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Results for “phase 3”

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PubMed2026

Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial.

BACKGROUND: Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes. METHODS: This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA1c (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J). FINDINGS: Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies. INTERPRETATION: Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes. FUNDING: Eli Lilly. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Aged↗

PubMed2026

A Phase 3 Trial of Vosoritide in Children with Hypochondroplasia.

BACKGROUND: Hypochondroplasia, a fibroblast growth factor receptor 3 (FGFR3)-related skeletal condition characterized by disproportionate short stature and a spectrum of clinical features, has no available targeted therapies. Vosoritide, a C-type natriuretic peptide analogue approved for the treatment of achondroplasia, is being investigated for hypochondroplasia. METHODS: In this phase 3, multicenter trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen. The primary end point was change from baseline in annualized growth velocity at week 52 versus placebo. Confirmatory statistical testing using hierarchical procedures to control for type I error at the one-sided 0.025 significance level (equivalent to the two-sided 0.05 level) was performed for the primary and six key secondary efficacy end points. The safety and side effect profile of vosoritide versus placebo was assessed. RESULTS: A total of 81 participants were randomly assigned to receive vosoritide (n=41) or placebo (n=40). At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus -0.39 cm/year with placebo (LSM difference of 2.33 cm/year; 95% confidence interval, 1.85-2.82 cm/year; two-sided P<0.0001). Most participants in the vosoritide group (87.8%) and the placebo group (72.5%) experienced at least one adverse event (AE). There were no reports of grade 3 or higher AEs, AEs leading to treatment discontinuation, or deaths. CONCLUSIONS: One year of vosoritide treatment significantly increased linear growth in children with hypochondroplasia. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT06455059.).

Journal Article↗

PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗

PubMed2026

Efficacy and safety of mitapivat in adults with transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: The absence of disease-modifying therapies for patients with α-thalassaemia and oral disease-modifying therapies for patients with β-thalassaemia has been a substantial unmet need in these patients. We assessed the efficacy and safety of mitapivat, an oral allosteric activator of pyruvate kinase, in adults with transfusion-dependent thalassaemia. METHODS: ENERGIZE-T is a global, double-blind, randomised, placebo-controlled, phase 3 trial, conducted across 19 countries in North America, Europe, Asia-Pacific, South America, and the Middle East. Patients aged 18 years or older with transfusion-dependent α-thalassaemia or β-thalassaemia were randomly allocated (2:1) with a central interactive response technology system, stratified by geographical region and thalassaemia genotype, to receive 100 mg mitapivat or placebo orally twice a day for 48 weeks. The primary endpoint was transfusion reduction response (TRR), defined as a reduction of at least 50% in transfused red blood cell units with a reduction of at least two units in any consecutive 12-week period until week 48 compared with baseline. Efficacy was analysed in the full analysis set, comprising all randomly allocated patients. Type, severity, and relationship of adverse events and serious adverse events were assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT04770779) and is active but not recruiting. FINDINGS: Between Nov 30, 2021 and May 2, 2023, 305 patients were screened, of whom 258 were randomly allocated (median age 33·5 years [IQR 27·0-44·0]; 136 [53%] female and 122 [47%] male participants). Of 258 patients allocated, 238 (92%) completed the double-blind treatment period. All patients were required to have a safety follow-up approximately 4 weeks after the final dose of study drug, regardless of completion of the double-blind period or continuation into the open-label extension period. In the full analysis set, TRRs occurred in 52 (30%) of 171 patients in the mitapivat group and 11 (13%) of 87 in the placebo group (adjusted difference 18 percentage points [95% CI 8-27]; two-sided p=0·0003). The safety analysis set comprised 172 patients in the mitapivat group (including one patient allocated to the placebo group who received one dose of mitapivat in error) and 85 in the placebo group. Adverse events were reported in 155 (90%) patients treated with mitapivat and 71 (84%) treated with placebo; the most common events with mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhoea, and fatigue. Serious adverse events were reported in 19 (11%) patients treated with mitapivat and 13 (15%) treated with placebo. Ten (6%) patients who received mitapivat and one (1%) who received placebo discontinued study treatment due to adverse events. No deaths were reported. INTERPRETATION: Mitapivat significantly reduced the transfusion burden and was generally well tolerated, showing a favourable benefit-risk profile. These findings support mitapivat as the first oral disease-modifying therapy for adults with transfusion-dependent α-thalassaemia or β-thalassaemia, providing a new treatment option to reduce transfusion burden in this patient population. FUNDING: Agios Pharmaceuticals, Inc.

