A Multicenter Trial of Sprifermin (AS902330 [Recombinant Human Fibroblast Growth Factor-18]) or Placebo After Microfracture Surgery for Cartilage Injury of the Knee

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, double-blind, multicenter, randomized, placebo-controlled trial to evaluate the efficacy and safety of Sprifermin (AS902330) (recombinant human fibroblast growth factor-18 [rhFGF-18]) as an adjunct treatment to subjects following microfracture (MFx) surgery for cartilage injury of the knee. Primary Objectives To evaluate the effect of Sprifermin (AS902330) intra-articular knee injections as adjunct to microfracture (MFx) surgery on the composition of the refilled cartilage in the target knee, as measured by gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) time constant 1 (T1) relaxation time at 6 months after MFx surgery To evaluate the safety profile of Sprifermin (AS902330) when administered intra-articular into the knee as adjunct to MFx surgery in subjects with cartilage injury of the knee Secondary Objectives To further support the efficacy and safety of Sprifermin (AS902330) as an adjunct to MFx for cartilage injury repair through symptomatic outcomes and quantitative MRI measurement

Official Title
-----------------
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase II Trial to Investigate the Efficacy and Safety of 30 mcg and 100 mcg AS902330 Given as One Cycle of Three Intra-articular Knee Injections Once a Week for Three Weeks as an Adjunct Treatment to Patients Following Microfracture Surgery for Cartilage Injury of the Knee.

