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PubMed2000

A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents.

OBJECTIVE: To compare the efficacy and tolerability of sumatriptan nasal spray (NS; 5 mg, 10 mg, and 20 mg) with placebo for the treatment of acute migraine in adolescents. METHODS: A randomized, double-blind, placebo-controlled, single-attack study was conducted in 653 US adolescents (12-17 years of age). Patients with at least a 6-month history of migraine, who met International Headache Society criteria for migraine (with or without aura) were eligible for participation. Headache relief 2 hours postdose, complete relief, presence or absence of associated symptoms, headache recurrence, and use of rescue medications were recorded. The primary efficacy endpoint was headache relief 2 hours postdose sumatriptan NS (20 mg) versus placebo. Safety and tolerability were assessed by examining adverse events, changes in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests. RESULTS: Headache relief 1 hour postdose was significantly greater for patients using 10 mg (56%) and 20 mg (56%) of sumatriptan NS compared with placebo (41%). Headache relief 2 hours postdose was significantly greater for patients using 5 mg of sumatriptan NS (66%) compared with placebo (53%), and approached statistical significance for 20 mg (63%) compared with placebo (53%). Complete relief 2 hours postdose was significantly greater for patients using 20 mg of sumatriptan NS compared with placebo (36% vs 25%, respectively). Each dose of sumatriptan (5 mg, 10 mg, and 20 mg) was superior to placebo with respect to the cumulative percentages of patients first reporting headache relief within 2 hours of dosing (Kaplan-Meier). The sumatriptan 20-mg dose was superior to placebo with respect to the cumulative percentages of patients first reporting complete relief within 2 hours of dosing (Kaplan-Meier). Photophobia and phonophobia were significantly reduced 2 hours postdose for sumatriptan NS (20 mg), compared with placebo (36% vs 48% and 25% vs 44%, respectively). Taste disturbance was the most commonly reported adverse event (2%, 19%, 30%, and 26% for placebo, 5 mg, 10 mg, and 20 mg, respectively). No drug-related serious adverse events or clinically relevant changes in laboratory parameters, electrocardiograms, or vital signs were reported. CONCLUSIONS: Sumatriptan NS is effective and well-tolerated for the treatment of acute migraine in adolescents, with the 20-mg dose providing the best overall efficacy and tolerability profiles.

Acute Disease↗

PubMedDate not supplied

[Placebo in clinical research--a continual compromise between ethical requirements and scientific rigor].

The use of placebo in clinical trials has been the object of continuous controversy. If effective treatment is not available, then the comparison of a new treatment versus placebo is the only sound and ethical approach. If effective treatment exists and its withdrawal can cause severe or irreversible harm or severe suffering, the use of placebo is forbidden. In all other instances, the scientific community has been divided into two extreme positions: the placebo orthodoxy considers the use of placebo as the only scientifically and hence ethically valid approach; and the active-control orthodoxy denies the use of placebo and recommends the comparison between active treatments. The latter has been supported by the Declaration of Helsinki that, until the Edinburgh 2000 Version, denied the use of placebo whenever effective treatment existed. This position has been the object of recent, strong criticism by ethicists and international Institutions, to the point that in October 2001 the World Medical Association decided to review paragraph 29 of the Declaration. The new version of the Declaration admits the use of placebo, even in the presence of effective treatment, when there are scientifically sound methodological reasons or when the patients receiving placebo are not exposed to any additional risk of serious or irreversible harm. The problem now is that the sudden opening of the World Medical Association may be interpreted as an encouragement to use placebo. Thus, it is necessary to define a new area for a scientifically motivated, but not unscrupulous use of placebo.

Ethics, Clinical↗

PubMed1987

[Study of the placebo effect in using the non-invasive ambulatory measurement of blood pressure].

