Placebo Run-in Period Research Articles

A Phase I Study of Indole-3-Carbinol in Women: Tolerability and Effects

We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect.

Deramciclane in the treatment of generalized anxiety disorder: A placebo-controlled, double-blind, dose-finding study

Deramciclane, a camphor derivative, is a novel anxiolytic agent with a unique mechanism of action. It acts as a potent and specific antagonist at serotonin 5-HT 2A/2C receptors, and exhibits anxiolytic efficacy in animal models. The aim of this double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of a range of doses of deramciclane in patients with generalized anxiety disorder (GAD). Adult patients with a diagnosis of GAD (DSM-IV) and a Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 18; a score ≥ 2 for the HAM-A items ‘Anxious Mood’ and ‘Tension’; a score ≥ 4 on the Clinical Global Impression of Severity of Illness (CGI-S) Scale; and a score ≤ 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS) were enrolled in the study. Following a 1–2 week placebo run-in period, patients were randomized to receive deramciclane (10, 30, or 60 mg/day in two divided doses) or placebo for 8 weeks, followed by a 2-week placebo wash-out period. The primary efficacy measure was change in HAM-A score from baseline to week 8. Adverse events were monitored throughout the study. Withdrawal reactions were assessed at the end of the study (week 8) and during the placebo wash-out period using the Physician's Withdrawal Checklist (34 items). In the intent-to-treat population ( n = 208), both the deramciclane 30 mg/day and 60 mg/day doses provided clinically relevant improvements in HAM-A total score after 8 weeks of treatment, reaching statistical significance compared with placebo in the 60 mg/day dose group ( p = 0.024) and a clear trend in the 30 mg/day group ( p = 0.059). On the HAM-A psychic anxiety factor, significant improvements were seen in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with those in the placebo group ( p < 0.05). Adverse events were reported at a similar frequency across all four treatment groups; the most commonly reported adverse event was headache. No withdrawal reactions were observed on abrupt discontinuation of deramciclane. In conclusion, deramciclane 60 mg/day showed significant evidence of efficacy for the treatment of GAD in adult patients. The efficacy for the 30 mg/day dose was close to the larger dose although not significant in the primary analysis, and there was no significant evidence of efficacy for the 10 mg/day dose. Deramciclane was safe and well-tolerated up to the 60 mg/day dose over an 8-week period.

Dose-response comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge

Bronchial hyperresponsiveness to adenosine monophosphate, an indirect measure of airway inflammation, is a sensitive marker of inhaled corticosteroid efficacy. To evaluate the relative therapeutic efficacy of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in patients with mild-to-moderate persistent asthma. In a double-masked, dose-response crossover study, 27 patients received inhaled budesonide in cumulative sequential doubling dose increments, 2 weeks per dose, of 200, 400, and 800 microg/d. Each treatment block was preceded by 1- to 3-week placebo run-in and washout periods. End points were measured after each placebo (ie, baseline) and treatment period. Adenosine monophosphate bronchial challenge was the primary outcome, and exhaled nitric oxide, serum eosinophilic cationic protein, spirometry, domiciliary peak expiratory flow, symptoms, and rescue medication use were the secondary outcomes. For the adenosine monophosphate provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20), a significant overall dose-response effect (P = .006) was found, and there was no significant difference between the devices (P = .8). The relative microgram dose potency ratio between Clickhaler and Turbuhaler was 1.11 (95% confidence interval [CI], 0.50-2.46). After administration of the highest dose of budesonide, the mean doubling dilution shift in adenosine monophosphate PC20 from placebo baseline was 3.46 (95% CI, 2.66-4.27) with the Clickhaler vs 3.41 (95% CI, 2.47-4.35) with the Turbuhaler. A significant overall dose-response effect was demonstrated for exhaled nitric oxide (P = .03) but not for any of the other secondary outcome measures. There were no significant differences between the devices for any of the outcome measures. Inhaled budesonide exhibited overall dose-response effects on adenosine monophosphate PC20 delivered via Turbuhaler and Clickhaler, with no significant difference between the devices.

Selected Abstracts From Other Journals

Context: There is a paucity of effective, well-tolerated drugs available for migraine prophylaxis. Objective: To determine whether treatment with the angiotensin II receptor blocker candesartan is effective as a migraine-prophylactic drug. Design and Setting: Randomized, double-blind, placebo-controlled crossover study performed in a Norwegian neurological outpatient clinic from January 2001 to February 2002. Patient: Sixty patients aged 18 to 65 years with 2 to 6 migraine attacks per month were recruited mainly from newspaper advertisements. Interventions: A placebo run-in period of 4 weeks was followed by two 12-week treatment periods separated by 4 weeks of placebo washout. Thirty patients were randomly assigned to receive one 16-mg candesartan cilexetil tablet daily in the first treatment period followed by 1 placebo tablet daily in the second period. The remaining 30 received placebo followed by candesartan.

