Publications by authors named "Jeppe Ragnar Andersen"

10 Publications

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Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.

Ann Rheum Dis 2021 May 7. Epub 2021 May 7.

Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.

Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression.

Results: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53).

Conclusion: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.

Trial Registration Number: NCT01919164.
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http://dx.doi.org/10.1136/annrheumdis-2020-219181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292562PMC
May 2021

Serum C-reactive protein metabolite (CRPM) is associated with incidence of contralateral knee osteoarthritis.

Sci Rep 2021 03 22;11(1):6583. Epub 2021 Mar 22.

Immuno-Science, Nordic Bioscience, Biomarkers and Research, Herlev Hovedgade, 2730, Herlev, Denmark.

The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We investigated the level of blood CRPM in OA compared to RA using data from two phase III knee OA and two RA studies (N = 1591). Moreover, the association between CRPM levels and radiographic progression was investigated. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3-8.8] ng/mL, n = 781) compared to the RA patients (12.8 [9.5-16.0] ng/mL, n = 60); however, a significant subset of OA patients (31%) had CRPM levels (≥ 9 ng/mL) comparable to RA. Furthermore, OA patients (n = 152) with CRPM levels ≥ 9 ng/mL were more likely to develop contra-lateral knee OA assessed by X-ray over a two-year follow-up period with an odds ratio of 2.2 [1.0-4.7]. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.
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http://dx.doi.org/10.1038/s41598-021-86064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985384PMC
March 2021

Clinical and biochemical factors associated with risk of total joint replacement and radiographic progression in osteoarthritis: Data from two phase III clinical trials.

Semin Arthritis Rheum 2020 12 15;50(6):1374-1381. Epub 2020 Mar 15.

Nordic Bioscience A/S, Herlev, Denmark.

Objectives: Clinical trials of new disease-modifying treatments for osteoarthritis should demonstrate a positive effect on a functional outcome or reduction in joint failure in order to be considered successful. Total joint replacement (TJR) surgery may be considered as joint failure, but great variation in the incidence of TJR complicates its use as a study endpoint. Factors predicting elevated risk of TJR could potentially be used to enrich such outcome-trials.

Methods: Using cumulative data from two phase three clinical trials with urine samples from 1255 knee OA patients followed for two years, we assessed the value of a series of baseline clinical variables including the uCTX-II biomarker, as predictors of joint-space narrowing, Kellgren-Lawrence-grade progression, and total joint replacement.

Results: A prediction-model incorporating age, sex, BMI, CTX-II and KL-grade predicted TJR within the two-year period with an AUC of 0.75 (95% CI: 0.72-0.77). The participants with a cumulative KL-grade between knees of 5, 6, or 7 had a more than 3 times higher risk of TJR in the study period compared to lower (HR: 3.03, 95% CI: 1.54 to 5.96, p = 0.001). Age was associated with increased TJR risk (per 5 years of age: HR: 1.28, 95% CI: 1.03-3.79, p = 0.05). Baseline u-CTX-II was associated with elevated risk of radiographic progression in terms of both JSN and KL-grade.

Conclusions: A composite model combining baseline age, sex, BMI, u-CTX-II and KL-grade was able to acceptably predict TJR during a two-year period. In the absence of baseline radiographic OA severity, u-CTX-II independently contributed to prediction of TJR. Baseline urine CTX-II was associated with risk of radiographic progression.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.002DOI Listing
December 2020

Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial.

JAMA 2019 10;322(14):1360-1370

Institute of Anatomy, Department of Imaging and Functional Musculoskeletal Research, Paracelsus Medical University Salzburg and Nuremberg, Salzburg, Austria.

Importance: Sprifermin is under investigation as a disease-modifying osteoarthritis drug.

Objective: To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis.

Design, Setting, And Participants: FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites. Eligible participants were aged 40 to 85 years with symptomatic, radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment began in July 2013 and ended in May 2014; the last participant visit occurred on May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years are reported.