The aim of this study is to evaluate the antihypertensive effect of placebo assessed by 24 hr non invasive blood pressure monitoring. 20 patients (16 males, 4 females, 55 +/- 10 years old) with primary hypertension (WHO stage I or II) were included with a diastolic blood pressure greater than or equal to 100 mmHg (mean blood pressure from three clinical readings). Casual blood pressure and blood pressure monitoring (Spacelabs - 4 measurements per hour during a 24 hr period) were established before and at the end of the placebo run in period (one placebo tablet given once daily at 8 h-8 h 30 a.m. for 15 days). Overall sample data: There was no antihypertensive effect of the placebo with casual BP (167 +/- 16-109 +/- 6 mmHg before and 167 +/- 16-109 +/- 7 mmHg after placebo) and with 24 hr B.P. monitoring (142 +/- 14-96 +/- 8 mmHg before and 141 +/- 14-96 +/- 8 mmHg after placebo). The circadian curves were similar. Individual patient data: A clinical placebo effect (B.P. decrease of at least 10 mmHg) was found in 5 patients for the systolic B.P. and in 2 for diastolic B.P. A significant ambulatory placebo effect (p less than 0.05) was found in 5 patients for the 24 hr systolic B.P. and in 4 patients for the 24 hr diastolic B.P. However, patients with clinical placebo effect were not the same as those with ambulatory placebo effect. There was no correlation between the clinical and the ambulatory response to placebo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1999

Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.

We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

Adult↗

PubMed2004

A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial.

BACKGROUND: Atrial fibrillation (AF) frequently occurs after cardiac surgical procedures, and beta-blockers, sotalol, and amiodarone may reduce the frequency of AF after open heart surgery. This pilot trial was designed to test whether each of the active oral drug regimens is superior to placebo for prevention of postoperative AF and whether there are differences in favor of 1 of the preventive strategies. METHODS AND RESULTS: We conducted a randomized, double-blinded, placebo-controlled trial in which patients undergoing cardiac surgery in the absence of heart failure and without significant left ventricular dysfunction (n = 253; average age, 65 +/- 11 years) received oral amiodarone plus metoprolol (n = 63), metoprolol alone (n = 62), sotalol (n = 63), or placebo (n = 65). Patients receiving combination therapy (amiodarone plus metoprolol) and those receiving sotalol had a significantly lower frequency of AF (30.2% and 31.7%; absolute difference, 23.6% and 22.1%; odds ratios [OR], 0.37 [95% CI, 0.18 to 0.77, P <.01 vs placebo] and 0.40 [0.19 to 0.82, P =.01 vs placebo]) compared with patients receiving placebo (53.8%). Treatment with metoprolol was associated with a 13.5% absolute reduction of AF (P =.16; OR, 0.58 [0.29 to 1.17]. Treatment effects did not differ significantly between active drug groups. Adverse events including cerebrovascular accident, postoperative ventricular tachycardia, nausea, and dyspepsia, in hospital death, postoperative infections, and hypotension, were similar among the groups. Bradycardia necessitating dose reduction or drug withdrawal occurred in 3.1% (placebo), 3.2% (combined amiodarone and metoprolol; P =.65 vs placebo), 12.7% (sotalol; P <.05 vs placebo), and 16.1% (metoprolol; P <.05 vs placebo). Patients in the placebo group had a nonsignificantly longer length of hospital stay as compared with the active treatment groups (13.1 +/- 8.9 days vs 11.3 +/- 7; P =.10), with no significant difference between the active treatment groups. CONCLUSIONS: Oral active prophylaxis with either sotalol or amiodarone plus metoprolol may reduce the rate of AF after cardiac surgery in a population at high risk for postoperative AF. Treatment with metoprolol alone resulted in a trend to a lower risk for postoperative AF.

Administration, Oral↗

PubMed2004

Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual(SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TES) was introduced at 3 release rates (35, 52.5, and 70 microg/h) for the treatment of chronic cancer and noncancer pain. OBJECTIVE: This study compared the analgesic efficacy and tolerability of buprenorphine TES at a release rate of 35 microg/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain. METHODS: This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TES 35 microg/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 02-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TES during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study. RESULTS: One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TES, 47 placebo). The buprenorphine TES group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight Patients receiving buprenorphine TES significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only. Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TES than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 292%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 463%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group. CONCLUSIONS: In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain.