Adult↗

PubMed2025

Vaccine efficacy of NVX-CoV2373 against SARS-CoV-2 infection in adolescents in the USA: an ancillary study to a phase 3, observer-blinded, randomised, placebo-controlled trial.

BACKGROUND: Although existing COVID-19 vaccines are known to be highly effective against severe disease and death, data are needed to assess their ability to reduce SARS-CoV-2 infection. We aimed to estimate the efficacy of the NVX-CoV2373 protein subunit vaccine against SARS-CoV-2 infection, regardless of symptoms, among adolescents. METHODS: We performed an ancillary observational study (SNIFF) to the phase 3, observer-blinded, randomised, placebo-controlled PREVENT-19 trial that assessed vaccine efficacy against symptomatic COVID-19 in the USA. Participants in the PREVENT-19 trial included healthy adolescents aged 12-17 years and with no history of laboratory-confirmed SARS-CoV-2 infection. They were randomly assigned (2:1) to receive either the NVX-CoV2373 (Novavax, Gaithersburg, MD, USA) vaccine (immediate NVX-CoV2373 group) or placebo (delayed NVX-CoV2373 group) on days 0 and 21 (initial series). After 2 months, in a crossover series, participants received two doses, 21 days apart, of the intervention that they did not receive in their initial series. Participants at 47 of the PREVENT-19 sites were invited to participate in the SNIFF study and self-collect nasal swabs at home twice weekly for SARS-CoV-2 testing to assess vaccine efficacy against SARS-CoV-2 infection. This primary outcome was defined as the first identification of SARS-CoV-2 detected by RT-PCR, regardless of symptoms, with onset within 4 weeks after the second dose of the initial vaccination series until the second dose of the crossover series. Secondary outcomes were vaccine efficacy against asymptomatic and minimally symptomatic SARS-CoV-2 infection, durability of vaccine efficacy against SARS-CoV-2 infection, and durability of vaccine efficacy against asymptomatic and minimally symptomatic infections. Outcomes were analysed in the modified intention-to-treat population, which included all participants without previous SARS-CoV-2 infection and was restricted to participants enrolled within 4 weeks of the second dose of the primary (primary analysis population) or crossover (post-crossover analysis population) series. This study is registered with ClinicalTrials.gov (NCT04611802). FINDINGS: Between June 1 and Dec 17, 2021, 1196 (53·2%) of the 2247 adolescent participants recruited in the PREVENT-19 trial enrolled in the SNIFF study. The primary analysis population included 471 participants in the immediate NVX-CoV2373 group and 220 in the delayed NVX-CoV2373 group. Incidence of SARS-CoV-2 infection was 14·9 cases per 100 person-years (95% CI 7·9-25·5) in the immediate group and 54·2 cases per 100 person-years (33·6-82·9) in the delayed group; vaccine efficacy was 73·5% (95% CI 47·1-86·7; p=0·0002). Incidence of minimally symptomatic or asymptomatic SARS-CoV-2 infection was 10·3 cases per 100 person-years (95% CI 4·7-19·6) in the immediate group and 36·1 cases per 100 person-years (19·8-60·7) in the delayed group; vaccine efficacy was 72·8% (95% CI 37·1-88·2; p=0·0023). After the second crossover dose, incidence of SARS-CoV-2 was 14·6 cases per 100 person-years (95% CI 8·6-23·0) in the immediate group (receiving placebo at crossover) and 9·1 cases per 100 person-years (3·0-21·3) in the delayed group, with a durability ratio of 160·3 (95% CI 59·5-431·6; p=0·35). Almost all infections after crossover were minimally symptomatic or asymptomatic, with a durability ratio of 151·4 (55·9-410·4; p=0·41). INTERPRETATION: Among adolescents participating in the PREVENT-19 trial during the delta (B.1.617.2) variant wave of the COVID-19 pandemic, the NVX-CoV2373 vaccine was highly efficacious against SARS-CoV-2 infection regardless of symptoms, indicating its potential to reduce the reservoir of infections that contribute to community transmission. FUNDING: US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Adolescent↗

PubMed2003

Unusual findings of benign enchondroma in the ulna on 3-phase bone scintigraphy.

