Interim Results Indicate that Emicizumab-kxwh Prevents Bleeding Episodes in Hemophilia A
Hemophilia A is an inherited disorder in which lack of intrinsic factor VIII leads to frequent bleeding into joints and muscles, resulting in chronic swelling, deformity, reduced mobility, and long-term joint damage. The World Federation of Hemophilia recommends early prophylaxis, but commonly, treatment is not initiated until after the first year of life because of the related high burden of care. The study design aims to address that by offering the parents options of dosage regimen and subcutaneous administration.
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Genentech released interim data from the HAVEN 7 study at the American Society of Hematology’s annual meeting in New Orleans in December. HAVEN 7 is a Phase III, multicenter, open-label study that evaluated the benefits of preventive treatment with emicizumab-kxwh, a factor IXa- and factor X-directed antibody, in previously untreated severe hemophilia A without factor VIII inhibitors. (A serious complication of treatment for hemophilia A is the development of inhibitors to factor VIII replacement therapies.) Hypothesizing that beginning treatment as early as possible could produce improved results, the study enrolled patients with severe hemophilia A, demonstrated by an intrinsic factor VIII level of less than 1%. The infants could begin treatment as early as birth to age 12 months, and were given emicizumab subcutaneously at 3 mg/kg once every 2 weeks for 52 weeks; after 1 year, parents could opt for their infants to continue with emicizumab treatment in three different dosage regimens: 1 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks.
On interim analysis, emicizumab-kxwh achieved meaningful control of bleeding: 77.8% (n = 42) of treated infants had no bleeds that required treatment, and 42.6% (n = 23) had no incidents of bleeding at all. The report showed that a total of 77 bleeds occurred in 31 participants; 88.3% of those bleeds were a result of injury rather than being spontaneous bleeds. No spontaneous bleeds were serious enough to require treatment. The annualized bleeding rate at the time of this analysis was 0.4 for treated bleeds. The safety profile in these younger patients was consistent with the findings in previous studies, with no new safety issues noted and all reported adverse events were local injection-site reactions.
These results are quite promising and suggest that treatment of hemophilia A with emicizumab can safely start at birth. Continued monitoring of these infants over the 7 years of follow-up should provide useful long-term data on joint health and safety.
(Genentech. (2022, December 10). Interim data from Phase III study presented at ASH 2022 show Hemlibra (emicizumab-kxwh) achieved meaningful bleed control in infants from birth. [Press release]. Retrieved January 2023 from
https://www.gene.com/media/press-releases/14975/2022-12-10/interim-data-from-phase-iii-study-presen)
Released: January 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
LSD Therapy Seen as Effective for Anxiety
Psychedelics such as LSD [lysergic acid diethylamide] and psilocybin induce profound, acute mood alterations and mystical-type experiences, primarily by interacting with the serotonin 5HT2A receptor. Because of those effects on mood, they have been posited as an alternative treatment option for anxiety. Most research in the therapeutic potential of psychedelics used psilocybin, but a current study investigated the effects of LSD on anxiety, depression, and overall psychiatric symptomatology in patients with anxiety associated with life-threatening illnesses and in those with anxiety without life-threatening illness.
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The Swiss study, a multicenter, randomized, double-blind, placebo-controlled, crossover design, aimed to corroborate the findings of a small pilot study, in which patients who received LSD demonstrated trends toward reduction in anxiety associated with life-threatening illness. The trial also included patients with psychiatric anxiety disorders in the absence of life-threatening illness. In the crossover design, the patients underwent two 200-µg LSD sessions and two placebo sessions. All patients were intended to receive both LSD and placebo. To be included in the study, patients with life-threatening disorders had to meet the DSM-IV criteria for anxiety disorder or score at least 40 points on the state or trait scales of the Spielberger State-Trait Anxiety Inventory (STAI) at study inclusion. Those without life-threatening illnesses had to meet DSM-IV criteria for at least one anxiety disorder; elevated STAI scores were not sufficient for inclusion.