Administration, Cutaneous↗

PubMed2005

Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo.

BACKGROUND: Lumiracoxib is a cyclooxygenase-2-selective inhibitor developed for the treatment of osteoarthritis (OA), rheumatoid arthritis, and acute pain. OBJECTIVES: This study assessed the efficacy and tolerability of lumiracoxib 100 mg QD compared with celecoxib and placebo in patients with OA of the knee. METHODS: In this 13-week, double-blind, double-dummy,placebo-controlled, parallel-group study, patients with primary OA of the knee and pain intensity in the target knee a 40 mm on a 100-mm visual analog scale after a 3- to 7-day washout of nonsteroidal anti-inflammatory drugs were randomized to receive lumiracoxib 100 mg QD, lumiracoxib 100 mg QD with a loading dose of lumiracoxib 200 mg QD for the first 2 weeks, celecoxib 200 mg QD, or placebo. Three primary efficacy variables were assessed at the end of the study: pain intensity in the target knee, the patient's global assessment of disease activity, and functional status (Western Ontario and McMaster Universities Osteoarthritis Index total score). In addition, the treatment response was assessed using the Outcome Measures in Clinical Trials-Osteoarthritis Research Society International (OMERACT OARSI) criteria. The safety profile and tolerability of all treatments were also examined. RESULTS: The study enrolled 1551 patients (primarily white; 62% female; mean age, 60.5 years): 391 were randomized to receive lumiracoxib 100 mg QD, 385 lumiracoxib 100 mg QD with a loading dose, 393 celecoxib 200 mg QD, and 382 placebo. Treatment groups were closely balanced at baseline with respect to demographic and disease characteristics. Lumiracoxib was superior to placebo (P < 0.001) and similar to celecoxib on all primary efficacy variables. Reductions in pain intensity in the target knee were similar in the 2 lumiracoxib groups at week 13 (estimated least square mean difference vs placebo: -6.7 and -8.1 mm for lumiracoxib 100 mg QD and lumiracoxib 100 mg QD with loading dose, respectively; both, P < 0.001); with celecoxib, the estimated least square mean difference was -5.7 mm (P < 0.001). Significant differences compared with placebo were seen in all variables starting at week 2 for all active treatments (all, P < 0.001). No significant differences were seen between the lumiracoxib groups at any time point. Based on OMERACT OARSI criteria, all active treatments were superior to placebo (all, P < 0.001). Lumiracoxib and celecoxib were well tolerated, with an incidence of adverse events similar to that with placebo (64.7% lumiracoxib 100 mg QD, 67.0% lumiracoxib 100 mg QD with loading dose, 58.8% celecoxib, 58.4% placebo). CONCLUSION: In this population of patients with OA of the knee, lumiracoxib 100 mg QD was of similar efficacy to celecoxib 200 mg QD and had similar tolerability to placebo.

Adult↗

PubMed2006

Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study.