Interventions: Participants were randomized to 1 of 5 groups: intra-articular injections of 100 μg of sprifermin administered every 6 months (n = 110) or every 12 months (n = 110), 30 μg of sprifermin every 6 months (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each treatment consisted of weekly injections over 3 weeks.

Main Outcomes And Measures: The primary end point was change in total femorotibial joint cartilage thickness measured by quantitative magnetic resonance imaging at 2 years. The secondary end points (of 15 total) included 2-year change from baseline in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The minimal clinically important difference (MCID) is unknown for the primary outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 9% to 18%).

Results: Among 549 participants (median age, 65.0 years; 379 female [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the changes from baseline to 2 years in total femorotibial joint cartilage thickness were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 μg of sprifermin administered every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 μg of sprifermin every 12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 μg of sprifermin every 6 months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 μg of sprifermin every 12 months. Compared with placebo, there were no statistically significant differences in mean absolute change from baseline in total WOMAC scores for 100 μg of sprifermin administered every 6 months or every 12 months, or for 30 μg of sprifermin every 6 months or every 12 months. The most frequently reported treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 μg of sprifermin administered every 6 months: n = 45 [41.3%]; 100 μg of sprifermin every 12 months: n = 50 [45.0%]; 30 μg of sprifermin every 6 months: n = 40 [36.0%]; and 30 μg of sprifermin every 12 months: n = 48 [44.0%]).

Conclusions And Relevance: Among participants with symptomatic radiographic knee osteoarthritis, the intra-articular administration of 100 μg of sprifermin every 6 or 12 months vs placebo resulted in an improvement in total femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; there was no significant difference for 30 μg of sprifermin every 6 or 12 months vs placebo. Durability of response also was uncertain.

Trial Registration: ClinicalTrials.gov Identifier: NCT01919164.
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http://dx.doi.org/10.1001/jama.2019.14735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784851PMC
October 2019

Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis.

Arthritis Res Ther 2019 09 3;21(1):203. Epub 2019 Sep 3.

Nordic Bioscience Biomarkers and Research, Herlev Hovedgade 207, DK2730, Herlev, Denmark.

Background: Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain categories with levels of uCTX-II and biomarkers of bone resorption and formation.

Methods: Baseline data of two randomised clinical trials (NCT00486434 and NCT00704847) in patients with radiographic OA and presence of pain were analysed post hoc. A subgroup with available urine samples and evaluable radiographs for both knees (N = 1241) was analysed. Urine CTX-I, urine CTX-II and serum osteocalcin were analysed for associations with combined Kellgren-Lawrence (KL) scores, gender and pain for both knees to assess the contribution of joints at different stages.

Results: Pain, BMI, age, gender and KL grade were all significantly associated with uCTX-II. The association between pain and CTX-II appeared to be driven by weight-bearing pain. The level of uCTX-II incrementally increased with higher radiographic severity of each knee. Levels of bone markers CTX-I and osteocalcin were both significantly associated with BMI and gender, but neither were associated with radiographic severity. Biomarker levels between male or female groups of identical KL scores were found to be higher in females compared to males in some but not all KL score groups.

Conclusions: These results indicate that levels of uCTX-II are independently associated with radiographic severity of OA and pain intensity. CTX-II was associated with weight-bearing pain, but not non-weight-bearing pain, independent of co-variates. Bilateral OA knee joints appear to contribute to uCTX-II levels in an incremental manner according to radiographic severity of single joints. The data suggest that biomarker differences between genders should be taken into account when evaluating these markers in the context of structural features of OA.
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http://dx.doi.org/10.1186/s13075-019-1987-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724319PMC
September 2019

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women.

Sci Rep 2018 03 29;8(1):5371. Epub 2018 Mar 29.

ProScion, Herlev, Denmark.