The study involved a screening visit and two 24-week treatment periods per participant. Each treatment period consisted of two treatment sessions and five study visits, with treatment sessions separated by 6 weeks. Study visits occurred at baseline, between treatment sessions, and at 2, 8, and 16 weeks after the second treatment session, with the 16-week visit counting as the end-of-study visit. Results were analyzed for 42 participants, 20 patients who had a life-threatening illness and anxiety and 22 with anxiety disorder not associated with an illness.
Use of LSD during two treatment sessions induced rapidand lasting reductions in anxiety, depression, and general psychiatric symptoms for up to 16 weeks. Effects were maximal at the 2-week study visit and were sustained up to 16 weeks. Least-square mean change for baseline in STAI-Global score at 16 weeks was –14.9 in the LSD group and +1.3 in the placebo group, for a significant difference in anxiety reduction. Similar effects were observed for ratings of comorbid depression: the difference on the Hamilton Depression Rating Scale, 21-item was –7.0 and on the Beck Depression Inventory was –6.1. Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Clinical response (30% or greater reduction in STAI-G scores) was seen in 65% (13/20) in the LSD group and in 9% (2/22) in the placebo group at any outcome visit.
Transient, mild adverse effects were reported by 8 patients (19%) and one serious treatment-related adverse event (acute treatment anxiety and delusions) occurred. The serious effect was successfully treated with lorazepam and olanzapine, and the patient then received 100 µg at the second treatment session. In addition, in 3 patients, the dose in the second session was decreased because the response during the first session was considered too strong. The authors strongly recommend the use of two doses, as such a schedule allows the patient to become more familiar with the effects of psychedelics and potentially have better experiences in cases like these, where the first dose was challenging.
No real blinding was possible in this study, because of the characteristic effects of LSD; in addition, due to the crossover design, patients who received LSD in the first treatment session had persistent therapeutic effects that continued into the second treatment period whether they received placebo or LSD. Also, both patients and therapists were highly motivated, which might be difficult to replicate in the general population. Larger trials will be needed to confirm these findings. (Holze, F., et al. (2023). Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: A randomized, double-blind, placebo-controlled phase II study. Biol Psychiatr, 93(3), 215-223. Retrieved January 2023 from https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01553-0/fulltext)
Released: January 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Rituximab for Connective Tissue Disease-Associated Interstitial Lung Disease
Management of interstitial lung disease (ILD) associated with connective tissue disease (CTD) has been challenging. International guidelines recommend IV cyclophosphamide for severe or progressive scleroderma-associated ILD, but its use is limited by adverse effects. Rituximab is often used as rescue therapy for treatment-refractory CTD-associated ILD but has not been studied in clinical trials. A report in The Lancet Respiratory Medicine described the findings of the first study to compare these two treatments for CTD-associated ILD.
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The RECITAL study is a randomized, double-blind, double-placebo, phase 2b trial that compared IV rituximab with IV cyclophosphamide for CTD-ILD, using a design that included a range of CTD diagnoses. Between December 2014 and March 2020, 145 participants were recruited from specialist ILD or rheumatology centers in the UK. Patients ages 18 to 80 (mean age, 56.6 years) with severe or progressive ILD related to scleroderma (n = 37), idiopathic inflammatory myositis (n = 44), or mixed connective tissue disease (n = 16) were randomized to IV rituximab (1,000 mg on day 0 and day 14, with placebo given every 4 weeks from week 4 to week 20; n = 51) or to IV cyclophosphamide (600 mg/m2 BSA every 4 weeks to week 20 with placebo given on day 14; n = 50).
Improvement in lung function was measured in changes from baseline in forced vital capacity at 24 weeks; researchers found no significant differences between the two groups: The unadjusted mean increase in forced vital capacity at 24 weeks was 99 mL with cyclophosphamide and 97 mL with rituximab. Improvements were also seen in quality of life scores on various tools: quality of life scores on the St. George’s Respiratory Questionnaire, in which higher scores indicate more respiratory-related limitations, fell by 4.8 points at week 24 in the cyclophosphamide group and by 3.4 points in the rituximab group; on the King’s Brief Interstitial Lung Disease questionnaire, scores improved by 9.4 points in the cyclophosphamide group and by 8.8 points in the rituximab group at 24 weeks. Overall survival, progression-free survival, and time to treatment failure did not differ significantly between groups.
