Search

We here explore whether observed treatment effects of a putative disease-modifying osteoarthritis drug (DMOAD) are greater when cartilage morphometry is performed with rather than without knowledge of magnetic resonance imaging (MRI) acquisition order (unblinded/blinded to time point). In the FORWARD (FGF-18 Osteoarthritis Randomized Controlled Trial with Administration of Repeated Doses) randomized controlled trial, 549 knee osteoarthritis patients were randomized 1:1:1:1:1 to three once-weekly intra-articular injections of placebo, 30 µg sprifermin every 6 or 12 months (M), or 100 µg every 6/12 M. After year 2, cartilage segmentation of BL through 24 M MRIs was performed, with blinding to acquisition order. After year 5, 24 and 60 M MRIs were analyzed together, with unknown relative order, but with segmented BL images as reference (24 M unblinded vs. BL), by the same operators. Total femorotibial joint cartilage thickness (TFTJ_ThC) change was obtained for 352 participants analyzed under both conditions. Twenty-four-month data read unblinded to order revealed a −35 ± 44 µm lower TFTJ_ThC than blinded analysis (all groups: lower/upper bounds −120/+51 µm; correlation r2 = 97%). With unblinded analysis, the placebo group lost −46 ± 57 µm TFTJ_ThC over 24 M, whereas 100 µg/every 6 M lost −2.2 ± 73 µm (difference =44 µm [95% CI: 22, 66]). With blinded analysis, placebo lost −11 ± 53 µm, whereas 100 µg/every 6 M gained 30 ± 62 µm (difference = 40 µm [95% CI: 21, 60]). 100 µg sprifermin injected every 6 M showed statistically significant (p < 0.001) treatment effects on TFTJ_ThC, with Cohen D = −0.66 for unblinded and D = −0.69 for blinded analysis. These results do not reveal that detection of proposed DMOAD treatment is enhanced with MRIs read unblinded to order; rather, the sensitivity is similar to blinded analysis. Choices on blinded vs. unblinded analysis may thus be based on other criteria. [ABSTRACT FROM AUTHOR]

Background: Varoglutamstat (PQ912) is an oral, small molecule inhibitor of glutaminyl cyclase, preventing the formation of neurotoxic N3pE amyloid. A Phase 2a study (NCT02389413, Scheltens et al., 2018) reported encouraging first evidence of varoglutamstat's disease‐modifying activity, most importantly with statistically significant changes from baseline in working memory after only 12 weeks of treatment. Method: VIVIAD (NCT04498650, Vijverberg et al., 2021) is an informed multicenter, randomized, placebo‐controlled, double‐blind, parallel group dose‐finding Phase 2b study in 250 patients with Mild Cognitive Impairment (MCI) and early Alzheimer´s disease (AD). Treatment duration varies between 48 and 96 weeks depending on the time of inclusion, with participants receiving 300mg or 600mg varoglutamstat, or placebo, twice‐daily (BID). The participants' disease status at time of inclusion was confirmed by Abeta1‐42 and phospho‐tau CSF biomarker profiles, various cognition tests including MMSE, DSST/WAIS‐IV Coding test (WAIS‐IV), and A‐IADL‐Q. Primary outcome is a composite score of the cognitive domains attention and working memory using the Cogstate Neuropsychological Test Battery (Cogstate NTB). Result: Enrollment has been completed, with a total of N = 259 patients randomized. The 300mg BID varoglutamstat arm was switched to 600mg BID based on positive independent Data Safety Monitoring Board review in June 2022. As of April 14, 2023, 23 patients had completed 96 weeks of treatment. The study will continue until the last patient has completed 48 weeks of treatment with the corresponding follow‐up visit. While most AD trials focus on cognitive tests assessing memory deficits rather than working memory and attention, VIVIAD uses WAIS‐IV to select patients with rescuable cognitive deficits in the target domains. In contrast to MMSE, WAIS‐IV performance shows a reasonably good correlation with the primary outcome measures. Comparing baseline data of male and female participants showed no significant gender differences except for Abeta1‐42 levels. Conclusion: The use of MMSE and DSST/WAIS‐IV together with CSF biomarkers is a valuable tool in identifying and recruiting patients with MCI or mild AD. The strategy of recruiting individuals with evidence of baseline deficits on the WAIS‐IV Coding test has successfully enriched the study cohort with respect to deficits in attention and working memory, enabling reliable assessment of potential cognitive improvement after treatment. [ABSTRACT FROM AUTHOR]

• Pain and the progressive loss of articular cartilage characterise knee osteoarthritis. • FORWARD was a phase II trial of sprifermin in patients with knee osteoarthritis. • This post-hoc analysis explored an advanced disease patient subgroup. • In the subgroup, sprifermin improved cartilage thickness and pain symptoms vs placebo. • The patient subgroup identified may represent a target population for future trials. To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin. Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40–90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint. The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]). Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials. : NCT01919164. [ABSTRACT FROM AUTHOR]