Enchondroma is a common benign cartilaginous tumor arising from the medullary cavity, most commonly in the phalanges and metacarpals of the hand. Enchondroma involving the ulna is very rare. Typically, benign enchondroma shows normal or only slightly increased uptake of a bone-seeking agent on delayed bone scintigraphy. Markedly increased activity of enchondroma with pain is most often associated with pathologic fracture or malignant degeneration. The authors present the 3-phase bone scintigraphic findings of a benign enchondroma associated with pain, which showed focal hyperperfusion, hyperemia, and intense bone uptake in the distal right ulna.

Adult↗

PubMed2006

A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma.

OBJECTIVES: This study compared the complications and the cancer control of elective nephron-sparing surgery (NSS) and radical nephrectomy (RN) in patients with a small (<or=5 cm), solitary, low-stage N0 M0 tumour suspicious for renal cell carcinoma (RCC) and a normal contralateral kidney. METHODS: 541 patients were randomised in a prospective, multicentre, phase 3 trial to undergo NSS (n=268) or RN (n=273) together with a limited lymph node dissection. RESULTS: This publication reports only on the complications reported for both surgical methods. The rate of perioperative blood loss<0.5l was slightly higher after RN (96.0% vs. 87.2%) and the rate of severe haemorrhage was slightly higher after NSS (3.1% vs. 1.2%). Ten patients (4.4%), all of whom were treated with NSS, developed urinary fistulas. Pleural damage (11.5% for NSS vs. 9.3% for RN) and spleen damage (0.4% for NSS and 0.4% for RN) were observed with similar rates in both groups. Postoperative computed tomography scanning abnormalities were seen in 5.8% of NSS and 2.0% of RN patients. Reoperation for complications was necessary in 4.4% of NSS and 2.4% of RN patients. CONCLUSIONS: NSS for small, easily resectable, incidentally discovered RCC in the presence of a normal contralateral kidney can be performed safely with slightly higher complication rates than after RN. The oncologic results are eagerly awaited to confirm that NSS is an acceptable approach for small asymptomatic RCC.

Aged↗

PubMed2026

Desmodium styracifolium Total Flavone Capsules for Urolithiasis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: No oral medication is currently approved for the management of urolithiasis. Guang Jing Qian Cao (Desmodium styracifolium total flavone capsules; hereinafter, Guang Jing), a traditional Chinese herbal extract, has shown clinical benefits for urolithiasis, but randomized clinical trials are needed to assess its effectiveness. OBJECTIVE: To evaluate whether Guang Jing improves stone passage rates (SPRs) compared with placebo in adults with urolithiasis. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 34 sites in China from December 2017 to April 2020. Participants included adults (aged 18-70 years) with diagnosed ureteral stones. Data analysis was conducted on November 4, 2020. INTERVENTION: Participants were randomized 3:1 to receive oral Guang Jing (0.6 g) or matching placebo 3 times daily for 28 days, in addition to investigator-prescribed background medication. MAIN OUTCOMES AND MEASURES: The primary outcome was SPR by day 28, confirmed by computed tomography. Secondary outcomes included SPR by day 14, stone migration rate, and stone migration distance. Between-group comparisons were performed using the Cochran-Mantel-Haenszel test for categorical outcomes and t tests for continuous outcomes. RESULTS: A total of 606 participants were randomly assigned to receive Guang Jing (n = 458) or placebo (n = 148). Their mean (SD) age was 43.0 (12.0) years, 474 (78.2%) were male, and the mean (SD) stone size was 0.6 (0.1) cm. The SPR by day 28 was significantly higher for the Guang Jing group compared with the placebo group (204 of 457 [44.6%] vs 50 of 148 [33.8%]; relative risk, 1.32 [95% CI, 1.03-1.69]; P = .03), with an absolute risk difference of 10.9 (95% CI, 2.0-19.7) percentage points. No significant between-group differences in SPR by day 14 (Guang Jing vs placebo: 133 [29.1%] vs 33 [22.3%]; P = .14) or stone migration distance (mean [SD], 29.5 [51.8] mm vs 29.7 [43.8] mm; P = .11) were observed. Adverse event rates were similar for the Guang Jing and placebo groups (88 [19.3%] vs 27 [18.2%]). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, treatment with Guang Jing significantly increased the expulsion of 5- to 10-mm ureteral stones by day 28, with a favorable safety profile. These findings suggest that Guang Jing may be an additional medical expulsive therapy option for appropriately selected patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR-IIR-17013275.

