scholarly journals Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome

2017 ◽  
Vol 35 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Matthew H. Kulke ◽  
Dieter Hörsch ◽  
Martyn E. Caplin ◽  
Lowell B. Anthony ◽  
Emily Bergsland ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Treatment Period ◽  
Carcinoid Syndrome ◽  
Tryptophan Hydroxylase ◽  
Phase Iii ◽  
Gamma Glutamyl Transferase ◽  
Open Label ◽  
Double Blind ◽  
Open Label Extension ◽  
Glutamyl Transferase

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were –0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were –0.9, –1.7, and –2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

056 Perampanel and secondarily generalised seizures in a pooled analysis of phase III studies and their open-label extension: effect of enzyme-inducing antiepileptic drugs

2018 ◽  
Vol 89 (6) ◽  
pp. A23.2-A23
Author(s):  
David Ko ◽  
Betsy Williams ◽  
Anna Patten ◽  
Antonio Laurenza
Keyword(s):  
Antiepileptic Drugs ◽  
Phase Iii ◽  
Adjunctive Treatment ◽  
Seizure Freedom ◽  
Partial Seizures ◽  
Open Label ◽  
Double Blind ◽  
Link Type ◽  
Open Label Extension ◽  
Phase Iii Studies

IntroductionPerampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures (SGS), and primary generalised tonic-clonic seizures in epilepsy patients aged ≥12 years. Approval of perampanel for partial seizures was based on three randomised, double-blind, placebo-controlled, Phase III Studies 304 (NCT00699972), 305 (NCT00699582) and 306 (NCT00700310); patients completing these could enter open-label extension (OLEx) Study 307 (NCT00735397). Here, we report efficacy of perampanel as adjunctive treatment of SGS by co-administration of enzyme-inducing antiepileptic drugs (EIAEDs) versus non-EIAEDs in both the Phase III and OLEx studies.MethodsIn the double-blind studies, patients (≥12 years) with partial seizures, with or without SGS, receiving 1–3 AEDs at Baseline were randomised to placebo or 2–12 mg/day perampanel for 19 weeks. In the OLEx, patients received ≤12 mg/day perampanel for ≤272 weeks. Efficacy assessments included median percent change in SGS frequency/28 days, SGS 50% and 75% responder and seizure-freedom rates.ResultsFor patients with SGS at pre-perampanel Baseline, 564 were in the double-blind studies and 388 received perampanel for ≥1 year in the OLEx. In the double-blind studies, perampanel co-administered with an EIAED (carbamazepine, eslicarbazepine, oxcarbazepine, phenytoin) had reduced efficacy compared with non-EIAEDs due to increased clearance; this was particularly evident at higher doses, although these differences were still greater than placebo. In the OLEx, concomitant administration of both non-EIAEDs and EIAEDs was associated with sustained efficacy, with slightly better efficacy during the first, second and third years of perampanel exposure for non-EIAEDs compared with EIAEDs.ConclusionPerampanel demonstrated good and sustained long-term efficacy against SGS. With the recent FDA approval of perampanel for monotherapy use for partial seizures, non-EIAED data may be more relevant for consideration if perampanel is used as a single agent (no other AED) while real-world data and experience are accumulated.Study supportEisai Inc.

Eszopiclone for Insomnia

2005 ◽  
Vol 39 (10) ◽  
pp. 1659-1666 ◽  
Author(s):  
Sarah T Melton ◽  
Jill M Wood ◽  
Cynthia K Kirkwood
Keyword(s):  
Geriatric Patients ◽  
Data Extraction ◽  
Data Sources ◽  
Phase Iii ◽  
Chronic Insomnia ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Open Label Extension ◽  
Sleep Parameters

