Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial

Study design

Details of study design and patient inclusion have been reported 8]. In brief, in this multicenter, randomized, double blind, placebo-controlled trial,
(ClinicalTrials.gov identifier: NCT01033994), sprifermin was evaluated as a single
treatment and as a multiple-dose regimen with three doses of either 10 ?g, 30 ?g,
or 100 ?g with 21, 42 and 63 patients respectively, and matched placebo groups of
7, 14 and 21 patients, respectively. Patients were aged ?40 years, had an established
diagnosis of primary tibio-femoral knee OA according to American College of Rheumatology
clinical and radiologic criteria, with Kellgren-Lawrence (KL) grade 2 or 3 disease
in the target knee 10]. Altogether 477 patients were screened and 192 were randomized (24 to the single-dose
cohorts and 168 to the multiple-dose cohorts. All patients in the single-dose cohorts
received treatment with the study drug and completed the trial. All patients in the
multiple-dose cohorts received ?1 dose of study medication, with 168 forming the modified
intent-to-treat population; 156 (92.9 %) completed the trial.

Similar to the recently reported post-hoc analysis on quantitative cartilage parameters
11], the current sqMRI analysis focuses on subjects with baseline and 12 month data in
the cohort that received sprifermin 100 ?g (n?=?57) (since this was the dosing regimen on which significant drug efficacy was observed
8]), and in those who were randomized, in parallel, to receive matching placebo (n?=?18). Since this multicenter trial enrolled cohorts sequentially using a dose-ascending
approach across 30 sites on multiple continents 11], a comparison of the 100 ?g subgroup with a combined placebo subgroup incorporating
all dosages (n?=?42) was not warranted. The detailed flow-chart of inclusion of the current analysis
is presented in Fig. 1.

Fig. 1. Detailed flow-chart of subject inclusion to the 100 ?g subgroup

Primary end points and assessments

The primary efficacy end point was the longitudinal change from baseline in central
medial tibio-femoral compartment cartilage thickness at 6 months and 12 months, as
assessed using qMRI 8].

Secondary end points and assessments

Secondary imaging end points included total and compartmental femorotibial cartilage
thickness and volume as assessed by qMRI, measurement of joint space width by fixed-flexion
weight-bearing radiography, and assessment of bone marrow lesions (BMLs), cartilage,
menisci, osteophytes, effusion, and synovitis by sqMRI using the modified Whole-Organ
Magnetic Resonance Imaging Score (WORMS) at baseline, 3, 6, and 12 months follow-up
12].

MRI acquisition

MRIs were acquired using 1.5 T or 3 T systems. Axial, coronal, and sagittal intermediate-weighted
turbo or fast spin–echo fat-suppressed sequences were used for semiquantitative whole
joint assessment of structural tissue pathology, with identical parameters, software
and hardware used at baseline and follow-up. Image parameters were as follows: slice
thickness 3.0 mm, in-plane resolution 0.55 × 0.55 mm, repetition time 3,600–4,000 msec,
and echo time 30–40 msec. In addition the double-oblique coronal spoiled gradient-recalled
sequences with fat suppression or water excitation that were acquired for cartilage
thickness determination using quantitative MRI were considered for sqMRI assessment
with the following acquisition paramaters: contiguous slice thickness 1.5 mm, in-plane
resolutions 0.23 × 0.23 mm to 0.32 × 0.32 mm, repetition time 18–50 msec, echo time
6.5–14 msec, flip angle 15–20°.

MRI interpretation

Four musculoskeletal radiologists (FWR, AG, MDC, MDM), with 7–16 years experience
in standardized sqMRI assessment of knee OA, graded cartilage status, BMLs, osteophytes,
effusion, synovitis and meniscal morphology according to the WORMS system 12] with blinding to treatment, radiographic OA grade and clinical data. In addition
to the published WORMS scale medial and lateral meniscal extrusion was assessed on
the coronal plane according to previous publications 13], 14] and graded as follows: 0?=?no meniscal extrusion,1?=?extrusion??50 %, 2?=?extrusion???50 %.
Baseline and follow-up MRIs were presented sequentially, with the chronological acquisition
order known to the readers. The four readers assessed the images independently with
an equal number of examinations assigned to each reader.

Statistical analysis

Statistical analyses were performed using SAS software (version 9.1; SAS Institute).
Included in the current analysis were patients from the 100 ?g and matched placebo
subgroups with complete MRI datasets with all features and subregions scorable. Analyses
included multi-dimensional assessment: (a) A delta-subregional approach was applied,
which adds the number of subregions (total of 14 articular subregions for cartilage and BMLs on a knee level, 5 subregions
each for the medial and lateral tibio-femoral [MTFJ, LTFJ] and 4 subregions for the
patello-femoral [PFJ] compartment) showing worsening (0), no change (0) or improvement
(0). As an example, 5 subregions showing worsening, 7 subregions showing improvement
and 3 subregions showing no change will result in a delta-subregion change of ?2.
(b) In addition, a delta-sum approach was used, which adds the absolute scores of all subregions combined per compartment or for the whole knee. Analyses were performed on a whole
knee level and separately for MTFJ, LTFJ and PFJ compartments for all subgroups. Mann–Whitney???Wilcoxon
tests assessed differences between treatment groups. In sensitivity analysis adjusting
for baseline values, analysis of covariance (ANCOVA) on ranked baseline and post baseline
values was performed. P-values were not adjusted for multiple testing.