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PubMed1995

Registration of drugs for treating cancer and HIV infection: a plea to carry out phase 3 trials before admission to the market.

Drugs for cancer and HIV infection tend to be admitted to the market on the basis of results from phase 2 trials. Assessing the benefit-risk balance with phase 2 trials often is difficult--the effect of the drug is usually temporary; the correlation between response or improvement of clinical measurements and the patient's wellbeing is often poor; and the side effects of drugs for these fatal diseases are serious. Therefore, although sometimes difficult to conduct, comparative trials that use standard treatment, placebos, or best supportive care remain the cornerstone for reliably assessing the benefit-risk balance.

Acquired Immunodeficiency Syndrome↗
PubMed2007

Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial.

BACKGROUND: A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would "qualify" for a trial to define a correlate of efficacy. METHODS: A total of 330 healthy volunteers were enrolled into 4 groups: 120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISpot) assay. RESULTS: Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval [CI]: 40% to 71%) to 94% (95% CI: 85% to 99%). Net cumulative HIV-specific CD8 IFNgamma ELISpot assay responses were 13% (95% CI: -1% to 26%) for recipients of vCP1452 alone and 16% (95% CI: 2% to 29%) for recipients of vCP1452 plus rgp120. CONCLUSIONS: Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.

AIDS Vaccines↗
PubMed2026

Validation of the lung immune prognostic index in extensive-stage small cell lung cancer: Post hoc analysis of the caspian and IMpower133 phase 3 trials.

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is an inflammation-based biomarker associated with outcomes to immunotherapy across several tumor types. Its prognostic value in extensive-stage small-cell lung cancer (ES-SCLC), however, remains insufficiently validated. We aimed to validate the prognostic impact of LIPI in ES-SCLC using data from two phase III trials. METHODS: Patients enrolled in the CASPIAN (NCT03043872) and IMpower133 (NCT02763579) trials were included. LIPI groups were defined as good (dNLR<3 and LDH<ULN), intermediate (dNLR&#x2265;3 or LDH&#x2265;ULN) and poor (dNLR&#x2265;3 and LDH&#x2265;ULN). Overall survival (OS) and progression-free survival (PFS) were assessed across LIPI categories and treatment arms. RESULTS: LIPI was available for 1140 patients (Good: 34%, Intermediate: 49%, Poor: 17%), including 708 treated with chemotherapy-immunotherapy and 432 with chemotherapy alone. Poor LIPI was associated with unfavorable characteristics, including lower albumin levels and higher rate of liver metastases. Median OS was 14.6 months (95%CI: 12.4-15.9) for LIPI Good, 10.9 (10.1-11.5) for Intermediate, and 8.4 (7.1-9.3) for Poor (p&#x202f;<&#x202f;0.0001). In multivariate models adjusted on gender, age, ECOG, treatment arm and metastatic sites, LIPI remained an independent prognostic factor for OS (HR Poor vs. Good: 1.76, 95%CI: 1.45-2.15, p&#x202f;<&#x202f;0.001) and PFS (HR: 1.59, 95%CI: 1.33-1.90, p&#x202f;<&#x202f;0.001). Although patients with poor LIPI derived limited benefit from immunotherapy, no significant treatment-LIPI interaction was observed. CONCLUSION: This large post hoc analysis confirms LIPI as a robust and clinically applicable prognostic biomarker in ES-SCLC. Patients with poor LIPI have substantially worse outcomes and limited benefit from immunotherapy, highlighting the need for novel therapeutic strategies in this subgroup.

Humans↗
PubMed1996

[3-phase bone scintigraphy: perfusion and vitality of the femur head after media femoral neck fracture and osteosynthesis].

UNLABELLED: Perfusion and Vitality of the Femoral Head after Medial Neck Fracture and Osteosynthesis. AIMS: to analyse with regard to necrosis the perfusion and vitality of the femoral head after medial neck fracture and repair by placement of a dynamic hip screw. PATIENTS AND METHODS: Twenty-one patients were examined by scintigraphy immediately following operation as well as at 3 and 6 months postoperative for evaluation of dysfunctions of perfusion and mineralization. RESULTS: Complete perfusion and mineralization defects with a tendency for revascularization at 3 months will be normal at 6 months. Persisting dysfunctions at 3 and 6 months will progress to femoral head necrosis irrespective of the fracture staging. CONCLUSIONS: Three-phase skeletal scintigraphy is a highly sensitive, non-invasive method for evaluating perfusion and revascularization of the femoral head after femoral neck fracture and repair by means of a dynamic hip screw. When perfusion of the femoral head is observed one week after the trauma, femoral head necrosis will not arise. Immobilization is necessary after partial or complete perfusion and mineralization dysfunctions until the scintigraphic findings return to normal. The present results may serve as a recommendation for loading after fracture repair with a dynamic hip screw.

