scholarly journals Initial response of young people with thyrotoxicosis to block and replace or dose titration thionamide

2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Claire L Wood ◽  
Niamh Morrison ◽  
Michael Cole ◽  
Malcolm Donaldson ◽  
David B Dunger ◽  
...  
Keyword(s):  
Initial Response ◽  
Patient Characteristics ◽  
Thyroid Stimulating Hormone ◽  
Phase Iii ◽  
Dose Titration ◽  
Rank Test ◽  
Z Score ◽  
Open Label ◽  
Dose Time ◽  
Open Label Trial

Objective Patients with thyrotoxicosis are treated with anti-thyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT). Design A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy. Methods Patients commenced 0.75 mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum thyroid-stimulating hormone (TSH)/free thyroxine (FT4) normalisation and BMI Z-score change. Results There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9 mg/kg/day (BR) and 0.5 mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 vs 51.7 pmol/L; 95% CI for difference 1.73, 31.7; P = 0.029). Time to normalise FT4 levels was reduced in DT (log-rank test, P = 0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) vs 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57, 0.86; P < 0.001) and was greatest in patients with higher baseline FT4 concentrations. Conclusions DT-treated patients normalised FT4 concentrations more quickly than BR. Overall, 94% of patients have normal FT4 levels after 6 months, but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy.

scholarly journals Randomised trial of block and replace vs dose titration thionamide in young people with thyrotoxicosis

2020 ◽  
Vol 183 (6) ◽  
pp. 637-645
Author(s):  
Claire L Wood ◽  
Michael Cole ◽  
Malcolm Donaldson ◽  
David B Dunger ◽  
Ruth Wood ◽  
...  
Keyword(s):  
Young People ◽  
Reference Range ◽  
Randomised Trial ◽  
Thyroid Stimulating Hormone ◽  
Phase Iii ◽  
Dose Titration ◽  
Open Label ◽  
Levothyroxine Replacement ◽  
The Mean ◽  
Serum Tsh

Objective First-line treatment of thyrotoxicosis in young people is thionamide anti-thyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control. Design A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2–17 years with newly diagnosed thyrotoxicosis at 15 UK centres. Methods Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid-stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4 years outcome (remission/relapse). Results Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60.2% in BR and 63.8% in DT patients; adjusted difference 4.3%, 95% CI (−7.8 to 16.4); P = 0.48. Proportions for FT4 were 79.2% in BR and 85.7% in DT patients; adjusted difference 6.8%, (−0.2 to 15.6); P = 0.13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y. Conclusion This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.

scholarly journals Safety and Efficacy of Oral Octreotide in Acromegaly: Results of a Multicenter Phase III Trial

2015 ◽  
Vol 100 (4) ◽  
pp. 1699-1708 ◽  
Author(s):  
Shlomo Melmed ◽  
Vera Popovic ◽  
Martin Bidlingmaier ◽  
Moises Mercado ◽  
Aart Jan van der Lely ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Phase Iii ◽  
Dose Titration ◽  
Controlled Study ◽  
Open Label ◽  
The Core ◽  
End Of Treatment ◽  
Label Dose ◽  
Somatostatin Receptor Ligand ◽  
Oral Therapeutic

Background: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. Methods: We enrolled 155 complete or partially controlled patients (IGF-1 &lt;1.3 × upper limit of normal [ULN], and 2-h integrated GH &lt;2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Results: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 &lt;1.3 × ULN and mean integrated GH &lt;2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. Conclusions: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

scholarly journals Randomized Phase III Study Comparing Paclitaxel–Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC 30983

2012 ◽  
Vol 30 (8) ◽  
pp. 792-799 ◽  
Author(s):  
Ronald de Wit ◽  
Iwona Skoneczna ◽  
Gedske Daugaard ◽  
Maria De Santis ◽  
August Garin ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Cancer ◽  
Group Versus ◽  
Progression Free Survival ◽  
Germ Cell Cancer ◽  
Phase Iii ◽  
Rank Test ◽  
Primary Analysis ◽  
Open Label ◽  
Number Of Patients

Purpose To compare the efficacy of four cycles of paclitaxel–bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC). Patients and Methods Patients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m2 in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual. Results Accrual was from November 1998 to April 2009. A total of 169patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a good prognosis of GCC (eight patients administered BEP; six patients administered T-BEP) or a poor prognosis of GCC (one patient administered BEP; four patients administered T-BEP). PFS at 3 years (intent to treat) was 79.4% in the T-BEP group versus 71.1% in the BEP group (hazard ratio [HR], 0.73; CI, 0.47 to 1.13; P [log-rank test] = 0.153). PFS at 3 years in all eligible patients was 82.7% versus 70.1%, respectively (HR, 0.60; CI: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different. Conclusion T-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4514-4514 ◽  
Author(s):  
H. Narahara ◽  
W. Koizumi ◽  
T. Hara ◽  
A. Takagane ◽  
T. Akiya ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Primary Endpoint ◽  
Standard Treatment ◽  
High Response Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Open Label ◽  
Eligibility Criteria ◽  
Phase Iii Study

