E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
A disease characterized by deterioration of cartilage and its underlying bone within a joint. |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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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 |
To evaluate structural changes in cartilage thickness in the total femorotibial joint of the target knee in terms of imaging by magnetic resonance imaging (MRI) |
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E.2.2 | Secondary objectives of the trial |
* To evaluate different dose regimens of sprifermin * To evaluate changes in symptoms of osteoarthritis (OA) * To evaluate changes in structure in terms of imaging by X-ray * To evaluate other changes in cartilage morphology in terms of imaging by MRI (sub-regions) * To evaluate changes in physical functioning * To evaluate the safety of sprifermin * To evaluate the pharmacokinetics (PK) of sprifermin in serum and in synovial fluid following i.a. injection |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The trial will enroll adult subjects of either sex with primary femorotibial osteoarthritis according to American College of Rheumatology (ACR) clinical and radiographic criteria who have Kellgren-Lawrence grades of 2 or 3 and a minimum joint space width (JSW) of ≥ 2.5 mm in the medial compartment.
Subjects must have pain in the target knee on most days and/or require symptomatic treatment of knee pain with paracetamol (acetaminophen), systemic non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 selective inhibitor (coxibs), or tramadol on most days of the previous month, and must have both: * A history of pain due to OA in the target knee for at least 6 months, and * Pain score for the target knee of 4 to 9 points in response to Question 1 of the WOMAC pain index(“how much pain have you had [in the target knee, over the past 48 hours] when walking on a flat surface?”) at screening and baseline, after washout of at least 5-half-lives of analgesic medication(s): acetaminophen, topical or oral systemic NSAIDS, coxibs, opioids, and/or tramadol.
Women of childbearing potential must use a form of contraception with a failure rate of less than 1% per year throughout the trial. |
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E.4 | Principal exclusion criteria |
Main exclusion criteria are malalignment of > 5 degrees in the femorotibial axis of the target knee, clinical signs of inflammation (i.e., redness) in the target knee, i.a. administration of corticosteroids or hyaluronic acid into either knee within 6 months before screening, any plan for knee surgery (affecting either the target or the contralateral knee) within the next two years, concomitant conditions or treatments deemed to be incompatible with trial participation, contraindications to MRI scanning (including inability to fit in the scanner or knee coil), pregnancy or breastfeeding, participation in another clinical trial within the past 30 days, and legal incapacity or limited legal capacity. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in cartilage thickness in the total femorotibial joint as evaluated by MRI at 2 years |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are: * Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and stiffness index scores over 2 years * Change from baseline in the 20-meter walk test over 2 years * Change from baseline in the PGA over 2 years * Change from baseline in minimal joint space width in the medial and lateral compartments as evaluated by X-ray over 2 years * Change from baseline in cartilage thickness in the medial and lateral compartments as well as in the total femorotibial joint over 2 years * Change from baseline in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint over 2 years * Synovial fluid levels of sprifermin/FGF-18 * Serum levels of sprifermin/FGF-18
Safety endpoints are: * Nature, incidence and severity of local and systemic AEs * Incidence of acute inflammatory reactions (AIRs), defined as increase of pain by 30 mm on a 100 mm visual analogue scale (VAS) and a self-reported synovial fluid effusion (i.e., joint swelling) within 3 days following i.a. injection * Changes in laboratory safety parameters, vital signs, 12-lead electrocardiogram (ECG) parameters, weight, and physical examinations * Incidence of surgical interventions in the target knee (including any surgical revision, cartilage removal, or any other type of surgical intervention). * Occurrence of binding and neutralizing antibodies to sprifermin/FGF-18 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DBPC phase: * Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and stiffness: over 2 years * Change from baseline in the 20-meter walk test: over 2 years * Change from baseline in the PGA: over 2 years * Change from baseline in minimal joint space width in the medial and lateral compartments as by X-ray: over 2 years * Change from baseline in cartilage thickness in the medial and lateral compartments: over 2 years * Change from baseline in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint: over 2 years * Synovial fluid levels of sprifermin/FGF-18: at W0, W1, W2, W26, W27 and W28 * PK Serum collection: W0, W2 and W28 * AEs: Continuous |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
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 | Yes |
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 | 5 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | No |
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 |
Denmark |
Romania |
Argentina |
Czech Republic |
Estonia |
Hong Kong |
Poland |
United States |
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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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For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock at the end of the extended follow-up phase. This provides for a single and conservative definition across all trial sites. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 1 |