Adult↗
PubMed2001

Bridging phase 2 and phase 3 pneumococcal immunologic data for future combination vaccines.

Pneumococcal conjugate vaccines (PncCs) will be introduced into childhood vaccination programs now that the first PncC has been licensed for use. The next generation of PncCs and possible combination vaccines containing PncC will most probably be approved on the basis of phase 2 immunogenicity and safety data. PncCs are combination vaccines that include, at present, 7-11 components. Immune response to different components may vary. Furthermore, there seem to be population-based differences in immune response. Whether these differences are due to the other vaccines that are given simultaneously or due to the genetic background remains to be seen. Immune response can be evaluated by determining both the quantity and the quality of antibodies after vaccination. However, data are still missing on the minimal protective immune response and serologic correlates or surrogates of protection.

Antibodies, Bacterial↗
PubMed1999

[Combined use of MRI and MR cholangiopancreatography and contrast enhanced dual phase 3-D MR angiography in diagnosis of pancreatic tumors: initial clinical results].

PURPOSE: To evaluate the accuracy of a non-invasive "all-in-one" staging MR method in patients with pancreatic tumors. MATERIAL AND METHODS: 46 patients were prospectively evaluated by a combined MR imaging protocol including breath-hold T1- and T2-weighted pulse sequence, MRCP using a breath-hold 2D-RARE sequence, and breath-hold gadolinium-enhanced dual-phase 3D-MR angiography. RESULTS: All pancreatic tumors were detected by the combination of cross-sectional imaging and MRCP. In spite of the use of MRCP, definitive differentiation between pancreatic carcinoma and chronic pancreatitis was not possible in 3 (6.5%) out of 46 cases. High quality 3D-MR angiograms were obtained in 43 (93.5%) cases. In 6 (13%) patients 3D-MRA showed an aberrant right hepatic artery. The overall accuracy of MRI in assessing extrapancreatic tumor spread, lymph node metastases, liver metastases, and vascular involvement was 95.7%, 80.4%, 93.5%, and 89.1%, respectively. CONCLUSION: Due to its high accuracy, the "all-in-one" MR protocol may become the most important modality after clinical examination and ultrasound in the diagnostic work-up for most patients with suspicion of pancreatic tumors.

Arteries↗
PubMed2005

The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline.

BACKGROUND: Inhaled mannitol is a new bronchial provocation test (BPT) developed to improve portability and standardisation of osmotic challenge testing. Osmotic challenge tests have an advantage over the traditional methods of measuring airway hyperresponsiveness using methacholine as they demonstrate higher specificity to identify asthma and thus the need for treatment with inhaled corticosteroids (ICS). The safety and the efficacy of mannitol (M) as a BPT to measure airway hyperresponsiveness were compared to hypertonic (4.5%) saline (HS) in people both with and without signs and symptoms of asthma. METHODS: A phase III, multi-centre, open label, operator-blinded, crossover design, randomised trial, with follow-up. Asthmatics and non-asthmatics (6-83 yr) were recruited and 592 subjects completed the study. Mannitol was delivered using a low resistance dry powder inhaler and HS was delivered using an ultrasonic nebuliser. The FEV1 was measured 60 seconds after each dose of mannitol (5,10,20,40,80,160,160,160 mg) and after each exposure to HS (0.5,1.0,2.0,4.0,8.0 minutes). A 15% fall in FEV1 defined a positive test. Adverse events were monitored and diaries kept for 7 days following the tests. RESULTS: Mean pre-test FEV1 (mean +/- SD) was 95.5 +/- 14% predicted. 296 were positive to mannitol (M+) and 322 positive to HS (HS+). A post study physician conducted clinical assessment identified 82.3% asthmatic (44% classified mild) and 17.7% non-asthmatic. Of those M+, 70.1% were taking ICS and of those mannitol negative (M-), 81.1 % were taking ICS. The % fall in FEV1 for mannitol in asthmatics was 21.0% +/- 5.7 and for the non-asthmatics, 5.5% +/- 4.8. The median PD15 M was 148 mg and PD15 HS 6.2 ml. The sensitivity of M to identify HS+ was 80.7% and the specificity 86.7%. The sensitivity of M compared with the clinical assessment was 59.8% and specificity 95.2% and increased to 88.7% and 95.0% respectively when the M- subjects taking ICS were excluded. Cough was common during testing. There were no serious adverse events. The diarised events were similar for mannitol and HS, the most common being headache (17.2%M, 19%HS), pharyngolaryngeal pain (5.1%M, 3%HS), nausea (4.3%M, 3%HS), and cough (2.2%M, 2.4%HS). CONCLUSION: The efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.