Acute myocardial infarction (AMI) is often underdiagnosed in women. It is therefore of interest to identify biomarkers that indicate increased risk of AMI and thereby help clinicians to have additional focus on the difficult AMI diagnosis. Type I Collagen, a component of the cardiac extracellular matrix, is cleaved by matrix metalloproteinases (MMPs) generating the neo-epitope C1M. We investigated the association between serum-C1M and AMI and evaluated whether C1M is a prognostic marker for outcome following AMI. This study is based on The Prospective Epidemiological Risk Factor (PERF) Study including postmenopausal women. 316 out of 5,450 women developed AMI within the follow-up period (14 years, median). A multivariate Cox analysis assessed association between serum-C1M and AMI, and re-infaction or death subsequent to AMI. The risk of AMI increased by 18% (p = 0.03) when serum-C1M was doubled and women in the highest quartile had a 33% increased risk compared to those in the low quartiles (p = 0.025). Serum-C1M was, however not related to reinfarction or death subsequent to AMI. In this study C1M was be an independent risk factor for AMI. Measuring MMP degraded type I collagen could be useful for prediction of increased risk of AMI if replicated in other cohorts.
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http://dx.doi.org/10.1038/s41598-018-23458-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876321PMC
March 2018

Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis.

BMC Musculoskelet Disord 2018 01 17;19(1):17. Epub 2018 Jan 17.

University of Maryland School of Medicine, Baltimore, USA.

Background: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC).

Methods: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed.

Results: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee.

Conclusions: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted.

Trial Registration: NCT00486434 (trial 1) and NCT00704847 (trial 2).
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http://dx.doi.org/10.1186/s12891-018-1938-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773024PMC
January 2018

The impact of clinical trial monitoring approaches on data integrity and cost--a review of current literature.

Eur J Clin Pharmacol 2016 Apr 4;72(4):399-412. Epub 2016 Jan 4.

Nordic Bioscience Clinical Development A/S, Herlev Hovedgade 205-207, 2730, Herlev, Denmark.

Purpose: Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost.

Methods: The literature search was performed by keyword searches in MEDLINE and hand search of key journals. All publications were reviewed for details on how a monitoring approach impacted subject safety data, data integrity, or monitoring costs.

Results: Twenty-two publications were identified. Three publications showed that SDV has some value for detection of not initially reported adverse events and centralized statistical monitoring (CSM) captures atypical trends. Fourteen publications showed little objective evidence of improved data integrity with traditional monitoring such as 100 % SDV and sponsor queries as compared to reduced SDV, CSM, and remote monitoring. Eight publications proposed a potential for significant cost reductions of monitoring by reducing SDV without compromising the validity of the trial results.

Conclusions: One hundred percent SDV is not a rational method of ensuring data integrity and subject safety based on the high cost, and this literature review indicates that reduced SDV is a viable monitoring method. Alternative methods of monitoring such as centralized monitoring utilizing statistical tests are promising alternatives but have limitations as stand-alone tools. Reduced SDV combined with a centralized, risk-based approach may be the ideal solution to reduce monitoring costs while improving essential data quality.
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http://dx.doi.org/10.1007/s00228-015-2004-yDOI Listing
April 2016

Clinical Drug Development Using Dynamic Biomarkers to Enable Personalized Health Care in COPD.

Chest 2015 Jul;148(1):16-23

Respiratory and Allergy Research Group, Manchester Academic Science Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, England.

Despite massive investments in the development of novel treatments for heterogeneous diseases such as COPD, the resources spent have only benefited a fraction of the population treated. Personalized health care to guide selection of a suitable patient population already in the clinical development of new compounds could offer a solution. This review discusses past successes and failures in drug development and biomarker research in COPD, describes research in COPD phenotypes and the required characteristics of a suitable biomarker for identifying patients at higher risk of progression, and examines the role of extracellular matrix proteins found to be upregulated in COPD. Novel biomarkers of connective tissue remodeling that may provide added value for a personalized approach by detecting subgroups of patients with active disease suitable for pharmacologic intervention are discussed.
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http://dx.doi.org/10.1378/chest.15-0296DOI Listing
July 2015

Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials.

Br J Clin Pharmacol 2015 Apr;79(4):660-8

Nordic Bioscience A/S, Herlev, Denmark.

Aim: The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach.

Methods: We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points.

Results: Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.

Conclusions: The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.
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http://dx.doi.org/10.1111/bcp.12531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386950PMC
April 2015
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