Humans↗

PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗

PubMed2026

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged↗

PubMed2026

A phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vosoritide in children with hypochondroplasia: CANOPY HCH-3 study design.

BACKGROUND: Hypochondroplasia is a skeletal dysplasia characterized by disproportionate short stature that is caused by gain-of-function variants in the fibroblast growth factor receptor 3 gene (FGFR3), which negatively regulates endochondral bone growth. Current treatments are based on symptom management; there are no treatments targeting the signaling pathways that underlie hypochondroplasia. Vosoritide, a C-type natriuretic peptide analog that counteracts overactive FGFR3 signaling to stimulate endochondral bone growth, is approved for the treatment of achondroplasia in children. A phase 1/2 clinical trial demonstrated that vosoritide treatment for 1 year increased growth in children with hypochondroplasia and was well-tolerated. OBJECTIVES: The objectives of CANOPY HCH-3 are to evaluate the efficacy and safety of vosoritide for the treatment of hypochondroplasia in children. DESIGN: CANOPY HCH-3 was a phase 3, randomized, double-blind, placebo-controlled, multicenter study. METHODS AND ANALYSIS: Children aged ≥3 to <18 years with confirmed hypochondroplasia who had ≥6 months of pre-treatment standing height from a prior observational study before randomization were enrolled. Participants were randomized to receive 52 weeks of daily treatment with vosoritide or placebo, followed by 2 weeks of safety follow-up. The primary endpoint is change from baseline in annualized growth velocity at week 52 versus placebo. ETHICS: CANOPY HCH-3 was conducted in accordance with the Council for International Organizations of Medical Sciences International Ethical Guidelines, the principles of the Declaration of Helsinki and of Good Clinical Practice, and applicable laws and regulations. Protocols were approved by relevant local health authorities, ethics committees, and institutions. Written informed consent from the participant, or parent or legal guardian, was obtained prior to any study-related procedures being performed. DISCUSSION: CANOPY HCH-3 will provide further evidence for the efficacy and safety of vosoritide in children with hypochondroplasia.

clinical trial↗

PubMed1989

Prediction of terminal atrial myocardial repolarisation from incomplete phase 3 data.

The duration of the monophasic action potential (MAP) carries prognostic antiarrhythmic information when the recording is done during sinus rhythm (SR) after DC conversion of atrial fibrillation (AF). This study analyses whether it is possible to predict MAP duration during sinus rhythm by analysing the atrial MAP during AF, even though complete myocardial repolarisation is never reached during this arrhythmia. We have therefore evaluated the estimated duration of the action potential (AP) and MAP by exponential extrapolation of phase 3 data. (1) AP studies were done on 11 human atrial myocardial specimens. Resting membrane potential (RMP) and AP duration were better identified when more data obtained during repolarisation were used for prediction. Thus the predicted RMP deviated on average by -0.4% of AF amplitude from the real RMP level when data to 90% repolarisation were used for extrapolation. AP duration at 90% repolarisation correlated well with the real AP duration (r = 0.88) at this level of data aquisition. (2) Continuous recording of atrial MAPs was done in 15 patients during AF and in 12 of these during SR after DC conversion. Resting myocardial repolarisation level during AF, RP(EST), and estimated MAP duration, MAPD(EST), could be calculated by exponential extrapolation in 12 patients. The actual repolarisation during fibrillation reached below 90% of the RP(EST) level in eight patients and below 70% in all 12. The MAP duration during SR could be predicted with increasing precision when data closer to the RP(EST) were used for calculation of MAPD(EST). Thus MAPD(EST) correlated well with SR MAP duration when data reaching at least 90% of RP were used (r = 0.85).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed2001

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.

BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

Aged↗

PubMed1996

[A phase 3 clinical trial of 123I-iomazenil, a new central-type benzodiazepine receptor imaging agent (Part 1)--report on clinical usefulness in diagnosis of various brain diseases].

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.

Adolescent↗

PubMed2001

3-phase bone imaging and SPECT in the follow up of patients with allogenic vascularized knee joint transplants.