4514 Background: S-1 has been widely used against advanced gastric cancer (AGC) not only as monotherapy but also in combination with other cytotoxic compounds. Results of a phase I/II study combining S-1 + cisplatin (CDDP) were very encouraging with a high response rate (RR) of 76%, and the MST (Median Survival Time) of 383 days (Koizumi W et al, Br J Cancer, 2003). Based on these results, a phase III study comparing S-1 alone with S-1 + CDDP has been conducted to further evaluate the efficacy and safety for S-1 + CDDP as a standard treatment for AGC. Methods: This is a randomized, controlled, open-label, parallel, multicenter study. Patients (pts) are randomized to one of two treatment arms. Arm A: Pts receive oral S-1 (40 mg/m2) twice daily 28 days followed by 14 days rest. Arm B: Pts receive oral S-1 (40 mg/m2) twice daily 21 days followed by 14 days rest plus CDDP (60 mg/m2) iv on day 8. Eligibility criteria included unresectable/recurrent AGC, age 20–74, no prior chemotherapy for AGC. Primary endpoint was overall survival (OS). Main secondary endpoints included RR, time to treatment failure (TTF) and toxicity. Based on planned sample size of 284 pts, the trial was designed to have 90% power to detect an improvement in median OS from 8 to 12 months (2-sided log-rank test; significance level 0.05). Results: 305 pts (Arm A/B, 152/153) were randomized between Mar 2002 and Nov 2004. The eligible pts were 299 (Arm A/B, 150/149). Median age was 62.0/61.5 yrs. At a 2 yrs follow-up since last patient in, the MST for Arm A was 335.5 days (95%CI: 292.0 - 402.0) and for Arm B was 396.0 days (95%CI: 342.0 - 471.0). The OS for Arm B was superior to Arm A (log-rank p=0.0366, hazard ratio: 0.774, 95% CI: 0.608 - 0.985). RR was 31.1% for Arm A and 54.0% for Arm B. In Arm A vs Arm B, the most common grade 3/4 toxicities were: leucopenia, 2.0% vs 11.5%; neutropenia, 10.7% vs 39.9%; anemia (decreased Hb), 4.0% vs 25.7%; nausea, 1.3% vs 11.5%; anorexia, 6.0% vs 30.4%. No treatment related death was observed. Conclusions: The combination treatment of S-1 and CDDP met primary endpoint of OS, and was found to be effective and well tolerated in pts with AGC. Accordingly, this regimen can be regarded as one of first-line standard treatment for AGC. No significant financial relationships to disclose.

An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE).

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA5506-LBA5506 ◽  
Author(s):  
J. H. Machiels ◽  
S. Subramanian ◽  
A. Ruzsa ◽  
G. Repassy ◽  
I. Lifrenko ◽  
...  
Keyword(s):  
Supportive Care ◽  
Egf Receptor ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Dose Titration ◽  
Controlled Study ◽  
Rank Test ◽  
Meaningful Improvement ◽  
Platinum Based Chemotherapy ◽  
Ecog Ps

LBA5506 Background: Zalutumumab is a novel, fully human IgG1 mAb targeting the EGFr that has shown encouraging activity in SCCHN. Methods: Patients with noncurable SCCHN with an ECOG PS of 0-2 and centrally documented radiographic progressive disease (PD) within 6 months after platinum-therapy were randomized between zalutumumab monotherapy and best supportive care (BSC) in a 2:1 ratio. Stratification parameter was ECOG PS. Methotrexate (MTX) was allowed in the BSC arm only. Individual dose-titration of zalutumumab was applied (max. exposure 16 mg/kg). The primary endpoint was overall survival (OS), with progression free survival (PFS) as the only secondary endpoint to be compared between groups, using log-rank test. 231 deaths were required to statistically differentiate OS between groups with 80% power. Results: 286 patients (34F, 252M) were randomized. The median age was 57 years (range 18-78), 65% had distant metastasis and 17% were ECOG PS 2, all similar between groups. 78% of patients in BSC arm received MTX. Although a median OS of 6.7 months was observed in the zalutumumab group compared to 5.2 in the BSC group, this was not statistically significant (p=0.065). A clear improvement in PFS (P=0.001) was demonstrated. Zalutumumab showed a safety profile as expected within this drug class. Conclusions: This is the first controlled study to demonstrate that an EGFr-targeted antibody given as monotherapy induces a clinically meaningful improvement in PFS in patients with SSCHN who have failed platinum-based chemotherapy. [Table: see text] [Table: see text]

Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival

2003 ◽  
Vol 21 (4) ◽  
pp. 631-637 ◽  
Author(s):  
Jin-Ching Lin ◽  
Jian-Sheng Jan ◽  
Chen-Yi Hsu ◽  
Wen-Miin Liang ◽  
Rong-San Jiang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Concurrent Chemoradiotherapy ◽  
Combined Treatment ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Concurrent Chemotherapy ◽  
Phase Iii ◽  
Rank Test ◽  
Free Survival

Purpose: Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumor. This randomized phase III trial compared concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in patients with advanced NPC. Patients and Methods: From December 1993 to April 1999, 284 patients with 1992 American Joint Committee on Cancer stage III to IV (M0) NPC were randomly allocated into two arms. Similar dosage and fractionation of RT was administered in both arms. The investigational arm received two cycles of concurrent chemotherapy with cisplatin 20 mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Baseline patient characteristics were comparable in both arms. After a median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P = .0022). The 5-year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P = .0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for ≥ 1 week for another nine patients. There were no treatment-related deaths in either arm. Conclusion: We conclude that CCRT is superior to RT alone for patients with advanced NPC in endemic areas.

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