Administration, Inhalation↗
PubMed1988

Local nerve blockade by tetrodotoxin induces ectopic phase 3 of the migrating myoelectric complex in dogs.

The effect on the migrating myoelectric complex (MMC) of local nerve blockade in the jejunum was studied in five unanesthetized dogs. A silastic catheter was implanted in a terminal branch of a jejunal artery, perfusing a 5- to 10-cm segment, 45 cm below the ligament of Treitz. Small-bowel motor activity was studied electromyographically with implanted electrodes. Three different doses of tetrodotoxin (166, 333, 500 ng/kg/h) were administered intra-arterially for 5 h. During the 333- and 500-ng but not during the 166-ng/kg/h perfusions ectopic activity fronts started just below the perfused segment. At this time no phase-3 activity was observed in the proximal bowel. In addition to ectopic fronts normal MMCs were observed during the perfusions. These observations show that local nerve blockade induces phase-3 activity, probably by inhibiting an inhibitory nerve action.

Animals↗
PubMed1986

The occurrence of gingival brushing lesions during 3 phases of the menstrual cycle.

Since hormonal changes during the menstrual cycle may alter the vulnerability of the female gingiva, the present study was undertaken to investigate whether there are any differences in the number of toothbrushing lesions occurring during different phases of the menstrual cycle. 45 women of 20-35 years of age and with healthy gingiva were examined for overt signs of gingival laceration or ulceration. Such signs were recorded as a brushing injury. Dental plaque was assessed using the visible plaque index (VPI) and gingival inflammation using the gingival bleeding index (GBI). The examinations were made on the 1st day of menstruation (MD), on the estimated ovulation day (OD), and on the day with the predominance of progesterone secretion (PD). The examinations were made during 1-3 menstrual cycles for each individual; the study includes 78 cycles. No statistically significant differences were found between the numbers of brushing injuries on the 3 days of examination (MD, OD, & PD). During PD, a significantly positive correlation (p less than 0.01) was observed between VPI and GBI scores, but on OD and MD, the correlations were highly significant (p less than 0.001). A weak significant positive correlation (p less than 0.05) was found between GBI scores and the number of brushing injuries on the 1st day of menstruation, while during other phases of the menstrual cycle, no such correlation was found. The present study gave little evidence that the hormonal status of women could be of clinical significance in the development of soft tissue trauma from habitual toothbrushing.

Adult↗
PubMed2003

Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis.

BACKGROUND: There is a current lack of safe and effective psoriasis therapies that provide patients with lasting remissions after treatment is discontinued. Alefacept, a novel and selective biological agent, has demonstrated durable efficacy in patients with chronic plaque psoriasis, and its efficacy has been correlated with reductions in memory-effector T cells. OBJECTIVE: To demonstrate the efficacy and safety of both one and two 12-week courses of alefacept 7.5 mg given once weekly as an intravenous (IV) bolus injection in patients with chronic plaque psoriasis. METHODS: Multicentre (51 centres in the USA and Canada), randomized, double-blind, parallel-group study comparing once-weekly alefacept 7.5 mg IV or placebo for two 12-week treatment courses. Each course had a 12-week follow-up phase. Patients were eligible for enrollment if they were > or =16 years of age, had chronic plaque psoriasis for > or =12 months involving > or =10% body surface area, and had CD4+ T-cell counts at or above the lower limit of normal. RESULTS: 553 patients received treatment in Course 1, and 449 were treated in Course 2. The cohorts were well balanced for demographic and baseline disease characteristics. During the treatment and follow-up period of Course 1, 28% of patients treated with alefacept achieved > or =75% reduction in Psoriasis Area and Severity Index (PASI), compared with 8% of placebo-treated patients (P < 0.001). Patients achieving > or =75% reduction in PASI following a single 12-week course of alefacept maintained > or =50% reduction in PASI for a median of over 7 months. Among patients who received a second course of alefacept therapy, 71% achieved > or =50% reduction in PASI, and 40% achieved > or =75% reduction in PASI over two treatment courses. One or two 12-week courses of alefacept were similarly well tolerated. CONCLUSIONS: Treatment with alefacept 7.5 mg IV provided highly significant improvements in all measures of psoriasis disease activity compared with placebo. A second course of alefacept provided additional benefit.

Adolescent↗
PubMed2006

Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial.

OBJECTIVE: To prospectively assess whether low-molecular-weight heparin (LMWH) provides a survival benefit in patients with advanced cancer. PATIENTS AND METHODS: Between December 1998 and June 2001, we performed a randomized controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival. RESULTS: Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank P = .46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms.

Adult↗
PubMed2006

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial.

We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m(2) intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m(2) intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.

Adult↗