OBJECTIVE:Placebo response (PR) presents a significant challenge in osteoarthritis (OA) trials. Screening Period Pain Inconsistency (SPPI) has been associated with heightened PR in placebo-treated patients. However, existing studies have overlooked whether increasing versus decreasing pain during the screening period affects this relationship differently. This study examines the impact of SPPI magnitude and direction on PR. DESIGN:In a post-hoc analysis of a Phase 2b randomized, double-blind, placebo-controlled knee OA trial, 143 participants receiving intra-articular placebo were categorized into absolute and directional quartiles based on SPPI. The primary endpoint was the change in WOMAC pain from baseline at week 52 in the placebo group, assessed to determine the long-term impact of SPPI on pain changes, using a mixed model for repeated measures. RESULTS:Participants with the highest SPPI had a greater reduction in WOMAC pain scores across the trial period compared to those with more stable pain (group aQ4-aQ1: LSM -11.72, 95%CI: -17.43 to -6.02). The greatest PR was observed in participants whose pain increased during the screening period (group dQ4-dQ1: LSM -6.67, 95%CI: -12.47 to -0.86) and was significant from week 2 (LSM -7.92, 95%CI: -13.65 to -2.19). CONCLUSIONS:These findings extend earlier observations by revealing that not only the magnitude, but also the direction of screening pain fluctuation (worsening pain before randomization) predicts PR. These results highlight SPPI as a potential adjustment variable to enhance assay sensitivity and mitigate PR in intra-articular knee OA trials, supporting the development of more effective therapies for chronic pain conditions like OA.

OBJECTIVES:Intra-articular treatments for osteoarthritis (OA) are limited by their efficacy, safety, or duration of response. JTA-004 is a potential novel treatment for OA for intra-articular (IA) injection, combining hyaluronic acid (HA) and clonidine with human plasma to enhance the effects of HA. The objectives of the trial were to evaluate the efficacy and safety of JTA-004 in participants with symptomatic knee OA, where the primary objective was evaluating the efficacy of JTA-004 in terms of WOMAC pain, compared to placebo. DESIGN:The trial was a multicenter, Phase 3, randomized, double-blind, placebo- and active-controlled clinical trial, evaluating the efficacy and safety of a single IA injection of JTA-004, compared to saline (primary hypothesis) and an HA-comparator (Synvisc-One®) (secondary hypothesis) in knee OA with a Kellgren-Lawrence grade of 2 or 3. For the secondary hypothesis, non-inferiority of JTA-004 to active comparator by comparing the 2 treatment groups on the mean differences in WOMAC pain with a non-inferiority margin of Δ = 10 mm. Primary efficacy endpoint was the change from baseline in WOMAC pain to Month 3. The main secondary efficacy endpoints included changes from baseline in WOMAC function and stiffness at Months 3 and 6, OMERACT-OARSI responder rates, global assessments, and use of rescue medication. Safety assessments were based on adverse events (AE) reporting, and post-injection vital signs. RESULTS:A total of 746 participants were randomized, of which 687 (92.1%) completed the trial. The results indicated no significant differences in the primary endpoint between JTA-004 and placebo (LSmean difference: -1.50 mm, 95%CI 5.12; 2.12, p= 0.42) or Synvisc-One® (LSmean difference: 2.40, 95% CI: -1.22; 6.02, p=0.20) nor in either of the efficacy outcomes of the main study population. The safety and tolerability of JTA-004 was good, and there were no differences in the frequency of any of the reported AEs or trial discontinuations between the study groups. CONCLUSIONS:A single IA injection of JTA-004 was not superior to a saline solution (LSmean difference: -1.50 mm, 95%CI 5.12; 2.12, p= 0.42) or Synvisc-One® (LSmean difference: 2.40, 95% CI: -1.22; 6.02, p=0.20) for the treatment of OA symptoms in the overall study population.