UNLABELLED: Vascularized allotransplantation of knee joints under immunosuppression is a novel approach in orthopedic surgery. During the postoperative course immunosuppressive management depends on perfusion and viability of the graft. AIM: Evaluation of different diagnostic tools in regard to their usefulness and reliability to provide information about microvascularity and viability of vascularized knee joint allografts. METHODS: Four patients with allogenic knee joint transplants were studied up to 26 months after transplantation with 3-phase bone scans and SPECT. The results were compared with duplex sonography, angiography, and histology. RESULTS: Two cases without complications were characterized by adequate perfusion in duplex sonography, angiography and early bone scans. Late bone scans demonstrated increased bone metabolism of the transplant. Corresponding biopsy revealed viable bone cells. In one case with partial thrombosis and one case with complete thrombosis of the transplant vessels rapidly decreasing or missing perfusion was detected by duplex sonography, angiography, and bloodpool scintigraphy. Late bone scans showed reduced or absent bone metabolism. Biopsy demonstrated necrotic bone tissue. Due to the advantage of a tomographic technique SPECT allowed a more reliable assessment of graft viability as compared to planar imaging. CONCLUSION: Our findings confirm bone scintigraphy as a valuable diagnostic tool in patients with allogenic vascularized knee joint transplants. In contrast to other diagnostic approaches, scintigraphy provides reliable information on both viability and perfusion of the transplant within a single non-invasive clinical investigation.

Adolescent↗

PubMed2000

Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Acute Disease↗

PubMed1996

[The value of 3-phase spiral CT and magnetic resonance tomography in preoperative diagnosis of pancreatic carcinoma].

UNLABELLED: The purpose of this study was to assess the role of spiral computed tomography (SCT) and magnetic resonance imaging (MRI) in the preoperative work-up of patients with pancreatic carcinoma, regarding local resectability and vascular involvement. METHODS AND MATERIALS: A total of 28 patients (19 men and 9 women; mean age 58 years) with known or highly suspected carcinoma of the pancreas were included in this study. All patients prospectively underwent MRI ( +/- gadolinium-DTPA ) and SCT (3-phase examination) as preoperative diagnostic imaging studies, and laparotomy was carried out within 7 days, irrespective of the MRI or SCT findings. SCT and MR studies were reviewed independently by two radiologists, without knowing the results of the surgical exploration. Standardized image analysis was correlated with findings at laparatomy. RESULTS: Laparotomy identified 10 patients to be suitable for surgical resection and 18 pancreatic carcinomas to be unresectable. In 17 of 18 non-resectable carcinomas MRI and SCT were able to obtain correct information about unresectability (sensitivity 94%), in 7 (MRI), resp. 8 (SCT) carcinomas were correctly considered to be resectable (sensitivity 70% of MRI and 80% for SCT). The presence of vascular involvement was depicted by SCT with a sensitivity of 82-100% and 62-100% by MRI. The specificity varied between 85-100% for SCT and 77-100% for MRI. CONCLUSION: Both MRI and SCT are good techniques for the preoperative work-up of pancreatic carcinomas in order to obtain a correct assessment of local resectability.

Adult↗

PubMed2006

Demographic and behavioral contextual risk groups among men who have sex with men participating in a phase 3 HIV vaccine efficacy trial: implications for HIV prevention and behavioral/biomedical intervention trials.

Recent outbreaks of syphilis and gonorrhea coupled with reported increases in HIV-risk behavior among men who have sex with men (MSM) have raised concerns about a potential resurgence of HIV among MSM. These concerns have led some to suggest the need for a paradigm shift in how HIV-prevention programs are designed and implemented. In this analysis, baseline demographic, sexual partnership, and substance use information was used to identify contextual-risk groups among 5,095 HIV-seronegative MSM enrolled in a 36-month phase 3 HIV vaccine efficacy trial across 61 sites primarily in North America. Eight demographic and behavioral contextual risk groups were identified, with annualized HIV seroincidence ranging from 1.8% to 6.3% across groups. Men in primary HIV-serodiscordant relationships had the lowest HIV seroincidence (1.8%), while an older group of men with many sex partners had the highest (6.3%). Visit-schedule compliance and study retention were lowest among younger non-White men and highest among older popper users, with annualized HIV seroincidence of 2.9% and 3.5%, respectively. Differences in HIV incidence, study compliance, and retention observed among contextual-risk groups suggest that responsiveness to heterogeneity within risk group (eg, MSM) could benefit screening, enrollment, and retention of HIV-prevention programs and intervention trials, reducing the time and cost related to their design, implementation, and conclusion.

AIDS Vaccines↗