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

AbstractRecombinant 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.

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

Blood ◽

10.1182/blood-2011-10-386045 ◽

2012 ◽

Vol 119 (22) ◽

pp. 5111-5117 ◽

Cited By ~ 69

Author(s):

Aida Inbal ◽

Johannes Oldenburg ◽

Manuel Carcao ◽

Anders Rosholm ◽

Ramin Tehranchi ◽

...

Keyword(s):

Factor Xiii ◽

Autosomal Recessive Disorder ◽

Allergic Reactions ◽

Open Label ◽

Impaired Wound Healing ◽

Bleeding Rate ◽

Life Threatening ◽

A Subunit ◽

Bleeding Episodes ◽

Congenital Factor

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.

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A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG)

Clinical Infectious Diseases ◽

10.1093/cid/ciaa779 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kevinkumar Kansagra ◽

Deven Parmar ◽

Sanjeev Kumar Mendiratta ◽

Jatin Patel ◽

Shuchi Joshi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Neutralizing Antibodies ◽

Geometric Mean ◽

World Health ◽

Human Rabies ◽

Open Label ◽

Phase 3 ◽

Noninferiority Trial ◽

Rabid Animal ◽

Antibody Cocktail

Abstract Background Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. Methods This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. Results A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. Conclusions This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). Clinical Trials Registration CTRI/2017/07/009038.

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Peri-Operative Eltrombopag or Immune Globulin for Patients with Immune Thrombocytopaenia (The Bridging ITP Trial): Methods and Rationale

Thrombosis and Haemostasis ◽

10.1055/s-0038-1677531 ◽

2019 ◽

Vol 119 (03) ◽

pp. 500-507 ◽

Cited By ~ 2

Author(s):

Donald Arnold ◽

Erin Jamula ◽

Nancy Heddle ◽

Richard Cook ◽

Cyrus Hsia ◽

...

Keyword(s):

Platelet Count ◽

Randomized Trial ◽

Immune Globulin ◽

Elective Surgery ◽

Dose Titration ◽

Major Surgery ◽

Open Label ◽

Rescue Treatment ◽

Minor Surgery ◽

Secondary Endpoints

Background The Bridging ITP Trial is an open-label randomized trial designed to compare the oral thrombopoietin receptor agonist eltrombopag and intravenous immune globulin (IVIG) for patients with immune thrombocytopaenia (ITP) who require an increase in platelet count before elective surgery. Here, we report the study methods and rationale. Methods We designed a multi-centre, non-inferiority randomized trial comparing daily oral eltrombopag starting 3 weeks pre-operatively, and IVIG administered 1 week pre-operatively for patients with ITP requiring a platelet count increase prior to surgery. Starting dose of eltrombopag is 50 mg daily with a weekly pre-operative dose titration schedule, and treatment is continued for 1 week after surgical haemostasis is achieved. IVIG is administered at a dose of 1 to 2 g/kg 1 week pre-operatively with the allowance for a second dose within 1 week after surgical haemostasis. The objective of the study is to demonstrate non-inferiority of eltrombopag for the primary endpoint of achieving the pre-operative platelet count threshold (50 × 109/L for minor surgery; or 100 × 109/L for major surgery) and sustaining platelet count levels above the threshold for 1 week after surgical haemostasis is achieved, without the use of rescue treatment. Secondary endpoints include thrombosis, bleeding and patient satisfaction. Conclusion The Bridging ITP Trial will evaluate the efficacy and safety of eltrombopag as an alternative to IVIG in the peri-operative setting for patients with ITP. The protocol was designed to provide a management strategy that can be applied in clinical practice. ClinicalTrials.gov Identifier NCT01621204.

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Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

Blood ◽

10.1182/blood.v108.11.476.476 ◽

2006 ◽

Vol 108 (11) ◽

pp. 476-476 ◽

Cited By ~ 15

Author(s):

David Kuter ◽

James Bussel ◽

James George ◽

Louis Aledort ◽

Alan Lichtin ◽

...

Keyword(s):

Platelet Count ◽

Neutralizing Antibodies ◽

Sinus Thrombosis ◽

Therapeutic Option ◽

Subcutaneous Administration ◽

Transverse Sinus ◽

Platelet Response ◽

Open Label ◽

The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

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Long-Term Safety and Efficacy of Belimumab in Japanese Patients with SLE: a 7-Year Open-Label Continuation Study

Modern Rheumatology ◽

10.1093/mr/roab125 ◽

2021 ◽

Author(s):

Yoshiya Tanaka ◽

Paula Curtis ◽

Kathleen DeRose ◽

Regina Kurrasch ◽

Kyoko Kinoshita ◽

...

