Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A2 dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A2 efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A2; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A2 was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A2 prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A2 dose, and four were performed 10 to 21 days after the last dose.

The use of recombinant activated factor VII in patients with acquired haemophilia.

Acquired haemophilia (AH) is a rare, often severe bleeding disorder characterised by autoantibodies to coagulation factor VIII (FVIII). Observational studies offer crucial insight into the disease and its treatment. Recombinant activated factor VII (rFVIIa, eptacog alfa activated) was available on an emergency and compassionate use basis from 1988 to 1999 at sites in Europe and North America. In 1996, rFVIIa was approved in Europe for the treatment of AH; it was licensed for this indication in the United States in 2006. Recombinant activated FVII is approved for first-line treatment of bleeding episodes and prevention of bleeding in surgical/invasive procedures in patients with AH. This review provides an up-to-date summary of the haemostatic efficacy of rFVIIa in patients with AH, from the first emergency and compassionate use programmes, to patient registries and a post-marketing surveillance study. In acute bleeding episodes, rFVIIa provided high and consistent rates of control, and available data showed that acute bleed control rates were higher for first-line rFVIIa versus salvage rFVIIa. In surgical procedures, rFVIIa also provided high rates of control. In patients with AH, rFVIIa has a high rate of haemostatic efficacy in acute and surgical bleeding episodes.

Safety update on the use of recombinant activated factor VII in approved indications.

This updated safety review summarises the large body of safety data available on the use of recombinant activated factor VII (rFVIIa) in approved indications: haemophilia with inhibitors, congenital factor VII (FVII) deficiency, acquired haemophilia and Glanzmann's thrombasthenia. Accumulated data up to 31 December 2013 from clinical trials as well as post-marketing data (registries, literature reports and spontaneous reports) were included. Overall, rFVIIa has shown a consistently favourable safety profile, with no unexpected safety concerns, in all approved indications. No confirmed cases of neutralising antibodies against rFVIIa have been reported in patients with congenital haemophilia, acquired haemophilia or Glanzmann's thrombasthenia. The favourable safety profile of rFVIIa can be attributed to the recombinant nature of rFVIIa and its localised mechanism of action at the site of vascular injury. Recombinant FVIIa activates factor X directly on the surface of activated platelets, which are present only at the site of injury, meaning that systemic activation of coagulation is avoided and the risk of thrombotic events (TEs) thus reduced. Nonetheless, close monitoring for signs and symptoms of TE is warranted in all patients treated with any pro-haemostatic agent, including rFVIIa, especially the elderly and any other patients with concomitant conditions and/or predisposing risk factors to thrombosis.

Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive disorder, with most patients having an A-subunit (FXIII-A) deficiency. Patients experience life-threatening bleeds, impaired wound healing, and spontaneous abortions. In many countries, only plasma or cryoprecipitate treatments are available, but these carry a risk for allergic reactions and infection with blood-borne pathogens. The present study was a multinational, open-label, single-arm, phase 3 prophylaxis trial evaluating the efficacy and safety of a novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency. Forty-one patients ≥ 6 years of age (mean, 26.4; range, 7-60) with congenital FXIII-A subunit deficiency were enrolled. Throughout the rFXIII prophylaxis, only 5 bleeding episodes (all trauma induced) in 4 patients were treated with FXIII-containing products. The crude mean bleeding rate was significantly lower than the historic bleeding rate (0.138 vs 2.91 bleeds/patient/year, respectively) for on-demand treatment. Transient, non-neutralizing, low-titer anti-rFXIII Abs developed in 4 patients, none of whom experienced allergic reactions, any bleeds requiring treatment, or changes in FXIII pharmacokinetics during the trial or follow-up. These non-neutralizing Abs declined below detection limits in all 4 patients despite further exposure to rFXIII or other FXIII-containing products. We conclude that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. This study is registered at http://www..clinicaltrials.gov as number NCT00713648.

Computerized digital imaging techniques provided by digital X-ray radiogrammetry as new diagnostic tool in rheumatoid arthritis.

PURPOSE: Our study evaluates digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit (RK) as a new diagnostic method for the measurement of disease-related osteoporosis including quantification of joint space narrowing dependent on the severity of rheumatoid arthritis (RA). MATERIALS AND METHODS: A total of 172 unselected patients with RA underwent computerized measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as a semiautomated measurement of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP 2-5), both were analyzed from plain radiographs of the nondominant hand. RESULTS: Correlations between DXR-BMD and DXR-MCI vs. parameters of RK were all significant (0.34 < R < 0.61; p < 0.01). An expected negative association was observed between RK parameters and the different scoring methods (-0.27 < R < -0.59). The maximum relative decrease in BMD vs. MCI as measured by DXR between the highest and lowest RA severity group was -27.7% vs. -27.5% (p < 0.01) for the modified Larsen Score, whereas the minimal value of relative DXR-BMD and DXR-MCI reduction could be documented for the Sharp Erosion Score (-20.8% vs. -26.8%; p < 0.01). The relative reduction of mean JSD-MCP using RK significantly varied from -25.0% (Sharp Erosion Score) to -41.2% (modified Larsen Score). In addition, an excellent reproducibility of DXR and RK could be verified. CONCLUSION: DXR in combination with RK could be a promising, widely available diagnostic tool to supplement the different scoring methods of RA with quantitative data, allowing an earlier and improved diagnosis and more precision in determining disease progression.

Computerized quantification of joint space narrowing and periarticular demineralization in patients with rheumatoid arthritis based on digital x-ray radiogrammetry.

OBJECTIVES: The aim of our work was to evaluate digital x-ray radiogrammetry (DXR) for the quantification of disease-related periarticular demineralization and computerized analysis of joint space distances (JSDA) for the measurement of joint space narrowing as a new diagnostic method for the early detection of joint-associated alterations and for monitoring disease progression in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Digital radiographs in 313 patients with varying severity of RA were performed annually and assessed by 2 radiologists using modified Larsen and also the Sharp scores within an observation period of 3 years. The hand radiographs underwent measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as computerized JSDA at the metacarpal-phalangeal articulation (JSD-MCP) for a cross-sectional and longitudinal study design. RESULTS: Both DXR-BMD (-29.6%; P < 0.01) and DXR-MCI (-31.0%; P < 0.01) revealed a notable reduction dependent on the severity of RA (from grade 1 to grade 5 of the modified Larsen score); the severity dependent decrease of mean JSD-MCP ranged from -31.9% (P < 0.01; Sharp erosion part) to -39.1% (P < 0.01) for the modified Larsen score. Over an observation period of 3 years, a significant decrease of DXR-BMD (-22.3%) and DXR-MCI (-23.3%) as well as JSD-MCP mean (-17.5%) was observed (P < 0.05), whereas an accentuated decline of DXR and JSDA parameters was verified for patients without disease-modifying antirheumatic drugs or methotrexate therapy. CONCLUSION: Computerized analysis of hand radiographs by DXR and JSDA is a promising approach to assess the severity and to monitor the progression of RA because DXR and JSDA are timely able to measure periarticular demineralization and also narrowing of JSD-MCP dependent on the severity, the medical treatment and the course of RA.

Influence of image-capturing parameters on digital X-ray radiogrammetry.

The purpose of this study was to evaluate the importance of different image-capturing conditions, which might influence the characteristics of radiographs and, consequently, impact calculations of bone mineral density (BMD) and Metacarpal Index (MCI) using digital X-ray radiogrammetry (DXR). Radiographs of the left hand of deceased males were acquired three times using systematically varied parameters: 4-8 miliamp seconds (mA); 40-52 kV; film-focus distance (FFD); 90-130 cm; film sensitivity, 200/400; and different image modalities (conventional vs original digital radiographs as well as digital printouts). Furthermore, the interradiograph reproducibility using both conventional equipment and printouts vs originals of digital images and the intraradiograph reproducibility (either conventional or digital printouts) were evaluated. All BMD and MCI measurements were obtained with the DXR technology. The interradiograph reproducibility of DXR-BMD using conventional images under standardized conditions (6 mAs; 42 kV; 1 m FFD; film sensitivity of 200) was calculated to be coefficient of variation (CV) = 0.49% for Agfa Curix film and CV = 0.33% for Kodak T-MAT-Plus film, whereas reproducibility error using digital images ranged from CV = 0.57% (digital printouts; Philips) to CV = 1.50% (original digital images; Siemens). The intraradiograph reproducibility error was observed to be CV = 0.13% (conventional; Kodak film) vs CV = 0.27% (digital printouts; Philips). The BMD calculation was not noticeably affected by changes of FFD, exposure level, or film sensitivity/film brand, but was influenced by tube voltage (CV = 0.99% for Kodak film to CV = 2.05% for Siemens digital printouts). No significant differences were observed between the BMD and MCI data. DXR provides measurements of MCI and BMD with high precision and reproducibility. The measurements are unaffected by all tested image-capturing conditions, with the exception of tube voltage. In addition, different digital image devices clearly have an effect on DXR reproducibility.