Objectives To evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee osteoarthritis (OA). Methods This was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥20 out of 50 at screening and baseline visits. Subjects having any other knee condition were excluded. Use of analgesics was prohibited, except for rescue medication. The primary endpoint was change from baseline (CFB) in WOMAC pain at Week 8. Secondary endpoints were CFB in WOMAC function and total, ICOAP, Patient Global Assessment, and 20-meter walk test. Exploratory endpoints included structural CFB in magnetic resonance imaging entities. Results A total of 288 subjects were randomized to SB-061 (n = 145) or placebo (n = 143), and 252 (87.5%) completed injections. The groups were comparable at baseline. The primary endpoint was not met, as no significant difference in the CFB of the WOMAC pain score at Week 8 between groups was observed, nor at any other time point during the study. Similarly, neither of the secondary or exploratory endpoints indicated any significant difference between groups. The frequency and type of adverse events were similar between groups. SB-061 was well-tolerated. Conclusion Intra-articular injections of SB-061 administered at baseline, Week 16, and Week 32, over one year in subjects with knee OA, were safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo. Trial registration number EudraCT No 2019-004515-31

Purpose (the aim of the study): Clinical studies assessing novel pharmacological interventions for osteoarthritis (OA) face challenges due to a substantial placebo response (PR). Many previous studies have shown that OA trials tend to have high PRs, which are believed to have contributed to the long list of failed OA trials to date. The PR is commonly very large in pain studies, with magnitudes having increased during the last decade. This leads to risks of reduced statistical power and consequently failure in detecting significant differences between efficacious agents and placebo comparators. Failure to demonstrate that an active treatment separates from placebo is the most common cause of negative Phase II and III trials. Numerous efforts have been undertaken to mitigate elevated placebo responses, typically focused on the identification of high placebo responders and the development of trial designs aimed at mitigating the influence of such responders, but evidence describing their efficacy is scarce or non-existent.

Purpose (the aim of the study): Currently available treatments for osteoarthritis (OA) are suboptimal in magnitude and duration of effect. MOTYS (PTP-001), a placental tissue particulate, is a local treatment option with potential to positively affect inflammation and imbalance of tissue turnover in OA joints. MOTYS has shown beneficial effects in preclinical studies, and in an open-label Phase 1 trial. The objectives of this Phase 2 trial were to determine an effective dose of MOTYS and assess the durability of its response, safety, and tolerability in patients with symptomatic knee OA.

BackgroundThere is a great unmet need for the development of effective treatments to treat the symptoms of OA. Nuclear-Factor Kappa-B (NF-κB) and Nrf2 play a key roles in OA pathogenesis and have been identified as potential targets. A fixed-dose combination of apocynin and paenol in a ratio of 2:7 (APPA) has been shown to inhibit activation of NF-κB and upregulate Nrf2. [1]ObjectivesWe report the results of a phase 2a study evaluating the efficacy and safety of APPA in patients with symptomatic knee OA.MethodsThe trial was a 28-day randomized, placebo-controlled, double-blind study comparing 800 mg