Keyword(s):

Lupus Erythematosus ◽

Japanese Patients ◽

Organ Damage ◽

Open Label ◽

Open Label Extension ◽

Secondary Endpoints ◽

Treatment Responses ◽

Favorable Safety ◽

Over Time

Abstract Objectives Evaluate long-term safety, tolerability and efficacy of belimumab in Japanese patients with systemic lupus erythematosus (SLE). Methods This was a subgroup analysis of Japanese patients who completed studies BEL113750 or BEL112341 and were enrolled in a Phase 3, open-label extension study (BEL114333; NCT01597622). Eligible patients received intravenous belimumab 10 mg/kg every 28 days for ≤7 years. Primary endpoint: safety and tolerability. Secondary endpoints included SLE responder index (SRI)-4 response rate, SRI-4 components, severe SLE flare, use of corticosteroids/other SLE-related treatments. Analyses were based on observed data from first parent or current study belimumab dose through to study end. Results Of 71 Japanese patients enrolled, 69.0% completed the study. Overall, 98.6% patients had adverse events (AEs); 32.4% had serious AEs. The proportion of SRI-4 responders increased progressively (Year 1, Week 24: 40.9% [27/66]; Year 7, Week 48: 84.6% [11/13]) as did the proportion of SELENA-SLEDAI responders. The proportion of patients with no worsening in PGA (91.2−100.0%) and no new organ damage (92.6−100.0%) remained stable over time. Severe SLE flare was experienced by 11.3% (8/71) of patients. Corticosteroid and immunosuppressant use decreased over time. Conclusion : Favorable safety profile and treatment responses with belimumab were maintained for ≤7 years in Japanese patients with SLE.

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Long-Term Efficacy and Safety of Liquid Abobotulinumtoxina Formulation for Moderate-To-Severe Glabellar Lines: A Phase III, Double-Blind, Randomized, Placebo-Controlled and Open-Label Study

Aesthetic Surgery Journal ◽

10.1093/asj/sjab329 ◽

2021 ◽

Author(s):

Philippe Kestemont ◽

Said Hilton ◽

Bill Andriopoulos ◽

Inna Prygova ◽

Catherine Thompson ◽

...

Keyword(s):

Patient Satisfaction ◽

Neutralizing Antibodies ◽

Well Being ◽

Phase Iii ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Term Efficacy ◽

Patient Reported

Abstract Background A ready-to-use liquid formulation of abobotulinumtoxinA (aboBoNT-A solution) has been developed. Objectives To assess long-term efficacy and safety of aboBoNT-A solution for glabellar lines (GL) treatment. Methods Multicenter, multinational, Phase III study (NCT02493946), with randomized double-blind placebo-controlled (DBPC; 2:1 aboBoNT-A solution 50 U: placebo) and open-label (OL; 4 cycles aboBoNT-A solution) periods; additional patients were recruited into the OL period. Patients were 18-65 years old; BoNT-naïve; dissatisfied/very dissatisfied with moderate/severe GLs at maximum frown. Investigator’s live assessment (ILA; primary endpoint)/subject’s self-assessment (SSA) of GL severity at maximum frown, patient satisfaction with GL appearance, and FACE-Q patient-reported scales (facial appearance overall, psychological well-being, aging) were assessed. Adverse events (AEs) were monitored. Analyses were performed on DBPC and long-term analysis (LTA; all patients receiving ≥ aboBoNT-A solution injection) populations. Results Mean ages of patients were 46.6–47.8 years, and 89.1–91.3% were female, across DBPC (N=190 [n=126 aboBoNT-A solution, n=64 placebo]) and LTA (N=595) populations. Responder rates for ILA, SSA and patient satisfaction were consistent at Day 29 post-injection across repeat LTA cycles (82.2–87.8%, 62.8–80.6% and 72.2–87.8%, respectively), with statistically significantly higher responder rates versus placebo (DBPC cycle; 81.6% versus 0.8%, 68.1% versus 2.3% and 83.1% versus 5.7%, respectively; all p<0.0001). Consistent improvements on FACE-Q scales occurred with repeat cycles (aboBoNT-A solution versus placebo, p<0.0001 [DBPC cycle]). No new or unexpected AEs, or neutralizing antibodies were observed. Conclusions Results support long-term efficacy and safety of aboBoNT-A solution, and its superiority over placebo, for GL treatment in adults.

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A phase I open-label study to investigate safety and tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MT-5111 in subjects with HER-2 positive tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.tps465 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. TPS465-TPS465

Author(s):

Brian Andrew Van Tine ◽

Minal A. Barve ◽

Erika Paige Hamilton ◽

Andrew Jacob Brenner ◽

Zev A. Wainberg ◽

...

Keyword(s):

Locally Advanced ◽

Maximum Tolerated Dose ◽

Resistance Mechanisms ◽

Primary Objective ◽

Receptor Internalization ◽

Her2 Positive ◽

Open Label ◽

Binding Domains ◽

Secondary Endpoints ◽

A Subunit

TPS465 Background: Engineered toxin bodies (ETBs) are proprietarily engineered from a Shiga-like Toxin A subunit fused to antibody-like binding domains. ETBs can force receptor internalization, self-route to the cytosol, and induce cell-kill via inactivation of ribosomes. MT-5111 is a 55 kDa de-immunized ETB targeting HER2, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibodies. It binds a HER2 epitope distinct from trastuzumab or pertuzumab, could be combined with other HER2 targeting agents, and may have improved tumor penetration. Methods: MT-5111 is evaluated as monotherapy in subj with confirmed HER2+ locally advanced or metastatic cancers. The primary objective is to determine the maximum tolerated dose in subjects (subj) with advanced HER2-positive tumors. Secondary endpoints are PK, tumor response and immunogenicity. Part 1 will escalate doses to identify MTD in up to 42 subj. Part 2 will further evaluate MT-5111 at the MTD in up to 98 subj. All subj will receive MT-5111 on Days 1, 8, and 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent or another reason for withdrawal. Part 1 will include subj with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastroesophageal cancer (GEA), and other HER2+ solid cancers. HER2+ must be demonstrated on metastatic lesions in case of metastases. Tumors tested by immunohistochemistry (IHC) must have IHC status of 2+ or 3+, regardless of in-situ hybridization (ISH) results; for BC and GEA, if no IHC is available, ISH per ASCO-CAP guidelines is used. Subj with HER2+ BC should have had at least 2 lines of HER2-directed therapy; subj with HER2+ gastric cancer should have received trastuzumab or have been intolerant to trastuzumab. Subj with evaluable disease may be included in Part 1; in Part 2, all subj must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac function should be adequate. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment has begun in September 2019. Clinical trial information: NCT04029922.

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Oral Deferasirox (Exjade®, ICL670) Is Effective, with a Clinically Manageable Safety Profile, in Pediatric β-Thalassemia Patients with High Iron Burden.

Blood ◽

10.1182/blood.v110.11.2779.2779 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2779-2779 ◽

Cited By ~ 1

Author(s):

Ali Taher ◽

Abdullah Al Jefri ◽

Mohsen Saleh Elalfy ◽

Kusai Al Zir ◽

Shahina Daar ◽

...

Keyword(s):