Osteoarthritis Research Society International (OARSI) Expert Consensus Guidelines recommend topical non-steroidal anti-inflammatory drugs as first-line medications for osteoarthritis (OA) knee pain, but several voluminous daily applications are required to achieve efficacy. There is a need to develop new and improved topical analgesics with a faster onset, longer duration of action, and the requirement to apply less gel. This trial investigated the safety and efficacy of a new 3.06% diclofenac gel (AMZ001) in subjects with knee OA. In total, 444 subjects (AMZ001 twice daily (BID) [ n = 121], AMZ001 once daily (QD) + placebo QD [ n = 121], placebo BID [ n = 121], or Voltaren 1% 4-times daily [ n = 81]) were enrolled. All except Voltaren 1% (single-blinded) were applied topically in a double-blind manner for a total of 4-weeks. The primary endpoint was the change from baseline to week 4 in the WOMAC pain sub-score in the target knee. Secondary and exploratory endpoints included additional efficacy measures (WOMAC total score, WOMAC function and stiffness sub-scores, WOMAC pain weight-bearing and non-weight-bearing sub-scores, ICOAP, chair-stand test, OMERACT-OARSI responder rate, PGA, WPAI, EQ-5D, rescue medication use, satisfaction questionnaire) and safety. Treatment with AMZ001 QD was effective at reducing WOMAC pain sub-scores vs placebo (estimated treatment difference [ETD]: −4.61 [95% confidence interval (CI): −9.09, −0.12]; p = 0.0440); however, BID application was not (ETD: −3.76 [95% CI: −8.21, 0.68]; p = 0.0969). For several secondary endpoints, changes from baseline to week 4 conferred nominally statistically significant improvements in favor of AMZ001 vs placebo, including PGA score (AMZ001 BID vs placebo, ETD: −0.61 [95% CI: −1.11, −0.11]; p = 0.0162; AMZ001 QD vs placebo, ETD: −0.63 [95% CI: −1.13, −0.13]; p = 0.0134), WPAI overall work impairment score (AMZ001 QD vs placebo, ETD: −10.44 [95% CI: −20.84, −0.04]; p = 0.0492), and EQ-5D VAS score (AMZ001 BID vs placebo, ETD: 4.70 [95% CI: 0.55, 8.85]; p = 0.0264). Post-hoc analysis excluding 11–14 subjects per group with pain scores that decreased between screening and baseline suggests a consistent effect of both AMZ001 QD (ETD: −5.84 [95% CI: −10.71, −0.97]; p = 0.0189) and BID (ETD: −5.35 [95% CI: −10.16, −0.54]; p = 0.0292) in reducing WOMAC pain sub-scores vs placebo. In general, treatment satisfaction was high, as measured by the satisfaction questionnaire. The frequency and incidence of adverse events (AEs) was greatest in the placebo group. Most AEs (>99%) were of mild or moderate severity. There were no serious AEs. There were no notable effects of any treatment on vital signs, ECGs, physical examination findings, or other laboratory assessments. Treatment with AMZ001 BID for 4 weeks improved WOMAC pain sub-scores; however, only QD application conferred nominally statistically significant improvements vs placebo. AMZ001 was generally well tolerated. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Varoglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate‐3‐Aβ (N3pE‐Aβ), a toxic Aβ variant shown to play a pivotal role in the development and progression of Alzheimer's disease (AD). Encouraging results reported in a prior Phase 2a study (NCT02389413) led to the initiation of a state‐of‐the‐art Phase 2b trial investigating multiple cognitive, safety and biomarker endpoints. Methods: VIVIAD (NCT04498650) is a multicentre randomized, placebo‐controlled, double‐blind, parallel group dose finding Phase 2b study in patients with cognitive impairment (MCI) and mild AD. Objectives are to evaluate the longterm efficacy (primary endpoint Cogstate NTB), safety and tolerability of oral varoglutamstat. The study will recruit 250 patients. The first 90 patients are randomised 1:1:1 (600 mg twice daily, (BID) or 300 mg BID varoglutamstat or placebo BID). An independent DSMB will unblind safety results after 90 patients have completed 24 weeks of treatment in June 2022 and decide on the varoglutamstat dose to be carried forward. The data remain blinded outside the DSMB. After the DSMB decision, all patients will be randomised 1:1 between the final dose of varoglutamstat and placebo and continue treatment up to 48‐96 weeks dependent on study entry date. Results: The study is currently enrolling patients in 22 AD study centers in 5 European countries (160 patients are randomised as of April 25, 2022). The safety data providing the base for the DSMB dose decision, the DSMB decision itself and the baseline characteristics of the patients enrolled into the trial so far will be reported at AAIC. Conclusion: The state‐of‐the art Phase 2b study VIVIAD is designed to yield important results in early AD for varoglutamstat, the first small molecule and only project in clinical development selectively targeting the de novo production of neurotoxic N3pE‐Aβ. The DSMB decision represents an important milestone within the Phase 2b study as it will recommend the dose of varoglutamstat considered to be safe for being carried forward to the study completion. [ABSTRACT FROM AUTHOR]