Rituximab use was associated with a lower number of adverse events (445 vs. 646 with cyclophosphamide) and with a 13.3% reduction in concomitant corticosteroid use. Cyclophosphamide use has been limited by toxicity (nausea, GI upset, hematuria, and increased risk of gonadal failure and of bladder cancer). This trial offers evidence supporting rituximab use and demonstrating that it may be a safe alternative to cyclophosphamide in CTD-ILD patients. Future studies could examine its use as part of combination treatment for CTD-ILD patients. (Manfredi, A., et al. (2023). Rituximab for connective tissue disease-associated interstitial lung disease. Lancet Respir Med, 11(1), 3-4. Retrieved January 2023 from https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00356-3/fulltext?dgcid=raven_jbs_etoc_email; Maher, T. M., et al. (2023). Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): A double-blind, double-dummy, randomized, controlled, phase 2b trial. Lancet Respir Med, 11(1), 45-54. Retrieved January 2023 from https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00359-9/fulltext?dgcid=raven_jbs_etoc_feature_lanres#seccestitle10)
Released: January 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Rituximab for Connective Tissue Disease-Associated Interstitial Lung Disease
Management of interstitial lung disease (ILD) associated with connective tissue disease (CTD) has been challenging. International guidelines recommend IV cyclophosphamide for severe or progressive scleroderma-associated ILD, but its use is limited by adverse effects. Rituximab is often used as rescue therapy for treatment-refractory CTD-associated ILD but has not been studied in clinical trials. A report in The Lancet Respiratory Medicine described the findings of the first study to compare these two treatments for CTD-associated ILD.
The RECITAL study is a randomized, double-blind, double-placebo, phase 2b trial that compared IV rituximab with IV cyclophosphamide for CTD-ILD, using a design that included a range of CTD diagnoses. Between December 2014 and March 2020, 145 participants were recruited from specialist ILD or rheumatology centers in the UK. Patients ages 18 to 80 (mean age, 56.6 years) with severe or progressive ILD related to scleroderma (n = 37), idiopathic inflammatory myositis (n = 44), or mixed connective tissue disease (n = 16) were randomized to IV rituximab (1,000 mg on day 0 and day 14, with placebo given every 4 weeks from week 4 to week 20; n = 51) or to IV cyclophosphamide (600 mg/m2 BSA every 4 weeks to week 20 with placebo given on day 14; n = 50).
Improvement in lung function was measured in changes from baseline in forced vital capacity at 24 weeks; researchers found no significant differences between the two groups: The unadjusted mean increase in forced vital capacity at 24 weeks was 99 mL with cyclophosphamide and 97 mL with rituximab. Improvements were also seen in quality of life scores on various tools: quality of life scores on the St. George’s Respiratory Questionnaire, in which higher scores indicate more respiratory-related limitations, fell by 4.8 points at week 24 in the cyclophosphamide group and by 3.4 points in the rituximab group; on the King’s Brief Interstitial Lung Disease questionnaire, scores improved by 9.4 points in the cyclophosphamide group and by 8.8 points in the rituximab group at 24 weeks. Overall survival, progression-free survival, and time to treatment failure did not differ significantly between groups.
Rituximab use was associated with a lower number of adverse events (445 vs. 646 with cyclophosphamide) and with a 13.3% reduction in concomitant corticosteroid use. Cyclophosphamide use has been limited by toxicity (nausea, GI upset, hematuria, and increased risk of gonadal failure and of bladder cancer). This trial offers evidence supporting rituximab use and demonstrating that it may be a safe alternative to cyclophosphamide in CTD-ILD patients. Future studies could examine its use as part of combination treatment for CTD-ILD patients. (Manfredi, A., et al. (2023). Rituximab for connective tissue disease-associated interstitial lung disease. Lancet Respir Med, 11(1), 3-4. Retrieved January 2023 from https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00356-3/fulltext?dgcid=raven_jbs_etoc_email; Maher, T. M., et al. (2023). Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): A double-blind, double-dummy, randomized, controlled, phase 2b trial. Lancet Respir Med, 11(1), 45-54. Retrieved January 2023 from https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00359-9/fulltext?dgcid=raven_jbs_etoc_feature_lanres#seccestitle10)
Released: January 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer