1.1

Medical condition in easily understood language

Treatment of Osteoarthritis Knee Pain

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10031165
E.1.2	Term	Osteoarthritis knee
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 of this study is to evaluate the efficacy and safety of a single IA injection of BOTOX (200 U) compared with placebo as treatment for OA knee pain.

E.2.2

Secondary objectives of the trial

Secondary objectives are to explore the efficacy of a single IA injection of BOTOX (200 U) compared with placebo on OA knee pain in patients with different pain phenotypes and/or different knee synovial effusion neurotransmitter/biomarker concentration profiles.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, 40 to 75 years of age on the day of randomization (day 1).
2. Written informed consent and data protection consent has been obtained prior to initiating any study specific procedures.
3. Primary idiopathic knee OA diagnosed in accordance with the ACR modified clinical classification criteria (Altman et al, 1986; Altman 1991) and verified radiologically as Kellgren-Lawrence grade I, II or III (Kellgren and Lawrence, 1957).
4. For the study knee, the average daily worst pain score over the 14 days prior to day 1 (ie, days -14 to day -1) must be 4.0 to 9.0. The 14-day average score will be derived from daily worst pain scores recorded in a diary for the study knee.
5. Stable knee pain in the study knee for ≥ 6 consecutive months prior to visit 1. No evidence of abnormal mechanical symptoms such as locking or catching of the study knee per medical history or physical examination.
6. Body weight ≥ 40 kg and ≤ 150 kg with a body mass index (BMI) of 19 to ≤ 40 kg/m2 inclusive.
7. For females of childbearing potential, a negative urine pregnancy test at screening, baseline, and on the day of the treatment (prior to the administration of the study medication) is required.
8. Must be ambulatory without assistive walking devices, able to perform usual daily activities, and agree to maintain the similar activity level throughout the course of the study.
9. Ability to follow study instructions and likely to complete all required visits.
10. Stable medical condition, in the investigator’s opinion.

E.4

Principal exclusion criteria

1. Patient diagnosed with any condition suggestive of a secondary cause of knee OA including but not limited to knee trauma, articular fracture, major dysplasias or congenital abnormality, acromegaly, ochronosis, hemochromatosis, Wilson’s disease,or primary osteochondromatosis.
2. History of or current evidence of rheumatoid arthritis as diagnosed by ACR criteria, or history of prior synovial fluid analysis of the study knee showing a white blood cell count ≥2000 mm3 that is indicative of a diagnosis other than OA.
3. Presence of bursitis or tear of meniscus or ligament of the study knee, or history of significant knee injury to the study knee within 1 year of visit 1.
4. History of surgery in the study knee within 24 weeks prior to visit 1, or already planned surgery of the study knee such as, arthroplasty, arthroscopy inspection, or repair of knee ligaments.
5. Treatment with IA hyaluronic acid in the study knee within 24 weeks prior to visit 1.
6. Treatment with IA corticosteroid in any joint or intramuscular corticosteroid administration within 12 weeks prior to visit 1.
7. Concurrent chronic pain conditions such as back pain, hip pain (eg, disc herniation, peripheral nerve entrapment, multiple sclerosis), fibromyalgia that may interfere with assessment of the study knee. The study knee pain should be the predominant pain.
8. History or current diagnosis of gout or pseudogout with knee involvement.
9. History or current diagnosis of Reiter’s, Sjögren’s syndrome, psoriasis or systemic lupus erythematosus or other autoimmune diseases with joint involvement.
10. Patients at a high risk of joint infection complication (eg, infection of local skin, soft tissue and joint in the study knee, indwelling urinary catheter) or have immunocompromised conditions (eg, known HIV or organ transplant).
11. Evidence of abnormal coagulation status (eg, excessive tooth bleeding with brushing, abnormal bleeding time, partial thromboplastin time or prothrombin time) or patients with hemophilia or other blood diseases affecting coagulation (eg, aplastic anemia, leukemia, or under chemo-/radio-therapy).
12. Patients continue to take excluded analgesic medications after visit 2.
13. Patients with contraindications to the use of paracetamol (ie, rescue medication for this study).
14. History of severe, progressive, or current unstable medical conditions other than OA such as renal, hepatic, gastrointestinal, neurological, endocrine, metabolic, degenerative bone disorders, respiratory, and/or psychiatric disorder as determined by medical history, physical examination and /or laboratory tests.
15. History of severe cardiovascular diseases, stroke, recurrent seizures, frequent or severe allergic reactions to multiple medications.
16. Electrocardiogram (ECG) abnormality at screening that in the opinion of the investigator could increase risk associated with participation in the study.
17. Patients with an active malignancy of any type or a history of malignancy within the last 5 years (except basal cell carcinoma of the skin that has been excised at least 12 weeks prior to study start).
18. Have a history of substance abuse or dependence within the past year, excluding nicotine and caffeine.
19. Patient Health Questionnaire-9 (PHQ-9) score of >15 or a score of > 0 on item #9 of the PHQ-9 at week -4.
20. Known allergy or sensitivity to the study medication(s) or its components.
21. Females who are pregnant, nursing, or planning a pregnancy during the study period.
22. Females of childbearing potential, not using a reliable means of contraception (See protocol Section 4.5.1.1 for definition of acceptable methods of contraception).
23. Current enrollment in an investigational drug or device study or participation in such a study within 30 days prior to entry into this study.
24. Any medical or neurological condition that may put the patient at increased risk with exposure to BOTOX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, concomitant use of aminoglycosides, or any other significant diseases that might interfere with neuromuscular function.
25. Previous treatment with botulinum toxin of any serotype for any reason or immunization to any botulinum toxin serotype.

Too see full list of exclusion criteria see current Protocol.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline:
Daily worst pain score (11-point [0 to 10] NRS; 0 = no pain, 10 = worst pain possible) for the
study knee

E.5.1.1

Timepoint(s) of evaluation of this end point

4, 8 and 12 weeks post injection

E.5.2

Secondary end point(s)

Change from baseline:
• WOMAC Osteoarthritis Index NRS3.1:
o WOMAC Total Index Score (0-240 scale)
o WOMAC Pain Score (0-50 scale)
o WOMAC Physical Function (difficulty performing daily activities) Score (0-170 scale)

• Patient Global Impression of Change (Patient-GIC)
The Patient-GIC is a questionnaire used by the patient to provide a global impression of change in their health status since enrollment, whether or not in the patient’s judgment a change is related to the study treatment. The Patient-GIC is useful in assessing whether the impact of the study treatment is meaningful enough to have value to the patient (Turk et al, 2003). A 7-point scale with +3 equaling very much improved and -3 equaling very much worse will be used for scoring purposes (Guy and Bonato, 1976). The Patient-GIC and other global impression questionnaires have a long history of use across a number of therapeutic areas and chronic pain indications (Farrar et al, 2001).
Patient-GIC instructions: Since you enrolled into this study, how much have you changed? Please rate your total change whether or not, in your judgment, it is entirely due to the study treatment.
Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 4, 8 and 12 weeks post injection

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

Yes

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

120

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 return to previous treatment options

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

2011-11-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-24

P. End of Trial
P.	End of Trial Status	Completed

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