Clinical Trials Register

Summary
EudraCT Number:	2017-001185-20
Sponsor's Protocol Code Number:	167700-005CL
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-10-18
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

UK - MHRA

A.2

EudraCT number

2017-001185-20

A.3

Full title of the trial

A Randomized, Double Dummy, Parallel Arm, Placebo and Active Controlled, Double Blind, Study of the Safety and Efficacy of PRX167700 as Monotherapy in Adults with Moderate to Severe Knee Pain Due to Osteoarthritis who are Inappropriate for Oral Non steroidal Anti inflammatory Therapy.

A.3.1

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

A a study to assess the safety and efficacy of PRX167700 compared to placebo in patients with Moderate to Severe Knee Pain Due to Osteoarthritis who cannot be treated with oral non steroidal anti inflammatory therapy.

A.4.1

Sponsor's protocol code number

167700-005CL

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	Proximagen 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	Proximagen 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	Proximagen Limited
B.5.2	Functional name of contact point	not applicable
B.5.3	Address:
B.5.3.1	Street Address	Minerva Building 250, Babraham Research Campus
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB22 3AT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441223497300
B.5.5	Fax number	441223839521
B.5.6	E-mail	maeve.duffy@proximagen.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	PRX167700
D.3.4	Pharmaceutical form	Film-coated tablet
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	PRX167700
D.3.9.3	Other descriptive name	PRX167700
D.3.9.4	EV Substance Code	SUB36484
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	400
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	Tramadol HCL
D.2.1.1.2	Name of the Marketing Authorisation holder	Amneal Pharmaceuticals
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	Tramadol
D.3.4	Pharmaceutical form	Capsule
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	TRAMADOL HCL
D.3.9.1	CAS number	27203-92-5
D.3.9.3	Other descriptive name	TRAMADOL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04927MIG
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	50
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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 Knee Pain Due to Osteoarthritis in subjects who are Inappropriate for Oral Non steroidal Anti inflammatory Therapy

E.1.1.1

Medical condition in easily understood language

Knee Pain Due to Osteoarthritis

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10031161
E.1.2	Term	Osteoarthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10024776
E.1.2	Term	Localised osteoarthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10031166
E.1.2	Term	Osteoarthritis knees
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

E.2.2

Secondary objectives of the trial

To assess the safety of 6 weeks of PRX167700 treatment.
To assess additional measures of efficacy of PRX167700 treatment, versus placebo, at Day 42.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Participants who have symptomatic primary knee OA for at least 3 months prior to Screening. Participants must have had pain in the target knee for ≥ 14 days per month in the 3 months preceding screening.
2. A diagnosis of knee OA based on American College of Rheumatology criteria with X ray confirmation (a Kellgren Lawrence X ray grade 2 or 3) in the target joint. The investigator is allowed to grade the x-ray if Kellgren-Lawrence grading is not provided in the original interpretation.
One knee should be designated as the target joint. The pain in the target knee joint should exceed the pain experienced in other joints (including the contralateral knee joint and/or ipsilateral hip joint) and pain experienced from any concomitant medical condition.
3. Participants must be deemed inappropriate for oral NSAID therapy by their physician. Acceptable reasons for considering a participant inappropriate for oral NSAIDs include, but are not limited to, history of GI bleeding or GI intolerance of oral NSAIDs despite proton pump inhibitor treatment; inflammatory bowel disease; diverticular disease;hepatic or mild renal dysfunction; anticoagulation; presence of cardiovascular risk factors or disease; history of increased blood pressure with oral NSAID use; or asthma.
4. A moderate to severe pain score of ≥ 8 and ≤ 16 in the target knee joint evaluated by the WOMAC Pain Score at the Screening Visit (Visit 1), start of the single blind Placebo Run in (Visit 2), and at Baseline (Visit 3, Day 0).
5. The same or worse pain at Baseline (Visit 3, Day 0) compared to their WOMAC Pain Score at the start of the single blind Placebo Run in (Visit 2).
6. Body Mass Index (BMI) between 18 and 40 kg/m2, inclusive.
7. Male or female participants between 50 and 75 years of age, inclusive.
8. Female participants are eligible to participate in the study if they meet one of the following criteria:
a.They are not of child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is postmenopausal as defined in Appendix 5)
b.They are of child bearing potential, are not pregnant or lactating, are sexually active, and have a negative pregnancy test at Screening (Visit 1, serum test from central lab), Visit 2 (urine dipstick method in the clinic), and Baseline (Visit 3, urine dipstick method in the clinic). WOCBP who are sexually active must agree to use a highly effective contraception method during the study. A highly effective contraception method is defined as:
i.Established use of oral, injected or implanted hormonal methods of contraception.
ii.Placement of an intrauterine device (IUD) or intrauterine system (IUS).
iii.Sole male partner is vasectomized.
iv.Bilateral tubal occlusion.
c.They are of childbearing potential, are not pregnant or lactating, are sexually abstinent, and have a negative pregnancy test at Screening (Visit 1, serum test from central lab), Visit 2 (urine dipstick method in the clinic), and Baseline (Visit 3, urine dipstick method in the clinic). WOCBP who are sexually abstinent at the start of the study must agree to remain abstinent for the duration of the study.
9. Able to provide written informed consent to participate in the study and, in the opinion of the investigator, able to read, comprehend and record information as required by the protocol.
10. Participants who have been on a stable dose of analgesic therapy with agents other than the following for 30 days prior to screening:
a.Tramadol at a total daily dose of > 150 mg
b.Other opioids at any dose for more than 4 days per week
See exclusion criteria 24 to 35 for additional information on excluded concomitant medications.
11. Participants must be willing and able to discontinue all current analgesic therapy for a period beginning at Screening (Visit 2) and continuing for the entire duration of the study.

E.4

Principal exclusion criteria

1. Causes of secondary knee arthritis, including septic arthritis, autoimmune joint disease, crystalline diseases, gout, articular fracture, and inherited disorders.
2. Pain relating to the target joint that has characteristics of neuropathic pain (eg, shooting or burning pain, pins and needles, allodynia and reflex sympathetic dystrophy).
3. Disease of the spine or of lower extremity joints (other than OA) which contribute to the pain the target joint.
4. Lower extremity surgery (including arthroscopy) within 6 months prior to Screening (Visit 1) or scheduled for surgery of any kind during the study.
5. Significant injury to the target joint within 12 months prior to Screening (Visit 1).
6. Use of a handicap assistance device (ie, cane, walker) > 50% of the time.
7. Active autoimmune disease or conditions requiring chronic immunosuppressive therapy, including as rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, organ transplant recipient.
8. Participants with epilepsy, those with a history of seizures (with the exception of febrile childhood seizures) and participants with a recognized risk for seizure.
9. Drug or alcohol abuse or dependence in the past 10 years.
10. Participants at risk of suicide in the assessment of the investigator, including those who disclose any suicidal behavior or suicide attempt in the year prior to screening.
11. Participants who suffer from emotional disturbance or depression as judged by the investigator at screening.
12. Known history of hypersensitivity or intolerance to paracetamol, tramadol or opioids, or a history of anaphylactic reactions to codeine or other opioids.
13. Participants at risk of respiratory depression, or any other situation where opioids are contraindicated.
14. Clinically significant illness other than OA within 3 months prior to Screening (Visit 1) which might interfere with the conduct of the trial.
15. History of malignancy within past 5 years (except for basal cell carcinoma or carcinoma in situ of the cervix treated with curative intent).
16. A personal or family history of long QTc syndrome, sudden cardiac death or known mutations of the Human Ether à go go Related Gene (hERG) channel or any other significant cardiovascular disease.
17. Poorly controlled hypertension at Screening (Visit 1), defined as systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg after 5 minutes rest in the supine position.
18. Presence of congestive heart failure (New York Heart Association Functional Classification, Class III-IV, inclusive).
19. Substantial renal dysfunction, defined as creatinine clearance < 60 mL/min; calculated by the Cockroft Gault method.
20. Clinically significant known infections including human immunodeficiency virus (HIV) infection.
21.Chronic liver disease.
22.Pregnant or breastfeeding.
23.Participants with any active medical condition or previous major abdominal surgery or procedure that might, in the investigator’s opinion, have a significant effect on drug absorption, distribution, metabolism, or excretion.
24.Participants who have failed prior therapy with oral NSAIDs due to lack of efficacy.
25.Use of tramadol at doses greater than 150 mg/day or other opioid analgesics at any dose for more than 4 days a week in the 30 days preceding screening (Visit 1).
26.Use of moderate or strong CYP3A4 or CYP2D6 inhibitors within 5 half lives prior to Visit 3.
27. Need for concomitant use of serotonergic drugs including SSRIs, SNRIs, TCAs and other tricyclic compounds , MAOIs, triptans, linezolid, lithium, or St John’s Wort
28.Need for concomitant use of carbamazepine, neuroleptics or other drugs that reduce the seizure threshold.
29.For 14 days prior to first dose of study treatment, administration of any agent with high risk to prolong the QTc interval or to cause Torsades de Pointes (TdP) (see protocol Appendix 8).
30. Corticosteroid injections before Screening (Visit 1)
31.Other therapeutic injections into the target joint within previous 3 months.
32.Systemic corticosteroids within 1 month of Screening (Visit 1).
33.Use of any anti inflammatory biological therapy within 12 months prior to Screening (Visit 1).
34.Start or change in dosing regimen of other therapies for OA within 3 months of Screening (Visit 1); including but not limited to chondroitin or keratin sulphate, glucosamine, non specific rubefacients, and nutraceutical products.
35.Start or change in an established physiotherapy program within 2 weeks of Screening (Visit 1).
36.Receipt of an investigational product within 30 days or 5 half lives or twice the duration of the biological effect of the IMP, whichever is the longer, prior to Screening (Visit 1).
37.QTcF ≥ 450 msec for males and ≥ 470 msec for females based on an average QTcF value of triplicate ECGs evaluated via a central reading facility at Screening.

E.5 End points

E.5.1

Primary end point(s)

To assess the effect of 6 weeks of PRX167700 treatment, as monotherapy, on the WOMAC Pain Score in participants with moderate to severe knee pain due to OA who are inappropriate for oral NSAID therapy, assessed by WOMAC Pain Score change from Baseline (Day 0) to End of Treatment (Day 42) in participants treated with PRX167700 versus placebo

E.5.1.1

Timepoint(s) of evaluation of this end point

at every visit

E.5.2

Secondary end point(s)

• Incidence and severity of treatment emergent adverse events (TEAEs) throughout the dosing period
• Incidence of TEAEs leading to withdrawal
• Change in physical examination findings at each visit
• Incidence of clinically significant changes on triplicate 12 lead electrocardiograms (ECGs) at each visit
• Incidence and severity of treatment emergent changes in laboratory values at each visit
• Change from Baseline in vital signs at each visit
• Change from Baseline to Day 42 in the WOMAC Total Score
• Change from Baseline to Day 42 in the WOMAC Stiffness Score
• Change from Baseline to Day 42 in the WOMAC Function Score
• Change from Baseline to Day 42 in the Patient Global Assessment (PGA)
• Clinical Global Impression of Change (CGI C) at Day 42
• Proportion of participants with a response at Day 42 as defined by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trial Response Criteria Initiative (OMERACT OARSI) Response Criteria
• Proportion of participants with a reduction in the WOMAC Pain Score of ≥ 50% at Day 42
• Withdrawal for lack of efficacy

E.5.2.1

Timepoint(s) of evaluation of this end point

at every visit

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Double-Dummy

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

Australia

New Zealand

United Kingdom

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

The end of the study is defined as the date of the last visit of the last participant in the study.

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