E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Osteoarthritis of the medial knee joint compartment and/or symptomatic varus deformity. |
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E.1.1.1 | Medical condition in easily understood language |
Errosion of knee cartilage and/or bowleg. |
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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 | 10031300 |
E.1.2 | Term | Osteotomy |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective:
•Evaluate safety and tolerability of a single dose of Osteogrow delivered locally into the osteotomy site
•Evaluate systemic pharmacokinetics (PK) of rhBMP6 after single dose of Osteogrow delivered locally into the osteotomy site
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
•Evaluate bone-healing acceleration effect of a single dose of Osteogrow delivered locally into the osteotomy site.
•Explore relationship between systemic PK and systemic safety/tolerability.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients meeting ALL of the following criteria at screening will be eligible for participation in the study:
1.Willing and able to provide informed consent. A signed informed consent form must be provided before any study assessments are done. Patients must be fluent in the language that is spoken by the investigator and the trial staff and in which the informed consent is written.
2.Male or female, age ≥18 years. Females of childbearing potential must be using a highly effective method of birth control and must have a negative urine pregnancy test prior to the randomization.
3.Symptomatic varus deformity, assigned for unilateral high tibial opening wedge osteotomy (HTO).
4.Patients not receiving platelet aggregation inhibitors at least 5 days prior to surgery.
5.Patients should be otherwise healthy as defined by absence of clinically relevant abnormalities identified by a detailed medical history, full physical examination (including blood pressure and pulse rate measurement), 12-lead ECG, and clinical laboratory tests.
6.Willing and able to be confined to the hospital/inpatient unit for at least 5 days postoperatively and to comply with all other follow-up procedures according to the protocol.
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E.4 | Principal exclusion criteria |
Patients meeting ANY of the following criteria at screening will NOT be eligible for participation in the study:
1.Previous osteotomies of the tibia.
2.Inflammatory and neoplastic diseases of the knee joint.
3.Previous treatment with bone morphogenic proteins (e.g. Ossigraft)
4.Evidence or history of clinically significant hepatic disease (>3 x ULN for AST/ALT and total bilirubin) or other abnormalities in screening laboratory tests, which in the judgment of the investigator, would interfere with the patient’s participation in the study.
5.Presence or history of an uncontrolled, unstable, clinically significant medical condition (bone metabolic, renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, and malignancy) that in the judgment of the investigator may interfere with the interpretation of safety.
6.Other clinically significant systemic diseases.
7.History of symptomatic nephro- or urolithiasis within two years.
8.Diabetes mellitus.
9.Treatment with an investigational drug within 6 months or 5 half-lives (whichever is longer) preceding the first dose of study medication.
10.Screening 12-lead ECG demonstrating at least 1 of the following: Heart rate >100 bpm, QRS >120 msec, QTc > 430 msec (males), QTc >450 msec (females), or PR interval >220 msec.
11.Positive urine pregnancy test.
12.Breastfeeding a child or planning to become pregnant within 6 months.
13.Use within 7 days prior to surgery and postoperative for the duration of the study of the following medications: NSAIDs (paracetamol accepted) and systemic corticosteroids except for dexamethasone for the first 2 days postoperatively.
14.Known serological evidence of human immunodeficiency virus (HIV) antibody,
15.History of hepatitis B infection within the past year or history of non-adequately treated hepatitis C infection.
16.Patient is a known drug or alcohol abuser.
17.Donation of blood in excess of 500 mL within 56 days prior to and 1 month following surgery.
18. Current participation in any other clinical trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety outcomes - Safety will be assessed continuously throughout the trial based on clinical signs, serial vital signs assessments, laboratory assessments and spontaneously reported adverse events. Local safety/tolerability will be specifically assessed by clinical inspection (e.g., signs of inflammation), pain and functional assessment, and radiological assessment with a particular focus on possible soft tissue ossification. Potential antibody formation and dynamics will be evaluated.
PK outcomes - Plasma samples will be assayed using a validated assay system for total rhBMP6 immediately before application (time 0) and then at 15, 30, 45, 60 min and 1.5, 2, 4, 6, 12 and 24 hours post-dose. Urine will be collected cumulatively over the first 24 hours post-dose. Concentrations will be used to calculate PK parameters.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety outcomes: throughout the study
PK outcome: up to 24 hours post dose
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E.5.2 | Secondary end point(s) |
HTO-defect healing acceleration effect will be estimated based on x-ray analysis according to the established radiological scoring system. The bone mineral density, reflecting as well bone formation in the defect area, will be measured on CT scans by ITK-SNAP program (designed and validated at the University of Pennsylvania and University of Utah, 2014). Efficacy outcome will be defined as percentage of defect filled with newly formed bone, based on x-ray analyses of day 1, week 6 and 24, month 12, 18 and 24; and CT assessments performed at weeks 9 and 14 post-surgery.
Relationship between systemic PK and systemic safety/tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bone healing acceleration effect: Up to month 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |