1374. Integrated Safety Summary of Omadacycline: A Novel Aminomethylcycline Antibiotic

Abstract Background Omadacycline (OMC) is a novel aminomethylcycline with activity against Gram-positive, many Gram-negative, anaerobic, and atypical pathogens. It is in clinical development as once-daily oral (PO) and intravenous (IV) monotherapy for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Cumulative safety results from Phase 3 clinical trials are reported. Methods This pooled safety analysis is based on 2,150 subjects: OASIS-1 (N = 645), OASIS-2 (N = 735) in ABSSSI; OPTIC (N = 770) in CABP. Comparators were linezolid (LZD) 600 mg IV then PO in ABSSSI (n = 689); moxifloxacin (MOX) 400 mg IV then PO in CABP (n = 388). Safety parameters included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and electrocardiogram (ECG) findings. Results A total of 1,073 subjects received OMC: 705 received OMC IV then PO (ABSSSI, n = 323; CABP, n = 382); 368 received OMC PO only for ABSSSI. Overall, 60.6% were male and 91.6% white; mean age ranges were 44.7–45.1 and 60.9–62.1 years in ABSSSI and CABP studies, respectively. TEAEs were observed in 47.5% (OMC), 41.2% (LZD), and 48.5% (MOX) of subjects, with gastrointestinal events the most common TEAEs. Serious TEAEs were low (3.6% OMC, 1.9% LZD, 6.7% MOX). Nausea (14.9% OMC, 8.7% LZD, 5.4% MOX) and vomiting (8.3% OMC, 3.9% LZD, 1.5% MOX) were the most frequently reported TEAEs. Diarrhea was observed in 2.4% OMC, 2.9% LZD, and 8.0% MOX subjects, with no cases of Clostridium difficile in OMC-treated subjects. Most TEAEs were mild to moderate and did not result in study drug discontinuation (3.1% OMC, 1.5% LZD, 7.0% MOX); 4 OMC, 1 LZD, and 0 MOX subjects discontinued for nausea and vomiting. Frequency of hepatic TEAEs was similar for OMC, LZD, and MOX: 4.3% OMC, 4.1% LZD, and 4.5% MOX subjects had post-baseline ALT >3× upper limit of normal. Vital signs and ECGs had comparable clinically notable values post-baseline in each treatment group. Known tetracycline class adverse events such as fungal infections were similar in all groups. Conclusion Pooled analyses demonstrate a favorable OMC safety profile, consistent with its tetracycline heritage. OMC was generally well tolerated in subjects with ABSSSI and CABP, with infrequent treatment discontinuations. Disclosures T. M. File Jr., BioMerieux: Consultant, Consulting fee; Curetis: Consultant, Consulting fee; Melinta Therapeutics: Consultant, Consulting fee; Merck: Consultant, Consulting fee; Motif Bio: Consultant, Consulting fee; Nabriva Therapeutics: Consultant and Investigator, Consulting fee and Research grant; Paratek Pharmaceuticals: Consultant, Consulting fee; Pfizer: Consultant, Consulting fee. T. Van Der Poll, Paratek Pharmaceuticals: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary.

Download Full-text

Liposomal Amphotericin B IV (LIPO AB) Once Per Week Is Effective in the Prevention of Invasive Fungal Infections (IFI) in Patients (Pts) with Acute Leukemia: Preliminary Analysis of a Randomized Trial.

Blood ◽

10.1182/blood.v110.11.1824.1824 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1824-1824

Author(s):

Gloria Mattiuzzi ◽

Jorge Cortes ◽

Deborah Blamble ◽

Elihu Estey ◽

Hagop Kantarjian

Keyword(s):

Adverse Events ◽

Randomized Trial ◽

Fungal Infections ◽

Performance Status ◽

Study Drug ◽

Disease Status ◽

Myelogenous Leukemia ◽

Remission Induction ◽

Drug Discontinuation ◽

Grade 3

Abstract Background: IFI remain an important cause of morbidity and mortality in pts with acute myelogenous leukemia or high risk myelodysplastic syndrome (AML/HR-MDS). We have previously shown that voriconazole (VORI) or LIPO AB 3 mg/kg/day TIW were effective prophylactic regimens in AML/HR-MDS. LIPO AB given once every week achieves tissue levels expected to prevent IFI, decreases the risk for infusion-related adverse events (IRE) and would simplify prophylaxis. Materials and Methods: We conducted a 3-arm randomized trial comparing LIPO AB, 3 mg/kg/d TIW (LIPO AB 3); versus LIPO AB 9 mg/kg/d, 1/week (LIPO AB 9); versus VORI 200 mg PO 2/day among pts with AML/MDS undergoing induction or salvage chemotherapy (CHEMO). Pts were stratified by age and disease status and randomized to receive any of the 3 regimens 24 hours after completion of CHEMO. Serum Galactomannan Index (GMI) was obtained 2/week while CT scan of chest (CT) was performed for persistent fever after 3 days of broad spectrum antibiotics. Proven and probable IFI were defined according to EORTC/MSG criteria. The results of the first 59 pts (of 150 planned) enrolled between Dec 06 -July 07 are presented. Results: Pts characteristics and response are shown in Table 1. All pts had Zubrod performance status ≤ 2 and most underwent remission induction chemo (90% in each group). No significant differences were observed on key baseline characteristics. Three of the 59 pts did not receive study drug (AMBI 9=2; VORI=1) and were excluded from efficacy and safety analysis. There were no proven IFI; 3 pts developed probable pulmonary Aspergillosis [GMI(+); CT (+), cultures (−) ], while 10 pts received additional empirical antifungal therapy (AFT) because of FUO [ 7 pts; GMI (−), CT (−), cultures (−)] or pneumonia [ 3 pts; GMI (−), cultures (−)]. None of these 10 pts developed proven/probable IFI. Two pts in each study arm developed reversible side effects that lead to drug discontinuation [AMBI 3: Grade 2 hyperbilirubinemia (1); Grade 3 infusion related events (1); AMBI 9: Grade 3 infusion related event (2); VORI: Grade 2 hyperbilirubinemia (1), visual hallucinations (1)]. Overall mortality was 5% (1 pt/arm). There were no IFI-related deaths. Conclusion: Intermittent LIPO AB (3 mg/kg/d TIW or 9 mg/kg/d, 1/week) and VORI 200 mg PO 2/day prophylaxis appear to be effective and well-tolerated regimens. Enrollment of additional pts is ongoing. Table 1 LIPO AB 3 (n=20) LIPO AB 9 (n=20) VORI (n=19) *p=ns; **p=0.061 Median age* (range) 60 (40–79) 60 (23–69) 58 (31–77) Pts in protected environment* (%) 80 65 79 Diabetes mellitus**, n(%) 1 (5) 1 (5) 5 (26) Median days on prophylaxis* (range) 17 (1–34) 14 (1–37) 17 (1–37) Efficacy and adverse events LIPO AB 3 (n=20) LIPO AB 9 (n=18) VORI (n=18) No IFI*, n(%) 14 (70) 14 (78) 15 (83) Proven/Probable IFI*, n(%) 2 (10) 1 (5) 0 Empiric AFT*, n(%) 4 (10) 3 (17) 3 (17) Adverse events*, n 4 4 3 All drug-related*, n(%) 2 (10) 2 (11) 2 (11)

Download Full-text

684. Cardiac Safety in Adults with Community-Acquired Bacterial Pneumonia (CABP) Treated with Lefamulin (LEF) or Moxifloxacin (MOX): Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.752 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S311-S311

Author(s):

Borje Darpo ◽

Anita F Das ◽

Daniel Stein ◽

Jennifer Schranz ◽

Steven P Gelone

Keyword(s):

Torsade De Pointes ◽

Significant Risk ◽

Study Drug ◽

Qt Prolongation ◽

Drug Discontinuation ◽

Cardiac Safety ◽

Study Results ◽

Minute Interval ◽

Clinically Significant ◽

Study Drug Discontinuation

Abstract Background Preclinical data suggest potential effects of LEF on cardiac interval parameters. We therefore assessed LEF cardiac safety from the LEAP 1/2 trials. Methods In LEAP 1, PORT III–V patients received LEF 150mg IV q12h for 5–7 days or MOX 400mg IV q24h for 7 days, with optional IV-to-oral switch (600mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Patients with known QT prolongation or on medication with potential to prolong the QT interval were excluded as per MOX label. After 5 minutes of rest in the supine position, triplicate 12-lead ECGs were obtained within a 5-minute interval at Screening in both studies, on Days 1/3 in LEAP 1 (predose and ≤15 minutes after first IV dose), and on Days 1/4 in LEAP 2 (predose and 1–3 hours after first oral dose), and sent to a central ECG reader for adjudication. Results Of 1,282 randomized/treated patients (n = 641/group), 1,274 had baseline (BL) and post-BL ECG data (n = 636 LEF, n = 638 MOX). Consistent with the resolution of infection, ECGs revealed mean reductions of 7–8 beats/minute for both groups in both studies. The largest mean change in QTcF from BL to post-BL was on Day 3 in LEAP 1 (13.6 and 16.4 msec with IV LEF and MOX, respectively) and on Day 4 in LEAP 2 (9.3 and 11.6 msec with oral LEF and MOX, respectively). The proportion of patients meeting potentially important post-BL QTcF values/changes was comparable between treatment groups (table). In the standardized MedDRA query of Torsade de pointes/QT prolongation (broad), the most common treatment-emergent adverse event was ECG QT prolonged (n = 4 LEF, n = 5 MOX). All events were nonserious and mild or moderate in severity. 6 events were considered study drug related (n = 4 LEF, n = 2 MOX). 5 events led to study drug discontinuation (n = 2 LEF, n = 3 MOX). In 2 patients with cardiovascular disease, 1 had ventricular arrhythmia on Day 20 (18 days after last LEF dose) and 1 had cardiac arrest on Day 18 (9 days after last MOX dose); both events were fatal and considered unrelated to study drug by investigator. Conclusion Mild prolongation of the QTcF interval was seen with LEF and MOX, with somewhat smaller effects seen with LEF. Given the small effect, LEF is unlikely to pose a clinically significant risk of ventricular proarrhythmia with appropriate precautions and use. Disclosures All authors: No reported disclosures.

Download Full-text

MMRM vs joint modeling of longitudinal responses and time to study drug discontinuation in clinical trials using a “de jure” estimand

Pharmaceutical Statistics ◽

10.1002/pst.2045 ◽

2020 ◽

Vol 19 (6) ◽

pp. 909-927

Author(s):

Alberto García‐Hernandez ◽

Teresa Pérez ◽

María del Carmen Pardo ◽

Dimitris Rizopoulos

Keyword(s):

Clinical Trials ◽

Study Drug ◽

Joint Modeling ◽

Drug Discontinuation ◽

Study Drug Discontinuation

Download Full-text

Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00425-10 ◽

2010 ◽

Vol 54 (10) ◽

pp. 4143-4149 ◽

Cited By ~ 29

Author(s):

Andreas H. Groll ◽

Gerda Silling ◽

Charlotte Young ◽

Rainer Schwerdtfeger ◽

Helmut Ostermann ◽

...

Keyword(s):

Stem Cell ◽

Combination Therapy ◽

Adverse Events ◽

Amphotericin B ◽

Hematopoietic Stem Cell ◽

Liposomal Amphotericin ◽

Fungal Infections ◽

Study Drug ◽

Invasive Fungal Infections ◽

Hematopoietic Stem

ABSTRACT The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.

Download Full-text

Therapeutic care in metastatic renal cell carcinoma during the follow-up phase of the RECORD-1 phase III trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e17531 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e17531-e17531

Author(s):

D. Wiederkehr ◽

R. Casciano ◽

L. Stern ◽

J. Zheng ◽

J. Baladi

Keyword(s):

Clinical Trial ◽

Mtor Inhibitor ◽

Kinase Inhibitors ◽

Study Drug ◽

Protein Kinase Inhibitors ◽

Phase Iii ◽

Drug Discontinuation ◽

Study Drug Discontinuation ◽

Trial Setting

e17531 Background: Following drug discontinuation for progression or adverse event in a clinical trial for relapsed or stage IV kidney cancer, supportive care including surgery, palliative radiotherapy, or bisphosphonates continue to be recommended by National Comprehensive Cancer Network (NCCN). However, published data on active therapeutic agents given to patients following study drug discontinuation in recent clinical trials is limited. Methods: World Health Organization Anatomical Therapeutic Chemical codes or therapeutic names, captured from the follow-up phase in a phase III clinical trial (RECORD-1) of patients with metastatic renal cell carcinoma (mRCC) patients, were used to describe antineoplastic therapies following discontinuation of study drug. Prior to trial, patients had progressed on at least one VEGFr-TKI therapy. Results: Of the 130 patients with follow-up after discontinuation of study drug, 78.5% received at least one of the following: corticosteroids, radiotherapy, protein kinase inhibitors, mTOR inhibitor, pyrimidine analogues, monoclonal antibodies, interferons, and investigational drugs. Among patients who received an active agent, nearly three-quarters (73.5%) utilized targeted therapy (protein kinase inhibitors, mTOR inhibitor, monoclonal antibodies). Conclusions: In a clinical trial setting with mRCC patients who have received several classes of systemic therapy, care delivered following study drug discontinuation often includes an active antineoplastic agent, despite the limited supportive evidence in this setting. While the placebo control with supportive care in a double-blind phase is acceptable to evaluate the efficacy and safety of a therapy for regulatory approval purposes, decision makers must also consider how these data may inform comparisons with the usual alternatives available to and used by physicians and patients in the non-trial setting. [Table: see text]

Download Full-text

Comparison of Time-to-First Event and Recurrent-Event Methods in Randomized Clinical Trials

Circulation ◽

10.1161/circulationaha.117.033065 ◽

2018 ◽

Vol 138 (6) ◽

pp. 570-577 ◽

Cited By ~ 22

Author(s):

Brian Claggett ◽

Stuart Pocock ◽

L.J. Wei ◽

Marc A. Pfeffer ◽

John J.V. McMurray ◽

...

Keyword(s):

Clinical Trials ◽

Statistical Power ◽

Recurrent Events ◽

Randomized Clinical Trials ◽

Cox Model ◽

Study Drug ◽

Recurrent Event ◽

Drug Discontinuation ◽

Patient Heterogeneity ◽

Study Drug Discontinuation

Background: Most phase-3 trials feature time-to-first event end points for their primary and secondary analyses. In chronic diseases, where a clinical event can occur >1 time, recurrent-event methods have been proposed to more fully capture disease burden and have been assumed to improve statistical precision and power compared with conventional time-to-first methods. Methods: To better characterize factors that influence statistical properties of recurrent-event and time-to-first methods in the evaluation of randomized therapy, we repeatedly simulated trials with 1:1 randomization of 4000 patients to active versus control therapy, with true patient-level risk reduction of 20% (ie, relative risk=0.80). For patients who discontinued active therapy after a first event, we assumed their risk reverted subsequently to their original placebo-level risk. Through simulation, we varied the degree of between-patient heterogeneity of risk and the extent of treatment discontinuation. Findings were compared with those from actual randomized clinical trials. Results: As the degree of between-patient heterogeneity of risk increased, both time-to-first and recurrent-event methods lost statistical power to detect a true risk reduction and confidence intervals widened. The recurrent-event analyses continued to estimate the true relative risk (0.80) as heterogeneity increased, whereas the Cox model produced attenuated estimates. The power of recurrent-event methods declined as the rate of study drug discontinuation postevent increased. Recurrent-event methods provided greater power than time-to-first methods in scenarios where drug discontinuation was ≤30% after a first event, lesser power with drug discontinuation rates of ≥60%, and comparable power otherwise. We confirmed in several actual trials of chronic heart failure that treatment effect estimates were attenuated when estimated via the Cox model and that increased statistical power from recurrent-event methods was most pronounced in trials with lower treatment discontinuation rates. Conclusions: We find that the statistical power of both recurrent-events and time-to-first methods are reduced by increasing heterogeneity of patient risk, a parameter not included in conventional power and sample size formulas. Data from real clinical trials are consistent with simulation studies, confirming that the greatest statistical gains from use of recurrent-events methods occur in the presence of high patient heterogeneity and low rates of study drug discontinuation.

Download Full-text

Abstract 078: Implications of Patient-Reported Treatment Satisfaction for Discontinuation of Rivaroxaban versus Warfarin in ROCKET-AF

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.10.suppl_3.078 ◽

2017 ◽

Vol 10 (suppl_3) ◽

Author(s):

Fatima Rodriguez ◽

Leo Ungar ◽

Anne Hellkamp ◽

Richard C Becker ◽

Scott D Berkowitz ◽

...

Keyword(s):

Treatment Satisfaction ◽

Patient Reported Outcomes ◽

Study Drug ◽

Drug Discontinuation ◽

Women Patients ◽

Double Blind ◽

Loss To Follow Up ◽

Patient Reported ◽

Study Drug Discontinuation

Background: Patient-reported outcomes and satisfaction are important in both trials and clinical practice and may be associated with treatment adherence. Methods: ROCKET-AF was a randomized, double-blind trial of rivaroxaban versus warfarin for prevention of thromboembolism in patients with atrial fibrillation. In a substudy, we compared treatment satisfaction scores: Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). Patient-driven discontinuation included stopping study drugs due to withdrawal of consent, non-compliance, or loss to follow-up. Rates of discontinuation were calculated for participants above and below the median scores for each scale. Results: Of 14,264 patients in ROCKET AF, 1,181 (8.3%; median age 75 years; 34% women) patients completed both the ACTS and TSQM II questionnaires 4 weeks after starting the study drug. Over a median follow-up of 1.6 years, 450 premature study drug discontinuations occurred, 116 (26%) patient-driven. Patients less satisfied with treatment by the ACTS Benefits and Burdens and TSQM II scales had higher rates of study drug discontinuation ( Table ). Conclusions: Patient-reported satisfaction was lower in patients with study drug discontinuation, suggesting that collecting patient-reported outcomes early in clinical trials may guide interventions that improve adherence and clinical outcomes.

Download Full-text

Comparison of the effects of Tripterygii totorum and sulfasalazine on rheumatoid arthritis: A retrospective cohort study

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i2.26 ◽

2020 ◽

Vol 19 (2) ◽

pp. 421-425

Author(s):

Renchun Huang ◽

Yongliang Tang ◽

Jiali Zeng

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Events ◽

Retrospective Cohort ◽

Therapeutic Potential ◽

Vital Signs ◽

Controlled Trials ◽

American College Of Rheumatology ◽

Safety Parameters ◽

Biochemical Indices

Purpose: To compare, in a retrospective study, the effects and safety profiles of Tripterygii totorum and sulfasalazine in patients with rheumatoid arthritis (RA) following 24 weeks of treatment. Methods: RA patients (n = 164) who were treated with Tripterygii totorum or sulfasalazine from August 2012 to February 2016 were included in this study. The major end-point was ≥ 20 % improvement as per American College of Rheumatology (ACR) criterion (ACR 20 response) after 24 weeks. Moreover, ACR 50 and ACR 70 responses were studied. The safety parameters investigated comprised of adverse events, vital signs, as well as hematological and biochemical indices (blood counts, electrolyte levels, and kidney and liver function). Results: At 24 weeks, ACR 20 response was 57.32 % in patients on Tripterygii totorum, while the corresponding value in patients on sulfasalazine was 39.02 % (p = 0.02). In the Tripterygii totorum group, ACR 50 response was 41.46 %, while ACR 70 response was 29.27 %. In sulfasalazine group, ACR 50 response was identified in 26.83 % of the patients, while ACR 70 response was seen in 21.95 % of patients. Adverse events were greater in the Tripterygii totorum group than in sulfasalazine group. Conclusion: These results suggest that Tripterygii Totorum significantly mitigates RA, with a tolerable safety profile. However, there is need for long-term or controlled trials to ascertain the therapeutic potential of Tripterygii totorum in RA. Keywords: Traditional Chinese medicine, Tripterygii totorum, Sulfasalazine, Rheumatoid arthritis

Download Full-text

Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1073 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A526-A527

Author(s):

Monica R Gadelha ◽

Murray B Gordon ◽

Mirjana Doknic ◽

Emese Mezősi ◽

Miklós Tóth ◽

...

Keyword(s):

Adverse Events ◽

Treatment Period ◽

Somatostatin Receptor ◽

Study Drug ◽

Receptor Ligands ◽

Primary Analysis ◽

Once Daily ◽

Safety And Efficacy ◽

Somatostatin Receptor Ligands ◽

Long Acting

Abstract Patients with acromegaly not cured by surgery are often initially treated with injected peptide long-acting somatostatin receptor ligands (SRLs). Non-peptide small molecules can also activate the somatostatin receptor and do so with a high degree of precision for the target therapeutic receptor subtype. Paltusotine (formerly CRN00808) is a small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%) and pharmacokinetic profile suitable for once daily dosing. In healthy volunteers, paltusotine has been shown to lower growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. We hypothesized that patients with acromegaly could switch from injected SRLs to once daily oral paltusotine while maintaining baseline IGF-1 levels. ACROBAT Edge (NCT03789656) was a single-arm study designed to evaluate the safety and efficacy of switching from injected SRLs to paltusotine in patients with acromegaly. The primary analysis population consisted of those who had not achieved normal IGF-1 levels despite stable therapy with long-acting octreotide or lanreotide. Eligible patients received their last injection of SRL 4 weeks prior to switching to once daily oral paltusotine monotherapy for a 13-week treatment period. The starting dose of 10 mg per day was uptitrated in 10 mg increments at specified study visits to a maximal dose of 40 mg per day based on protocol specified study drug toleration and IGF-1 criteria. The primary endpoint was change in IGF-1 from baseline to the completion of the 13-week treatment period. Statistical testing was based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. In addition, the rise in IGF-1 during a 4-week washout period was used to provide supportive evidence of efficacy. Twenty-five patients were enrolled in the primary analysis group, three patients discontinued from the study for non-study drug related reasons, two during the treatment period and one during the washout period after completing treatment. The primary endpoint was achieved as paltusotine treatment resulted in no significant change in IGF-1 levels at week 13 compared to baseline [change in IGF-1 =-0.034 (-0.107, 0.107), median (IQR), p>0.6]. Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-1 levels at the end of treatment that were within 20% of baseline or lower. Median IGF-1 values rose significantly after paltusotine washout (p<0.0001). The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment related serious adverse events. These results suggest that patients with acromegaly treated with injected SRLs can switch to oral paltusotine while maintaining IGF-1 and that paltusotine appeared to be well tolerated.

Download Full-text

Abstract 15140: Older Participant Perspectives on Permanent Study Drug Discontinuation in an Ongoing Primary Prevention Trial of Statins: A Qualitative Study

Circulation ◽

10.1161/circ.142.suppl_3.15140 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Zhen Zhou ◽

Mark R Nelson

Keyword(s):

Side Effects ◽

Primary Prevention ◽

Study Drug ◽

Prevention Trial ◽

Drug Discontinuation ◽

Primary Prevention Trial ◽

Trial Entry ◽

Study Drug Discontinuation ◽

Major Factors ◽

Older Populations

Introduction: Study drug discontinuation is commonplace in clinical trials of older populations and poses a major challenge to trial investigators. Little is known about why older participants discontinue the study drug. This study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥70 years within an ongoing primary prevention trial of statins by tapping into their experiences and perceptions. Methods: Trial participants who had permanently discontinued the study drug within 2 years of randomization were purposively sampled based on age (<75 and ≥75 years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analyzed thematically. Results: Thirty participants took part (21 females; mean age, 77 years) and three themes were identified from the data. Perceived adverse events (AEs) and their impact on daily living (mobility, functional capacity, quality of life, etc.) were identified as the major factors leading to the participants permanently discontinuing their study drug. Muscle symptoms were the most commonly reported AE. Selected participant quotes which describe symptoms and their impact are presented in Table. For some, a challenging life circumstance further lowered their tolerance to the perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. concerns about possible side effects, GP advice, unrelated illness). Conclusion: Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry and offering timely medical assistance and support when AEs occur may be useful to reduce drug discontinuation rates.

Download Full-text