Safety Profile ◽

Treatment Success ◽

Surrogate Marker ◽

Open Label ◽

Therapeutic Goals ◽

Prior Therapy ◽

Secondary Endpoints ◽

Baseline Creatinine ◽

The Relationship

Abstract Background: The ESCALATOR study evaluated once-daily deferasirox in β-thal pts unsuccessfully chelated with DFO and/or deferiprone (L1). Phase II/III studies have shown that deferasirox 20–30 mg/kg/d maintains/reduces iron burden, depending on transfusional iron intake. However, PK evaluation indicated that exposure to deferasirox was lower in children than adults. To examine the relationship between dose and efficacy in heavily transfused children, a subanalysis of ESCALATOR pts (2–<16 years) was performed. Methods: ESCALATOR was a prospective, open-label, 1-year study. Enrolled pts had β-thal and transfusional iron overload (LIC ≥2 mg/g dw, serum ferritin [SF] ≥500 ng/mL), and had been unsuccessfully treated with prior mono- or combination therapy with DFO and/or L1. Pts began treatment with deferasirox 20 mg/kg/d, except 3 who started on 10 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as LIC reduction of ≥3 mg/g if baseline LIC was ≥10 mg/g, or final LIC of 1–7 mg/g if baseline LIC was 2–<10 mg/g. Secondary endpoints included absolute reduction in LIC and safety; SF was assessed as a surrogate marker for LIC. Results: Of 252 pts, 167 were children. In the year before study start, 150 received DFO, 1 L1 and 16 DFO + L1. Median (range) deferasirox dose was 22.6 (12–30) mg/kg/d. Overall, 130 children received dose adjustments to ≥25 mg/kg/d. Median (range) time to dose increase was 31 (8–48) wks. Treatment success rate was 56.9% (95% CI 49.5, 64.4). Mean (SD) baseline LIC and SF levels were 17.1 (8.5) mg/g and 3938 (2262) ng/mL, respectively. The most common drug-related AEs were mild/moderate skin rash (n=16) and vomiting (n=15). No deaths were reported. 46 pts with normal baseline creatinine values experienced increases >33% on ≥2 consecutive visits; values also exceeded ULN in 4 pts. Increases in ALT to >5 × ULN on ≥2 consecutive visits were noted in 21 children; baseline values were high in 16/21 pts. Mean (SD) LVEF increased by 2.5% (8.2). Physical and sexual development progressed normally. At EOS, most pts reported greater satisfaction, convenience and less time lost compared with prior therapy. In total, 94.6% of pts preferred deferasirox. Conclusions: These data suggest that with appropriate dosing, deferasirox can effectively control iron burden with a clinically manageable safety profile in heavily iron-overloaded children who were previously unsuccessfully chelated. Dose increases to ≥25 mg/kg/d were required to reach target reductions in iron burden, with no safety concerns. This highlights the importance of timely dose adjustments to achieve therapeutic goals. Pts preferred deferasirox to previous chelation therapy, which may improve long-term compliance. Mean (SD) change from baseline 95% CI LIC, mg/g (n=163) −3.0 (6.1) – Baseline LIC ≥7 mg/g (n=143) −3.5 (6.2) −4.5, −2.5 Baseline LIC <7 mg/g (n=20) +1.0 (3.9) – SF, ng/mL (n=165) −236 (1237) – Baseline EOS Satisfaction with chelator, % 17.4 92.8 Convenience of therapy, % 12.6 95.8 Hrs lost in past mo, mean (SD) 33.8 (47.8) 3.8 (9.6)

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Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study

SLEEP ◽

10.1093/sleep/zsz174 ◽

2019 ◽

Vol 42 (11) ◽

Cited By ~ 14

Author(s):

Yves Dauvilliers ◽

Isabelle Arnulf ◽

Zoltan Szakacs ◽

Smaranda Leu-Semenescu ◽

Isabelle Lecomte ◽

...

Keyword(s):

Adverse Effect ◽

Weight Gain ◽

Sleep Paralysis ◽

Open Label ◽

Safety And Efficacy ◽

Titration Period ◽

Secondary Endpoints ◽

First Time ◽

Histamine H3

Abstract Study Objectives To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy. Methods This open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters. Results Patients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case. Conclusions Long-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.

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Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz374 ◽

2019 ◽

Vol 74 (12) ◽

pp. 3588-3595 ◽

Cited By ~ 2

Author(s):

Pier Giorgio Cojutti ◽

Maria Merelli ◽

Matteo Bassetti ◽

Federico Pea

Keyword(s):

Trough Level ◽

Term Treatment ◽

Therapeutic Drug ◽

Interventional Study ◽

Open Label ◽

Long Term Treatment ◽

Group A ◽

Linezolid Therapy ◽

Dose Dependent

Abstract Background Thrombocytopenia may be a dose-dependent adverse effect of linezolid therapy. Objectives To assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment. Methods This was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2–8 mg/L) and platelet count assessment at day 3–5 and then once weekly up to the end of treatment. Results Sixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54 days. Thrombocytopenia occurred overall in 14.8% of cases (9/61). The incidence rate of thrombocytopenia was significantly lower (P=0.012) in both group A (10.7%; 3/28) and subgroup B1 (10.3%; 3/29) than in subgroup B2 (75.0%; 3/4). Thrombocytopenic patients belonging to both group A and group B1 recovered from thrombocytopenia without the need for discontinuing therapy. Multivariate linear regression analysis revealed that thrombocytopenia was independently associated with baseline platelet count and with median linezolid trough concentrations. Conclusions Proactive TDM of linezolid may be beneficial either in preventing or in recovering from dose-dependent thrombocytopenia, even when treatment lasts for more than 28 days. Larger prospective studies are warranted to confirm our findings.

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