Clinical Trials Register

Summary
EudraCT Number:	2015-003230-26
Sponsor's Protocol Code Number:	MIV-711-201
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-23
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

Bulgarian Drug Agency

A.2

EudraCT number

2015-003230-26

A.3

Full title of the trial

A Randomised, Double-blind Placebo-controlled Phase IIa Study to Evaluate Efficacy, Safety and Tolerability of MIV-711 in Knee Joint Osteoarthritis

A.3.1

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

A study comparing the efficacy, safety and tolerability of two doses of MIV-711 with placebo in patients with knee joint osteoarthritis

A.4.1

Sponsor's protocol code number

MIV-711-201

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	Medivir AB
B.1.3.4	Country	Sweden
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	Medivir AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medivir AB
B.5.2	Functional name of contact point	MIV-711 Clinical Study Information
B.5.3	Address:
B.5.3.1	Street Address	Blasieholmsgatan 2
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	SE-111 48
B.5.3.4	Country	Sweden
B.5.6	E-mail	clinicaloperations@medivir.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	MIV-711(HCl)
D.3.2	Product code	MIV-711, MV076159
D.3.4	Pharmaceutical form	Capsule, hard
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.3.8	INN - Proposed INN	MIV-711
D.3.9.1	CAS number	1657002-22-6
D.3.9.2	Current sponsor code	MIV-711
D.3.9.3	Other descriptive name	MIV-711(HCL), MV076159(HCL), CK 1509
D.3.9.4	EV Substance Code	SUB34470
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	100
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	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	MIV-711(HCl)
D.3.2	Product code	MIV-711, MV076159
D.3.4	Pharmaceutical form	Capsule, hard
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.3.8	INN - Proposed INN	MIV-711
D.3.9.1	CAS number	1657002-22-6
D.3.9.2	Current sponsor code	MIV-711
D.3.9.3	Other descriptive name	MIV-711(HCL), MV076159(HCL), CK 1509
D.3.9.4	EV Substance Code	SUB34470
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	200
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, hard
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

Knee Joint Osteoarthritis

E.1.1.1

Medical condition in easily understood language

Knee Joint Osteoarthritis

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	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

To assess the effect of MIV-711 on target knee average pain over 26 weeks as measured by an 11-point numerical rating scale (1 week recall) in patients with symptomatic and radiographic knee osteoarthritis

E.2.2

Secondary objectives of the trial

To assess the effect of MIV-711 on MRI target knee bone area in patients with symptomatic and radiographic knee OA over 26 weeks
The effect of MIV-11 on:
- worst target knee pain (1 week recall)
- average contralateral knee pain (1 week recall)
- constant and intermittent OA pain
- global improvements in knee problem, knee pain and knee function
- knee joint OA symptoms (function, pain, stiffness)
- global disease activity
- quality of life (QOL)
- MRI bone marrow lesion volume
- MRI cartilage thickness loss
- in the semi quantitative MRI Osteoarthritis Knee Score (MOAKS) parameters
- patient reported e-diary daily recall knee joint pain
- patient reported e-diary daily recall analgesics use
- The safety and tolerability of MIV-711
- biomarkers for bone resorption (serum CTX-I) and for cartilage degradation (urine CTX-II) assessment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Current average knee pain, defined as pain in either knee, within 1 week before Visit 1, for which the patient gives a severity score of ≥4, <10 on a 0-10 NRS.
2. Inclusive of 40-80 years old.
3. Diagnosis of primary knee osteoarthritis, based upon the following:
- Fulfilling the American College of Rheumatology Clinical and Radiographic (ACR) criteria for OA defined as knee pain for most days of the prior month and at least one of the following three factors: age >50 years, morning stiffness of less than 30 minutes and knee crepitus on motion.
- X-ray evidence within the last 12 months for Kellgren and Lawrence (K-L) classification grade 2 or 3.
4. Female patients must be non-pregnant, non-lactating and of non-childbearing potential either as naturally (spontaneously) post-menopausal or due to hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy (as determined by patient medical history). Naturally (spontaneously) post-menopausal is defined as being amenorrhoic for 12 months without an alternative medical cause and with a screening follicle stimulating hormone indicating post-menopausal state.
5. Male patients should avoid fathering a child by either of the following methods:
- True sexual abstinence: meaning that heterosexual abstinence is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence such as that based on calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of a trial, or withdrawal/coitus interruptus are not acceptable methods of contraception).
- Willingness to use two effective means of contraception with their partner from the time of first IMP administration until 3 months after the last dose of IMP. Two or more of the following methods are acceptable and must include at least one barrier method: i) Surgical sterilisation (i.e., bilateral tubal ligation for female partners; vasectomy for male), ii) placement of an intrauterine device or intrauterine system, iii) hormonal contraception (implantable, patch, oral), iv) barrier methods including condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Male patients who have been sterilised are required to use one barrier method of contraception (condom).
6. The patient’s usual analgesic regimen (in case of use) should remain the same for 4 weeks prior to the signature of the informed consent form.
7. Needs to be able to communicate well with the investigators and staff.
8. Able to comply with the requirements of the study procedures and provide written informed consent prior to any study related procedures.

E.4

Principal exclusion criteria

1. The presence of any inflammatory arthritis (e.g., gout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, seronegative spondylarthropathy) or any underlying condition, other than OA, that may result in abnormal cartilage and bone metabolism.
2. Any generalised pain condition that may interfere with the evaluation of the target knee pain (e.g., fibromyalgia) as judged by the investigator.
3. A history of cancer within the previous 5 years (except for cutaneous basal-cell or squamous-cell cancer resolved by excision and cancer in situ which are allowed).
4. Ongoing or a history of atrial fibrillation.
5. Currently receiving medication that affects cartilage or bone metabolism (hormone replacement therapy taken for more than 6 months is allowed).
6. Current or recurrent disease that could affect the action, absorption or disposition of MIV-711, or could affect clinical assessments or clinical laboratory assessments.
7. Any clinically severe or significant uncontrolled concurrent illness, which, in the opinion of the Investigator, would impair ability to give informed consent or take part in or complete this clinical study.
8. Known or suspected intolerance or hypersensitivity to the investigational product, closely related compounds, or any of the stated ingredients.
9. A positive human immunodeficiency virus (HIV) antibody screen, a positive Hepatitis B surface antigen (HBsAg) screen, and/ or a positive Hepatitis C virus (HCV) antibody screen. A positive anti-HBc test in conjunction with a negative anti-HBs test.
10. History of alcohol or other substance abuse within the last year.
11. Use of an investigational product within 30 days prior to receiving the first dose of investigational product or active enrolment in another drug or vaccine clinical study.
12. Significant target knee injury or surgery within the 6 months preceding enrolment in the study.
13. A history of partial or complete joint replacement surgery in the target knee at any time, listed for knee surgery, or anticipating knee surgery during the study period.
14. Any factor which, in the opinion of the investigator, would jeopardise the evaluation or safety of the patient or be associated with poor adherence to the clinical study protocol (e.g., inability to complete study diary, poor tolerability of venipuncture or lack of adequate venous access for required blood sampling during the study period).
15. Use of intra-articular hyaluronic acid in the target knee within the 3 months preceding enrolment in the study.
16. Use of intra-articular, intra-muscular or oral corticosteroids in the 2 months preceding enrolment.
17. Commencement of non-pharmacological OA interventions within two months preceding enrolment.
18. Vulnerable patients, e.g., patients kept in detention, soldiers, and employees of the sponsor or the contract Research Organisation (CRO) with direct involvement in the proposed study or other studies under the direction of the investigator or the CRO, as well as family members of the employees or the investigator.
19. Patients with contra-indication to MRI of the knee.

E.5 End points

E.5.1

Primary end point(s)

Change from visit 2 (baseline) to visit 8 in NRS average target knee pain score

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout the study

E.5.2

Secondary end point(s)

Efficacy endpoint:
- Change from visit 2 (baseline) to visit 8 in knee joint MRI bone area
- Change from visit 2 (baseline) to visit 8 in NRS worst target knee pain score
- Change from visit 2 (baseline) to visit 8 in NRS average contralateral knee pain score
- Change from visit 2 (baseline) to visit 8 in constant and intermittent OA pain
- Change from visit 2 (baseline) to visit 8 in knee joint OA symptoms; WOMAC (function, pain, stiffness)
- Change from visit 2 (baseline) to visit 8 in global disease activity
- Change from visit 2 (baseline) to visit 8 in global improvements in knee problem, knee pain and knee function
- Change from visit 2 (baseline) to visit 8 in quality of life (QOL)
- Change from visit 2 (baseline) to visit 8 in MRI bone marrow lesion volume
- Change from visit 2 (baseline) to visit 8 in MRI cartilage thickness loss
- Change from visit 2 (baseline) to visit 8 in the semi quantitative MRI Osteoarthritis Knee Score (MOAKS) parameters
- Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall knee joint pain
- Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall analgesics use
- Changes from visit 2 (baseline) to visit 8 in serum biomarkers C-terminal telopeptide of collagen type I (sCTX-I for bone resorption assessment) and urinary C-terminal telopeptide of collagen type II (uCTX-II for cartilage degradation assessment)
Safety endpoints:
- Incidence and severity of adverse events
- Incidence and severity of clinical laboratory abnormalities
- Summary of changes in physical examination compared to baseline by patient
- Mean change from visit 2 (baseline) in vital signs (blood pressure, heart rate and temperature)
- Categorical summary of absolute vital signs and vital sign changes compared to visit 2 (baseline) by patient

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the study

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

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

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

Bulgaria

Georgia

Germany

Moldova, Republic of

Romania

United Kingdom

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

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

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:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

105

F.4.2.2

In the whole clinical trial

240

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)

Standard of care

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

2016-01-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-23

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