Conditions
-----------------
Cartilage Injury of Knee

Intervention / Treatment
-----------------
* Drug: Sprifermin (AS902330)
* Drug: Sprifermin (AS902330)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with candidature for MFx surgery on the femoral articular surfaces (medial or lateral condyles or trochlear groove), with intact subchondral bone Subjects with moderate to severe pain in the target knee prior to surgery; average score greater than equal to (>=) 4.0 over 7 consecutive days on numeric rating scale of pain intensity (completed within 30 [+15] days before surgery) Intraoperative inclusion criteria: Subjects with 1 or 2 focal chondral lesions per target knee, where peripheral debridement to healthy cartilage results in all of the following: Each lesion has an area of >= 1 square centimeter (cm^2) and less than equal to (<=) 4 cm^2 Each lesion is <= 6 millimeter (mm) in depth, as measured from the surrounding subchondral plate Arthroscopic confirmation that each non-osteochondritis dissecans (OCD) lesion is between International Cartilage Repair Society (ICRS) Grades I and III (D); a Grade III non-OCD lesion is equivalent to an Outerbridge Grade IV lesion with minimal subchondral bone loss Other protocol-defined inclusion criteria could apply Exclusion Criteria: Subjects with prior marrow stimulation treatment of the target knee, that is, MFx, micro-drilling, abrasion chondroplasty or cartilage repair including, but not limited to, autologous chondrocyte implantation (ACI), matrix/membrane autologous chondrocyte implantation (MACI), or osteochondral transplantation (autologous or allogeneic) Subjects with body mass index (BMI) of greater than 35 kilogram per square meter (kg/m^2) at screening Malalignment of the target knee greater than 5 degrees as measured from the mechanical axis, as confirmed by alignment (long bone) X-ray images Subjects with clinical and/or radiographic disease diagnosis of the target knee joint including, but not limited to the following: generalized osteoarthritis (OA), rheumatoid arthritis, or avascular necrosis Subjects who have any contraindication to MRI or gadolinium-based or iodinated contrast agents according to the site's standard practice guidelines Other protocol-defined exclusion criteria could apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sprifermin (AS902330), 30 mcg<br> | Drug: Sprifermin (AS902330)<br>* Sprifermin (AS902330) will be administered at a dose of 30 microgram (mcg) as intra-articular injection once every week for 3 weeks, starting from 2 weeks after MFx surgery.<br>|
| Experimental: Sprifermin (AS902330), 100 mcg<br> | Drug: Sprifermin (AS902330)<br>* Sprifermin (AS902330) will be administered at a dose of 100 mcg as intra-articular injection once every week for 3 weeks, starting from 2 weeks after MFx surgery.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo matched to Sprifermin (AS902330) will be administered as intra-articular injection once every week for 3 weeks, starting from 2 weeks after MFx surgery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composition of the Refilled Cartilage Measured by Delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) Using T1 Relaxation Time at Month 6 Post-MFx Surgery | The dGEMRIC is an imaging technique that estimates the proteoglycan (and glycosaminoglycan) content of joint cartilage using spin-lattice relaxation time T1 after penetration of gadolinium contrast agent. Composition of the refilled cartilage was to be reported. | 6 months post-MFx surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composition of the Refilled Cartilage Measured by dGEMRIC Using T1 Relaxation Time Beyond Month 6 Post-MFx Surgery | The dGEMRIC is an imaging technique that estimates the proteoglycan (and glycosaminoglycan) content of joint cartilage using spin-lattice relaxation time T1 after penetration of gadolinium contrast agent. Composition of the refilled cartilage was to be reported. | Every 6 months up to 5 years beyond 6 months post-MFx surgery | 
| Change From Baseline in Participant-reported Outcome Measure: Knee Injury and Osteoarthritis Outcome Score (KOOS) Sub-scores for Pain and Activities of Daily Living (ADL) | The KOOS Version LK1.0 is a knee-specific self-administered questionnaire used to assess pain, function, quality of life, and ADL. It consists of 42 items grouped into 5 subscales: pain, other symptoms (including swelling, restricted range of motion, and mechanical symptoms), function in ADL, function in sport and recreation (FSR), and impact on quality of life (QOL) (knee-related QOL, including awareness of the knee condition and changes in lifestyle). The subscales are scored separately; each yields a score between 0 and 100, with 0 representing extreme knee problems and 100 representing absence of problems. Total KOOS score is the average of all 5 subscale scores; ranging from 0 to 100; where 0 represents extreme knee problems and 100 represents absence of knee problems. Change from baseline in pain and ADL sub-scores was to be calculated by the respective scores at the specific time point minus the scores at baseline. | Every 6 months up to 5 years | 
| Change From Baseline in Participant-reported Outcome Measure: Total KOOS Score, Three KOOS Sub-scores and Total KOOS Minus FSR Sub-score | The KOOS Version LK1.0 is a knee-specific self-administered questionnaire used to assess pain, function, quality of life, and ADL. It consists of 42 items grouped into 5 subscales: pain, other symptoms (including swelling, restricted range of motion, and mechanical symptoms), function in ADL, FSR, and impact on QOL (knee-related QOL, including awareness of the knee condition and changes in lifestyle). The subscales are scored separately; each yields a score between 0 and 100, with 0 representing extreme knee problems and 100 representing absence of problems. Total KOOS score is the average of all 5 subscale scores; ranging from 0 to 100; where 0 represents extreme knee problems and 100 represents absence of knee problems. Change from baseline in total KOOS score; other symptoms, knee-related QOL, and FSR sub-scores; and total KOOS minus FSR sub-score was to be calculated by the respective scores at the specific time point minus the scores at baseline. | Every 6 months up to 5 years | 
| Change From Baseline in Participant-reported Outcome Measure: Numeric Rating Scale (NRS) Score | Knee pain was to be rated by the participant using an 11-point NRS of pain intensity. The NRS is scaled from 0 (no pain) to 10 (worst possible pain). Change from baseline in NRS score was to be calculated by the score at the specific time point minus the score at baseline. | Every 6 months up to 5 years | 
| Change From Baseline in Participant-reported Outcome Measure: Lower Extremity Activity Scale (LEAS) Score | The LEAS is an 18-level single-question self-administered scale that has been validated as a clinical outcome measure for the assessment of participants' actual activity levels. The LEAS is scaled from 1 to 18, with 18 indicating levels of highest activity. Change from baseline in LEAS score was to be calculated by the score at the specific time point minus the score at baseline. | Every 6 months up to 5 years | 
| Change From Baseline in the Physician-reported Outcome Measure: Lysholm Knee Scale Score | The Lysholm knee scale is a physician-reported outcome measure to assess knee function after ligament injury. It is scaled from 0 to 100 with higher scores representing better function. Change from baseline in Lysholm knee scale score was to be calculated by the score at the specific time point minus the score at baseline. | Every 6 months up to 5 years | 
| Composition of the Refilled Cartilage Using T2 Mapping | The transverse relaxation time T2 mapping is an MRI technique that is able to evaluate collagen organization and orientation within cartilage. Composition of the refilled cartilage was to be reported. | Every 6 months up to 5 years | 
| Volume of the Refilled Cartilage | Volume of the refilled cartilage was to be measured by MRI. | Every 6 months up to 5 years | 
| Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Score | The MOCART score is used to describe the constitution of the cartilage repair tissue and the surrounding structures. | Every 6 months up to 5 years | 
| Six-minute Walk Test | Six (6)-minute walk test is used to measure gait function and for pre- and post-operative evaluation in cartilage injury repair. Maximum comfortable distance (in meters) that a participant can walk in 6 minutes was to be reported. | Every 3 months up to 5 years beyond Month 6 post-MFx surgery | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE is an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. | Baseline up to Month 60 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Microfracture surgery, Cartilage repair, Knee surgery