BACKGROUND: Several large, randomized, double-blind, placebo-controlled trials have found topiramate (TPM) to be effective and generally well tolerated as a preventive therapy for migraine. OBJECTIVE: This paper evaluates efficacy and safety data from a pilot study of TPM 200 mg/d as preventive therapy in adult subjects with a history of migraine with or without aura. METHODS: The pilot study had a randomized, double-blind, placebo-controlled design. Subjects were randomized in a 2:1 ratio to receive TPM 200 mg/d or placebo. The double-blind treatment phase consisted of an 8-week titration period (25 mg/d for the first week, followed by weekly increases of 25 mg) and a 12-week maintenance period. The primary efficacy measure was the change in mean monthly migraine frequency. Additional measures were the median percent reduction in monthly migraine frequency and the proportion of responders (those with > or =50%, > or =75%, or 100% reduction in monthly migraine frequency). RESULTS: The intent-to-treat (ITT) population included 211 subjects (138 TPM, 73 placebo; mean [SD] mean weight, 76.7 [18.7] kg). Of 45 subjects who discontinued the study in the TPM group, 21 discontinued during the titration period, compared with 3 of 13 subjects who discontinued in the placebo group. When the efficacy data were assessed using the per-protocol, analysis-of-covariance model, TPM 200 mg/d was not associated with a significant reduction in mean monthly migraine frequency compared with placebo. A post hoc analysis using a Poisson regression model in the ITT population suggested that TPM significantly reduced mean monthly migraine frequency compared with placebo (P=0.04). A significantly larger proportion of TPM-treated subjects had a > or =75% reduction in monthly migraine frequency compared with placebo (P=0.03). At least 1 adverse event was reported by 90.0% and 69.9% of the TPM and placebo groups, respectively. Treatment-emergent adverse events (AEs) occurring in > or =10% of subjects in the TPM group were paresthesia (45%), dizziness (16%), fatigue (16%), nausea (14%), and weight loss (14%). Most treatment-emergent AEs were rated mild or moderate in severity. Of 3 serious AEs (depression, abdominal pain, leg pain) occurring during the trial, none were considered related to either TPM or placebo. CONCLUSION: In this pilot study, mean monthly migraine frequency did not differ significantly between TPM and placebo.

Adolescent↗

PubMed2005

A double-blind placebo-controlled study evaluating the onset of action of doxazosin gastrointestinal therapeutic system in the treatment of benign prostatic hyperplasia.

OBJECTIVE: To determine the onset of improvement in benign prostatic hyperplasia symptoms in patients after treatment with doxazosin gastrointestinal therapeutic system (DOX GITS) versus placebo. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, baseline values, including International Prostate Symptom Score (IPSS) and maximum urine flow rate (Q(max)), were determined following a 2-week placebo run-in. Patients received DOX GITS 4 mg/d (n = 108) or placebo (n = 105) for 14 days. IPSS was measured on Days 3, 7, and 14; Q(max) on Days 1, 3, 7, and 14; and the patients' perception of improvement was measured on Days 1 and 2 in the evening at home and in the office on Day 14. RESULTS: Significantly more patients treated with DOX GITS than placebo perceived improvement after Day 1 (60.6% vs. 41.9%) through Day 14 (84.3% vs. 64.1%). On Day 1, improvement in Q(max) with DOX GITS was not significantly different compared with placebo. On Day 3 of the trial (1) IPSS improvement was significantly greater with DOX GITS than with placebo; (2) proportion of patients with > or =30% improvement in IPSS was significantly greater with DOX GITS (49.5%) than placebo (28.4%) and remained so through Day 14; (3) improvement in Q(max) was significantly greater with DOX GITS (3.7 mL/s) than placebo (1.9 mL/s) and remained so through Day 14; (4) proportion of patients with > or =3 mL/s increase in Q(max) was statistically greater with DOX GITS (54.4%) versus placebo (30.8%) and remained so through Day 14. CONCLUSIONS: DOX GITS significantly improved IPSS and Q(max) by Day 3 of treatment, and these changes were maintained through Day 14. More patients receiving DOX GITS than placebo perceived improvement in symptoms as early as Day 1.

Adrenergic alpha-Antagonists↗

PubMed2004

A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss.

BACKGROUND: To pical minoxidil solution 2% stimulates new hair growth and helps stop the loss of hair in men with androgenetic alopecia and women with female pattern hair loss. Results can be variable, and historic experience suggests that higher concentrations of topical minoxidil may enhance efficacy. OBJECTIVE: The purpose of this 48-week, double-blind, placebo-controlled, randomized, multicenter trial was to compare the efficacy and safety of 5% topical minoxidil with 2% topical minoxidil and placebo in the treatment of female pattern hair loss. METHODS: A total of 381 women (18-49 years old) with female pattern hair loss applied 5% topical minoxidil solution (n = 153), 2% topical minoxidil solution (n = 154), or placebo (vehicle for 5% solution; n = 74) twice daily. Primary efficacy variables were change in nonvellus hair count at week 48, and patient and investigator assessments of change in hair growth/scalp coverage at week 48. RESULTS: After 48 weeks of therapy, 5% topical minoxidil was superior to placebo for each of the 3 primary efficacy measures. The 2% topical minoxidil group demonstrated superiority over placebo for hair count and investigator assessment of hair growth/scalp coverage at week 48; differences in patient assessment of hair growth at week 48 were not significantly different from placebo. The 5% topical minoxidil group demonstrated statistical superiority over the 2% topical minoxidil group in the patient assessment of treatment benefit at week 48. Both 5% and 2% topical minoxidil helped improve psychosocial perceptions of hair loss in women with female pattern hair loss. An increased occurrence of pruritus, local irritation, and hypertrichosis was observed with 5% topical minoxidil versus 2% topical minoxidil and placebo. CONCLUSION: In this 48-week study of 381 women with female pattern hair loss, 5% topical minoxidil was superior to placebo on each of the 3 primary efficacy end points: promoting hair growth as measured by change in nonvellus hair count and patient/investigator assessments of hair growth and scalp coverage. Application of 2% topical minoxidil was superior to placebo for assessments of nonvellus hair counts and investigator assessment of hair growth/scalp coverage at week 48; differences in patient assessment of hair growth at week 48 were not significantly different from placebo. At week 48, the 5% topical minoxidil group demonstrated statistical superiority over the 2% topical minoxidil group in the patient assessment of treatment benefit. Both concentrations of topical minoxidil were well tolerated by the women in this trial without evidence of systemic adverse effects. With the introduction of numerous herbal remedies for hair loss, of which most have not been tested in randomized, double-blind, placebo-controlled trials, it is important to describe well-controlled trials that demonstrate the efficacy and safety of topical drugs.

Administration, Topical↗

PubMed2003

A multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled, parallel-group comparison of diclofenac-K and ibuprofen for the treatment of adults with influenza-like symptoms.

BACKGROUND: The alleviation of influenza-like symptoms, such as fever, headache, and muscle/joint aches and pains, is important so that sufferers can return to their normal daily activities. A flexible dosing regimen is proposed, starting with an initial dose of 2 tablets (2 x 12.5 mg), followed by 1 to 2 tablets every 4 to 6 hours as needed, to a maximum daily dose of 75 mg for up to 3 days for fever and 5 days for pain. This flexible dosing regimen matches the existing over-the-counter dosing regimen of ibuprofen, which allows the patient to adjust the treatment according to the type, duration, and severity of symptoms. OBJECTIVE: This study assessed the efficacy and tolerability of diclofenac-K 12.5 mg versus ibuprofen 200 mg and placebo against influenza-like symptoms (oral temperature > or = 38.1 degrees C, and at least moderate headache and muscle/joint aches and pains). METHODS: This was a 3-day, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial conducted in Germany. The flexible dosing regimens comprised 2 tablets of diclofenac-K (12.5 mg), ibuprofen (200 mg), or placebo, then 1 to 2 tablets every 4 to 6 hours as needed, to a maximum of 6 tablets/d. Primary efficacy outcomes were fever reduction after the initial dose and an end-of-study global assessment of overall symptom relief. Secondary efficacy outcomes included reduction of feverishness; relief of headache; and relief of muscle/joint aches and pains, after the first dose and at the end of days 1, 2, and 3. Use of rescue medication (paracetamol 500-mg tablets) and usage patterns of study medication were also studied. Tolerability was monitored by recording of patients' adverse events. RESULTS: A total of 356 patients were enrolled (n = 121, 120, and 115 patients in the diclofenac-K, ibuprofen, and placebo groups, respectively). All patients were white except 1 Asian patient in the diclofenac-K group; 55% to 60% of patients in all 3 groups were male; the mean age in each treatment group was approximately 40 years. At baseline, mean oral temperature ranged from 38.65 degrees C in the placebo group to 38.74 degrees C in the diclofenac-K group. Mean oral temperatures in both active groups were significantly lower than that of the placebo group from 30 minutes through 6 hours (P < 0.001), dropping 0.85 degrees C after 4 hours in the diclofenac-K group and 0.76 degrees C in the ibuprofen group versus 0.32 degrees C for placebo. In the end-of-study global treatment assessment, 89.0% of diclofenac-K and 89.1% of ibuprofen patients rated global efficacy as "good" to "excellent" versus only 32.1% for placebo. Diclofenac-K was superior to placebo (P < 0.001) and similar to ibuprofen on all direct assessments of fever and aches and pains. Both active treatments were as well tolerated as was placebo. CONCLUSIONS: In this 3-day study, diclofenac-K 12.5 mg taken in a flexible dosing regimen was more effective than placebo in relieving influenza-like symptoms, with comparable tolerability Efficacy and tolerability of diclofenac-K were similar to those of ibuprofen 200 mg.

Adult↗

PubMed2004

Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial.

BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE: The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. METHODS: This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged > or =18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P < or = 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. CONCLUSIONS: In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.

Adult↗

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↗

PubMed2000

Efficacy of orally administered extract of red vine leaf AS 195 (folia vitis viniferae) in chronic venous insufficiency (stages I-II). A randomized, double-blind, placebo-controlled trial.

UNLABELLED: Red vine leaf extract (RVLE) is a herbal medicine containing several flavonoids, with quercetin-3-O-beta-glucuronide and isoquercitrin (quercetin-3-O-beta-glycoside) as the main components. OBJECTIVE: To assess the efficacy and safety of once-daily doses of 360 and 720 mg RVLE (pharmaceutical extract code AS 195; Antistax Venenkapseln) compared to placebo in patients with stage I and incipient stage II chronic venous insufficiency (CVI). DESIGN: A 12-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study. PATIENTS: Male and female outpatients aged 25 to 75 years with stage I to stage II CVI (i.e. without extensive trophic changes), not having any other significant medical conditions and not treated with compression stockings, diuretics or other drugs affecting fluid balance. INTERVENTION: Patients were randomly assigned to a double-blind treatment with placebo, 360 mg AS 195 or 720 mg AS 195 once daily for 12 weeks, preceded and followed by a single-blind 2-week placebo treatment for baseline run-in and end-of-trial washout, respectively. Study criteria were evaluated at baseline, after 6 and 12 weeks of treatment and 2 weeks after discontinuation of treatment. RESULTS: Of the 260 patients enrolled and randomized, 219 completed the study in accordance with the protocol. In the intention-to-treat analysis (N = 257), the mean (+/- SD) lower leg volume (measured by water displacement plethysmography) of the patients treated with placebo (N = 87) increased by 15.2 +/- 90.1 g (displaced water mass) and by 33.7 +/- 96.1 g after 6 and 12 weeks compared to baseline. In contrast, for patients treated with AS 195, lower leg volume decreased, and after 12 weeks of treatment, the difference in mean lower leg volume between the active treatment groups and the placebo group was -75.9 g (95% CI: -106.1 to -45.8 g) and -99.9 g (95% CI: -130.3 to -69.6 g) for the group treated with 360-mg AS 195 (N = 86) and 720-mg AS 195 (N = 84), respectively. The changes in calf circumference showed a similar pattern: in patients treated with AS 195, both the higher dose (720 mg) and, albeit to a lesser extent, the lower dose (360 mg) resulted in a clear reduction in circumference over time, whereas, circumference remained largely unchanged in patients treated with the placebo (95% CI of the estimated treatment effects vs. placebo after 12 weeks: -1.40 to -0.56 cm and -1.73 to -0.88 cm for 360 and 720 mg AS 195, respectively). These differences were statistically significant (p < 0.001). The reductions in ankle circumference were qualitatively similar but quantitatively less marked. Subjectively, there was an improvement in key CVI symptoms (VAS) at 6 weeks with all treatments, but a further improvement at week 12 was seen only in the active treatment groups; at 12 weeks, the changes compared to baseline were significantly greater (p < 0.001) in both active treatment groups than in the placebo group. The treatments were well tolerated; Adverse events were rare and usually mild. Two adverse events (AEs) during treatment with the placebo led to hospitalization and were hence labeled as 'serious'. Three further patients were withdrawn because of AEs which occurred during treatment with the placebo. CONCLUSION: Once-daily doses of 360 and 720 mg AS 195 were confirmed to be safe and effective in the treatment of mild CVI, reducing significantly lower leg edema and circumference whilst improving key CVI-related symptoms to a clinically relevant extent. The edema reduction is at least equivalent to that reported for compression stockings and/or other edema-reducing agents. The higher dose was as well tolerated as the lower dose but resulted in a slightly greater and more sustained improvement.

Adult↗

PubMed2006

Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study.

OBJECTIVE: The objective of this double-blind, randomised, placebo-controlled, multicentre clinical study was to demonstrate the non-inferiority and safety of the hypericum extract STW3-VI in a once-daily dosage regime in the treatment of moderate depression. During the 6-week treatment phase, the course of depression was documented by use of HAMD (items 1-17), the von Zerssen's Adjective Mood Scale (BfS) and the CGI scales. The primary objective of this 3-arm design study was to demonstrate the non-inferiority of hypericum extract STW3-VI (900 mg) to the SSRI citalopram (20 mg) and superiority of hypericum over placebo. METHODS: Outpatients (N = 388) suffering from moderate depression were enrolled. The safety and tolerability of hypericum extract in comparison to citalopram and placebo was investigated on the basis of CGI, the occurrence of adverse events and the investigation of laboratory parameters and vital signs. RESULTS: From almost identical baseline values of 21.9 +/- 1.2 points (hypericum extract), 21.8 +/- 1.2 points (citalopram) and 22.0 +/- 1.2 points (placebo), the HAMD score was reduced to 10.3 +/- 6.4 (hypericum extract), 10.3 +/- 6.4 (citalopram) and 13.0 +/- 6.9 (placebo), respectively. Based on this data, the statistical significant therapeutic equivalence of hypericum extract STW3-VI to citalopram (p < 0.0001) and the superiority of this hypericum extract over placebo (p < 0.0001) was demonstrated. At the end of treatment 54.2 % (hypericum extract), 55.9 % (citalopram) and 39.2 % (placebo) of the patients were assessed as therapy responders. The secondary efficacy parameters, change in BfS, CGI and amount of therapy responders showed that the hypericum group was not statistically different from the citalopram group, and significantly superior to the placebo group. Significantly more adverse events with "certain", "probable" or "possible" relation to study medication were documented in the citalopram group (hypericum: 17.2 %, citalopram: 53.2 %, placebo: 30 %). In most cases, the investigators assessed the tolerability of hypericum extract, citalopram and placebo as "good" or "very good". CONCLUSION: The non-inferiority of hypericum extract as compared to citalopram and the superiority of both active compounds to placebo were demonstrated, as well as a better safety and tolerability of hypericum extract in comparison to citalopram. These results revealed that hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression.

Adult↗

PubMed2003

Efficacy and safety of an extract of Pelargonium sidoides (EPs 7630) in adults with acute bronchitis. A randomised, double-blind, placebo-controlled trial.