of APPA twice daily with matched placebo capsules. Patients with radiographic knee OA KL-grade 2-3, and a WOMAC pain score ≥40 and ≤90/100 of target knee at screening and baseline were randomized 1:1 to APPA or placebo. Main exclusion criteria included recent intraarticular surgery or injection therapy, hip pain greater than the target knee, and BMI ≥40 kg/m2. The primary endpoint was change from baseline to Day 28 in the WOMAC pain score. Safety outcomes included reported adverse events (AE), clinical laboratory parameters, ECG, and vital signs.A pre-defined subgroup analysis in subjects with a baseline PainDETECT score >12 indicated a positive effect. Accordingly, post-hoc analyses were undertaken to further assess the effects of APPA in subgroups of participants with higher disease severity.Results152 participants were randomized, and 149 (98%) completed the trial. The mean (SD) WOMAC pain score at baseline was 55.3 (10.2). The two groups were comparable in terms of baseline pain score, gender, age, and BMI.The primary endpoint was not met, mean difference (MD) between APPA and placebo was -0.89 (95 % CI: -5.62, 3.84, p=0.71, Figure 1A). Similarly, no significant differences were found on other key secondary endpoints (WOMAC Function and WOMAC total Figure 1B and C, respectively.) APPA was well tolerated and no differences in frequencies of reported AEs were noted, apart from a higher proportion of subjects reporting mild to moderate gastrointestinal discomfort reported with APPA compared to placebo (12% vs. 6.5 %).In the pre-defined subgroup of participants with baseline PainDETECT ≥ 13 (N=45), the difference in mean change in pain from baseline favored the APPA-group (MD: -11.20, 95 % CI: -20.29 to -2.11, p=0.02). Analysis of participants > 50 WOMAC pain at baseline (Group 1, N=95, Figure 1D), and a KL-grade of the non-target knee >2 (Group 2, N=105, Figure 1E), and a combination of these two criteria (Group 3, N=64, Figure 1F) found a positive effect of APPA compared to placebo (Group 1 MD: -2.61, 95 % CI: -8.98 to 3.76, p=0.42, Group 2 MD: -4.01, 95 % CI: -9.35 to 1.33, p=0.14, and Group 3 MD: -8.32, 95 % CI: -15.48 to -1.16, p=0.02).ConclusionTreatment with APPA 800 mg twice daily for 28 days in patients with symptomatic knee OA overall was not associated with significantly improved outcomes compared to placebo. The treatment was well-tolerated and safe. Subgroup analyses, however, showed a significant effect of APPA in patients with moderate to severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted.References[1]Cross AL, Hawkes J, Wright HL, Moots RJ, Edwards SW. APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling. Inflammopharmacology. 2020 Oct; 28(5):1223-1235.Disclosure of InterestsAsger Reinstrup Bihlet Shareholder of: NBCD A/S, Employee of: NBCD A/S, Inger Byrjalsen Employee of: NBCD A/S, Jeppe Ragnar Andersen Shareholder of: NBCD A/S, Employee of: NBCD A/S, Anna Metnik Shareholder of: NBCD A/S, Employee of: NBCD A/S, Alan Reynolds Shareholder of: AKL R&D, Employee of: AKL R&D, Nicholas Larkins Shareholder of: AKL R&D, Employee of: AKL R&D, Peter Alexandersen: None declared, Helene Rovsing: None declared, Ulla Schmidt: None declared, Robert Moots Speakers bureau: Pfizer, Amgen, Novartis, Gilead, Grant/research support from: University of Liverpool received grant support from AKL on Phase 1 trial where Prof. Rob Moots was principal investigator. UoL also received grant support from AKL on basic neutrophil research., Philip G Conaghan Speakers bureau: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB, Consultant of: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB

Background Development of new products for OA treatment is difficult, partly due to excessive placebo response and high variability in patient-reported pain outcomes, and exclusion of trial subjects with potentially confounding pain from non-target joints may increase the effect size. This may in part be due to reductions in variability, and hence in standard deviation (SD) of the mean changes in pain scores, which improves the statistical power to detect differences between study groups. The impact of refining the study population in terms of added benefit to the SD and statistical power vs. added screen failures is poorly described. Objectives To investigate the impact of common demographic and pain characteristics on the SD of mean pain change from baseline in a large interventional OA trial database. Methods Data from 2 randomized controlled trials of oral salmon calcitonin in OA (1) were analyzed post-hoc. The SD of the mean change from baseline (SD-CFB) to Year 2 in the WOMAC knee pain score (0-100) was calculated. The SD-CFB was also calculated for subgroups (e.g. demographics, pain of the target and non-target knee). The sample size required to identify a statistically significant difference of at least 8 out of 100 between groups (with 80% power) was calculated, and the additional proportion of eligible subjects to be screen-failed if the particular subgroup was excluded was calculated to quantify the potential impact on the study feasibility. Results A total of 1,487 subjects had WOMAC pain data throughout the trial period. Results are shown in Table 1. Few clinical characteristics influenced the SD and hence the required sample size, except for Asian race, associated with a lower SD compared to Caucasians (19.71 vs. 21.85), to detect a significant difference. Exclusion of those with high BMI (≥ 35 kg/m2) led to a reduced sample size required of 113. Subjects with non-target knee pain above the median had higher pain variability and thus a larger sample sizes required to detect differences vs. those with pain scores below the median. However, exclusion of these groups required screen failing approx. extra 50 % of the eligible population to achieve this. A less exclusive method was excluding subjects with non-target knee pain not exceeding that of the target knee. Radiographic characteristics did not influence the SD, except for those with a KL grade 3 or 4 of the non-target knee (Table 1). This observation requires further scrutiny. Conclusion High BMI and high baseline pain of the non-target knee may contribute negatively to the study power, however, the added study cost in terms of additional screened subjects required to replace those excluded based on these parameters should be carefully evaluated. The potential impact of these parameters on the magnitude of the difference between study groups was not evaluated and may also differ, with additional statistical implications. Reference [1]Karsdal MA, Byrjalsen I, Alexandersen P, Bihlet A, Andersen JR, Riis BJ, Bay-Jensen AC, Christiansen C. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. CSMC021C2301/2 investigators. Osteoarthritis Cartilage 2015;23:532-543. Acknowledgements: NIL. Disclosure of Interests Asger Reinstrup Bihlet Employee of: Full-time employee and shareholder of NBCD, Peter Alexandersen Employee of: Part-time employee at NBCD, Jeppe Ragnar Andersen Employee of: Full-time employee and shareholder of NBCD, Yanqi Li Employee of: Full-time employee and shareholder of NBCD, Morten Karsdal Employee of: Full-time employee and shareholder of NBCD, Claire Prener Miller Employee of: Full-time employee at NBCD.Table 1SD of mean WOMAC pain changenSample size per group to detect mean WOMAC pain difference of 8 out of 100 (n)Proportion of eligible subjects screen failed if subgroup was excluded (%)All study completers21.581,4871150Male21.1251611034.7Female21.8297111765.3Age < 64 yrs21.4979911453.7Age ≥ 64 yrs21.6868811646.3BMI < 35 kg/m221.451,31611388.5BMI ≥ 35 kg/m222.5317112511.5Subgroups by Non-Target knee characteristics at BaselineKL grade 020.79601074.0KL grade I21.1927111118.2KL grade II20.8376610751.5KL grade III23.8034613923.3KL grade IV17.5542762.8WOMAC Pain ≤ 35 (0-100)20.087319949.2WOMAC Pain > 35 (0-100)22.9672213048.6Low VAS (0-100, ≤ 37)19.397149348.0High VAS (0-100, > 37)23.5472213648.6Nontarget knee WOMAC pain ≥ Target knee WOMAC pain22.6440812627.4Nontarget knee WOMAC pain < Target knee WOMAC pain20.841,02410768.9