Objective: To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of eszopiclone in the treatment of transient and chronic insomnia in adult and geriatric patients. Data Sources: A MEDLINE literature search (1966–May 2005) was conducted to retrieve articles and abstracts involving eszopiclone. The manufacturer of the drug provided a general summary of clinical data and abstracts of unpublished Phase III clinical trials. Study Selection and Data Extraction: All articles identified from the data sources were reviewed, and information deemed relevant was included for this review. Data Synthesis: Food and Drug Administration approval of eszopiclone was based on 6 double-blind, placebo-controlled trials. Five trials published in abstract or study form were reviewed. The sixth trial was not available for evaluation. An open-label continuation trial was also reviewed. All studies showed statistically significant improvements in sleep parameters in adult and elderly patients treated for insomnia with eszopiclone. CONCLUSIONS: The results of the 5 available double-blind, placebo-controlled studies (and 1 open-label, 6-month extension) showed that eszopiclone was safe and effective in the treatment of transient and chronic insomnia in adult and geriatric patients. Tolerance with long-term exposure (6 mo) and rebound insomnia were not observed. The results of the 6-month, open-label extension trial demonstrated that improvements in sleep parameters were sustained. Future studies comparing eszopiclone with other non benzodiazepine sedative–hypnotics (eg, zolpidem, zaleplon) are needed with cost data to clearly define the role of eszopiclone in the pharmacotherapy of chronic insomnia.

JAKARTA: A phase III, multicenter, randomized, double-blind, placebo-controlled, three-arm study of SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF with splenomegaly.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS6639-TPS6639 ◽  
Author(s):  
Animesh Dev Pardanani ◽  
Jorge E. Cortes ◽  
Francisco Cervantes ◽  
Claire N Harrison ◽  
Francesco Passamonti ◽  
...  
Keyword(s):  
Phase 1 ◽  
Primary Myelofibrosis ◽  
Phase Iii ◽  
Open Label ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Allele Burden ◽  
Open Label Extension ◽  
Symptom Response ◽  
Ecog Ps

TPS6639 Background: SAR302503 is an orally administered selective JAK-2 inhibitor being evaluated for the treatment of MF. In a phase 1 study, SAR302503 reduced spleen size and disease-related symptoms and provided clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing open-label extension of this trial confirmed the durability of those results and found that doses between 400–500 mg/day of SAR302503 represented the optimal balance between safety and efficacy (Pardanani, ASH 2011;Abs 3838). These results led us to initiate a Phase 3 trial in December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 mg/day, compared with placebo, for the treatment of patients with MF (NCT01437787; EFC12153). Methods: Eligibility criteria include age of at least 18 years, platelets >50,000/µl, ECOG PS 0–2, and a diagnosis of high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF according to IPSS criteria (Blood 2009;113:2895). Patients are being randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned treatment will continue as long as patients are deriving benefit or until progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or in case of progression before completion of 6 cycles according to predefined criteria. The primary endpoint is spleen response (≥35% reduction in spleen volume by MRI/CT at the end of cycle 6). Key secondary objectives are symptom response rate and durability of spleen response. Additional secondary endpoints include assessment of allele burden and bone marrow fibrosis reduction. It is planned to randomize 75 patients per treatment group at approximately 130 sites worldwide.

scholarly journals Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab

2020 ◽  
pp. 1-4
Author(s):  
G. Klein ◽  
P. Delmar ◽  
G.A. Kerchner ◽  
C. Hofmann ◽  
D. Abi-Saab ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Amyloid Plaque ◽  
Emission Tomography ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Positron Emission ◽  
Open Label Extension ◽  
Phase Iii Trials ◽  
Clinical Benefits

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer’s disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.

scholarly journals Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial

2018 ◽  
Vol 25 (3) ◽  
pp. 309-322 ◽  
Author(s):  
Marianne Pavel ◽  
David J Gross ◽  
Marta Benavent ◽  
Petros Perros ◽  
Raj Srirajaskanthan ◽  
...  
Keyword(s):  
Carcinoid Syndrome ◽  
Tryptophan Hydroxylase ◽  
Somatostatin Analogs ◽  
Confidence Limits ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Bowel Movements ◽  
Hydroxyindoleacetic Acid

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of −54.0% (95% confidence limits, −85.0%, −25.1%, P < 0.001) and −89.7% (95% confidence limits, −113.1%, −63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

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