BACKGROUND: New evidence-based treatment options are required to avoid antibiotic overuse in acute bronchitis and to replace potentially inefficacious initial antibiotic treatment. OBJECTIVE: To evaluate the efficacy and safety of an extract of Pelargonium sidoides (EPs 7630) compared to placebo in patients with acute bronchitis. DESIGN: Randomized, double-blind, placebo-controlled trial using a multi-stage adaptive design. SETTING: 36 primary care physicians (investigators) at the out-patient care setting. PATIENTS: 468 adults with acute bronchitis present < or = 48 hours, Bronchitis Severity Score (BSS) > or = 5 points, and informed consent. INTERVENTION: EPs 7630 or placebo (30 drops three times daily) for 7 days. MEASUREMENT: The primary outcome criterion was the change of BSS on day 7. RESULTS: The decrease of BSS from baseline to day 7 was 5.9 +/- 2.9 points under EPs 7630 (n = 233), and 3.2 +/- 4.1 points under placebo (n = 235). The 95% CI for the difference of effects between the two treatment groups (EPs 7630 minus placebo) was calculated as [-3.359; -2.060] showing a significant superiority of EPs 7630 compared to placebo on day 7 (p < 0.0001). Working inability decreased to 16% in the EPs 7630 group compared to 43% in the placebo group (p < 0.0001). In addition, the duration of illness was significantly shorter for patients treated with EPs 7630 compared to placebo (p < 0.001). Within the first four days, onset of treatment effect was recognized in 53.6% of patients under EPs 7630 compared to 36.2% of patients under placebo, only (p < 0.0001). Adverse events (AEs) occurred in 36/468 patients (EPs 7630: 20/233 patients, placebo: 16/235 patients). All events were assessed as non-serious. CONCLUSION: EPs 7630 was superior in efficacy compared to placebo in the treatment of adults with acute bronchitis. Treatment with EPs 7630 clearly reduced the severity of symptoms and shortened the duration of working inability for nearly 2 days.

Acute Disease↗

PubMed1998

Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study.

Of 580 patients randomly assigned to short-term, double-blind treatment with either mirtazapine, amitriptyline or placebo, a total of 217 patients clinically judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study (mirtazapine, n = 74; amitriptyline, n = 86 and placebo, n = 57). The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data. Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo (p < 0.05), and a significantly longer time to relapse was shown on the survival analysis. There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks, with fewer patients relapsing. There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis (p < 0.05). The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks. At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response. Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms, but there was no difference from placebo in the proportion of patients with sustained response. Mirtazapine was well tolerated with a side-effect profile similar to that of placebo. The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain. Objectively measured weight gain was more frequent with amitriptyline (22% of patients) compared with mirtazapine (13% of patients). Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo, in particular sedative and anticholinergic side effects. The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression, which on some measures showed an advantage compared with amitriptyline, coupled with its improved side-effect profile, commends this antidepressant for the long-term treatment of depression.

Adolescent↗

PubMed2001

Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study.

BACKGROUND AND AIMS: The benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn's disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of olsalazine in comparison with placebo for maintenance of remission in quiescent Crohn's colitis and/or ileocolitis. METHODS: In this randomised, double blind, parallel group study of olsalazine versus placebo, 328 patients with quiescent Crohn's colitis and/or ileocolitis were recruited. Treatment consisted of olsalazine 2.0 g daily or placebo for 52 weeks. The primary end point of efficacy was relapse, as defined by the Crohn's disease activity index (CDAI) and by clinical relapse. Laboratory and clinical disease activity indicators were also measured. Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% v placebo 45%) for either colitis or ileocolitis. The failure rate, defined as not completing the study, was significantly higher in olsalazine treated patients compared with placebo treated patients for the overall population (colitis and/or ileocolitis: olsalazine 65.4% v 53.9%; p=0.038). Similar failure rates were seen for patients with colitis. A significantly higher percentage of olsalazine treated patients experienced adverse gastrointestinal events. Drug attributed adverse events were reported more frequently in the olsalazine treated group with gastrointestinal symptoms being causally related to olsalazine treatment (olsalazine 40.7% v placebo 26.9%; p=0.010). Back pain was reported significantly more often by the placebo treated group. However, serious medical events did not differ between the two groups. Adverse events led to more early withdrawals in the olsalazine treated group than in the placebo treated group; thus average time in the study for patients in the olsalazine treatment group was significantly shorter than that of patients in the placebo group. CONCLUSIONS: Patients treated with olsalazine were more likely to terminate their participation in the trial than those taking placebo. This difference was not related to relapse of disease, as measured by CDAI and clinical measures, but rather was due to the development of intolerable adverse medical events of a non-serious nature related to the gastrointestinal tract. The gastrointestinal related events in the olsalazine treated group may be due to the difference in gastrointestinal status at baseline which favoured the placebo treatment group.

Adolescent↗