Purpose: Development of new products for the treatment of osteoarthritis (OA) is difficult, and the risk of trial failure due to discrepancies between structural and symptomatic outcomes, excessive placebo response and high variability in patient-reported pain outcomes is high. High pain reporting variability during shorter periods of time has been found to be associated with increased placebo response in other painful conditions, and post-hoc analyses of OA interventional trials have indicated that exclusion of trial participants with potentially confounding pain from non-target joints may increase the differentiation of treatment groups. These observations may in part be driven by reductions in the variability, and hence standard deviation (SD) of the mean changes in pain scores, which improves the statistical power to detect differences between study groups. The impact of refining the study population in terms of added benefit to the SD and hence statistical power versus added screen failures is poorly described. This report investigates the impact of common demographic and pain characteristics on the mean change from baseline standard deviation in a large interventional OA trial database.

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. 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 Abeta 1-42 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). 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 Abeta 1-42 levels. 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.

Background Osteoarthritis (OA) is a chronic disease characterized by degradation of joint structures including the subchondral bone, the synovium, and cartilage. Aggrecan constitutes a major component of hyaline cartilage and plays an important role for its normal function. In OA, aggrecan is gradually lost, which together with cytokines, proteases, and circulating pro-inflammatory fragments of hyaluronic acid (HA) further accelerates tissue destruction. SB-061 is an aggrecan mimetic, composed of a backbone of chondroitin sulfate conjugated to a HA peptide coating protein. SB-061 is believed to bind HA fragments in the synovium. Hence, SB-061 acts upstream in the inflammatory cascade, thereby potentially reducing both pain as well as structural deterioration [1]. Objectives To evaluate the efficacy and safety of intra-articular injections of SB-061 in subjects with knee OA. Methods This was a randomized, placebo-controlled, double-blind phase II study comparing quarterly intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks (EudraCT No. 2019-004515-31). Eligible subjects had a Kellgren-Lawrence (KL) grade of 2 or 3 on X-ray of the target knee and a Western Ontario and McMasters Osteoarthritis Index (WOMAC) pain score ≥20 out of 50 at screening and baseline visits. Subjects having used any medication known to affect the joints up to 3 months prior to the study or having any other knee condition were excluded. Any use of analgesic medication was prohibited during the study, except for rescue medication (paracetamol/acetaminophen). The primary endpoint was the change from baseline (CFB) in WOMAC pain at Week 8 after first injection. Secondary endpoints were CFB in WOMAC function and total, ICOAP and the Patient Global Assessment (PGA), and 20-meter walk test. Exploratory structural endpoints included CFB in knee cartilage thickness and volume, and bone shape as measured by magnetic resonance imaging (MRI), and CFB in the radiographic minimum joint-space width (JSW). Results A total of 288 subjects were randomized to SB-061 (n= 145) or placebo (n=143), and of these 252 (87.5%) completed injections. The two groups were well-balanced in terms of the main clinical and radiographic parameters, and reflective of a typical OA clinical trial population. The primary endpoint was not met, as there was no significant difference in the CFB of the WOMAC pain score (0-50) at Week 8 between the groups (LSmean difference: 0.00, 95% CI -4.33; 4.34, p=0.999, nor at any other time point during the trial (Figure 1). Similarly, neither of the secondary endpoints of changes from baseline in WOMAC function, WOMAC total, ICOAP, PGA, and 20-meter walk test indicated any significant difference between SB-061 and placebo. There was no significant difference between groups in CFB in JSW or any of the MRI parameters. The frequency and type of adverse events was similar between groups receiving SB-061 and placebo. SB-061 was well-tolerated. Conclusion Intra-articular injections of SB-061 administered quarterly for one year in patients with knee OA was safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo. Reference [1]Hauser-Kawaguchi A, Luyt LG, Turley E. Design of peptide mimetics to block pro-inflammatory functions of HA fragments. Matrix Biology. 2019 at https://doi.org/10.1016/j.matbio.2018.01.021. Acknowledgements: NIL. Disclosure of Interests Asger Reinstrup Bihlet Employee of: Employee and shareholder in Nordic Bioscience., Inger Byrjalsen Employee of: Previous employee in Nordic Bioscience., Kamilla Mundbjerg Employee of: Employee in Nordic Bioscience Clinical Development., Peter Alexandersen Employee of: Part-time employee Nordic Bioscience Clinical Development., Helene Rovsing: None declared, Tobias Axelsen: None declared, Jeppe Ragnar Andersen Employee of: Employee and shareholder in Nordic Bioscience., Anna Metnik Employee of: Employee in Nordic Bioscience Clinical Development., Nathan Bachtell: None declared, Alan Brett Employee of: Employee and shareholder in Stryker., Claus Christiansen Employee of: Shareholder in Nordic Bioscience.Figure 1

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. 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. 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. 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 Background Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. Methods This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. Results To be expected early 2023 Conclusion This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. Trial registration ClinicalTrials.gov Identifier: NCT04498650

Cohort Profile: The Prospective Epidemiological Risk Factor (PERF) study JS Neergaard,* K Dragsbæk, SN Kehlet, HB Hansen, G Hansen, I Byrjalsen, P Alexandersen, LM Lindgren, AR Bihlet, BJ Riis, JR Andersen, P Qvist, MA Karsdal and C Christiansen Nordic Bioscience A/S, Herlev, Denmark, Center for Clinical and Basic Research, Vejle, Denmark and Center for Clinical and Basic Research, Ballerup, Denmark

IMPORTANCE Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor. OBJECTIVE To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture. DESIGN, SETTING, AND PARTICIPANTS The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤-2.5 and >-5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤-2.0 and >-5.0 or without fracture criteria and a T score ≤-3.0 and >-5.0 could enroll. INTERVENTIONS Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months. MAIN OUTCOMES AND MEASURES Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants. RESULTS Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred less frequently in the active treatment groups vs placebo. The Kaplan-Meier estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo. BMD increases were greater with abaloparatide than placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) vs teriparatide (6.4%) (risk difference [RD], −2.96 [95%CI, −5.12 to −0.87]; P = .006). [table: see text]. CONCLUSIONS AND RELEVANCE Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01343004.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

To the Editor: Odanacatib, an oral selective inhibitor of cathepsin K, was previously in development for the treatment of osteoporosis.1 Because of morphea-like skin changes reported in 2 studies of the cathepsin K inhibitor balicatib (1.3% of patients),2,3 the occurrence of these lesions was assessed in the phase 3 Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373). Here, we describe morphea-like skin changes and systemic sclerosis in postmenopausal women receiving odanacatib or placebo in the LOFT base study and its preplanned extension.