Once-daily fexofenadine treatment for chronic idiopathic urticaria: a multicenter, randomized, double-blind, placebo-controlled study

Chronic idiopathic urticaria (CIU) can have a profound effect on patients' health and quality of life. To evaluate the efficacy and safety of once-daily dosing of fexofenadine hydrochloride, 180 mg, on CIU. This randomized, double-blind, parallel-group, placebo-controlled study consisted of a placebo run-in period followed by a 4-week treatment period. Patients 12 years and older with active CIU were randomized 2:1 to receive once-daily fexofenadine, 180 mg, or placebo. The primary end points were change from baseline in mean daily number of wheals (MNW score) and mean daily severity of pruritus during treatment. Secondary efficacy measures included modified total symptom scores and MNW and pruritus severity scores evaluated weekly and instantaneously at trough drug levels. Patients administered fexofenadine (n = 163) experienced significantly greater improvements in MNW and pruritus severity scores compared with the placebo group (n = 92) (P < .001 for both). Similarly, throughout treatment and at each individual week, the mean reductions in modified total symptom scores were significantly greater in the fexofenadine group (P < or = .005 for all comparisons vs placebo). The mean reductions in instantaneous MNW and pruritus severity scores were greater in patients in the fexofenadine group than in those who received placebo (MNW score: P = .015; pruritus severity score: P < .001). There were no significant differences in the frequency of treatment-emergent adverse events between the 2 treatment groups. A once-daily dose of fexofenadine hydrochloride, 180 mg, offered effective, well-tolerated relief for the management of CIU.

Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients

Sibutramine, a serotonin and norepinephrine transporter blocker, is a common adjunctive obesity treatment. Acute studies in healthy subjects suggested that an inhibitory central nervous mechanism might attenuate the peripheral stimulatory effect on the sympathetic nervous system. This notion has not been tested in overweight and obese patients. We conducted a randomized, controlled clinical study in hypertensive patients with BMI > or = 27 to < 40 kg/m(2). After 4 week placebo run-in period patients were randomized to four different antihypertensive treatments or placebo. After 4 weeks of antihypertensive therapy, patients were additionally treated with sibutramine 15 mg o. d. for 3 months. Patients underwent cardiovascular autonomic reflex testing and a graded head-up tilt test at the end of each phase. Mean body weight decreased from 98.5+/-4 to 94.7+/-4 kg (p<0.05) between end of placebo run-in and end of sibutramine treatment. Supine blood pressure was 154+/-3/80+/-2, 145+/-3/76+/-2 and 150+/-3/79+/-2mmHg at the end of placebo run-in, after antihypertensive titration (ns) and end of sibutramine treatment (ns), respectively. Blood pressure was affected similarly during head up tilt testing. The systolic blood pressure response to cold pressor testing was diminished with sibutramine (p<0.01). Sibutramine decreased low frequency systolic blood pressure oscillations in the supine position (p<0.01). Resting blood pressure tends to increase with sibutramine, whereas blood pressure during sympathetic stimulation and low frequency blood pressure oscillations are decreased. These paradoxical changes are consistent with previous studies in healthy subjects and suggest a combination of peripheral and central nervous system mechanisms.

Effects of nilvadipine and amlodipine in patients with mild to moderate essential hypertension: a double blind, prospective, randomised clinical trial

ABSTRACTObjective: This double blind, prospective, randomised, parallel group clinical trial was aimed at investigating the effects of nilvadipine or amlodipine in mild to moderate hypertensive patients over a 3-month treatment period.Research design and methods: Eligible outpatients (supine DBP ≥ 90 mmHg and ≤ 110 mmHg and supine SBP ≤ 180 mmHg) entered a maximum 15-day placebo run-in period and were randomised to receive once daily nilvadipine 8 mg or amlodipine 5 mg (to be doubled in the case of lack of response at day 30). Follow-up visits with measurement of supine and orthostatic blood pressure and heart rate were performed after 15, 30, 60 and 90 days of treatment. Standard laboratory tests and 12-lead ECG were performed at study entry and at the end of treatment; adverse events were collected at any time.Results: A total number of 168 patients, 83 in the nilvadipine and 85 in the amlodipine group, took part in the study: 15 and 14 in the two groups, respectively, were prematurely withdrawn. Supine DBP at endpoint similarly decreases in the two groups (–11.0 ± 7.1 mmHg in the nilvadipine group and –12.7 ± 8.2 mmHg in the amlodipine group), with no significant differences between groups at any time point. Measurements in the orthostatic position also did not show between-groups differences. Blood pressure was normalised in 61.8% of patients in the nilvadipine group and in 63.0% in the amlodipine group; responders to therapy were 64.5% and 69.1% in the two groups, respectively. Results of SBP also did not show differences between groups at any time point, except a more marked decrease in the amlodipine group compared to nilvadipine in the supine measurements at endpoint. A total number of 30 patients (36.6%) in the nilvadipine group and 23 (27.1%) in the amlodipine group reported adverse events ( p = 0.24 between groups), which mainly consisted of vasodilatory effects (e.g. oedema, flushing and headache). A favourable lipid profile, i.e. a significant ( p = 0.002 between groups) decrease of triglycerides levels and an increase of HDL-C, was observed in the nilvadipine group, compared with an increase of triglycerides in the amlodipine group. No effects on haematology, liver and renal function were observed in either group.Conclusions: Nilvadipine or amlodipine produced comparable effects on DBP and shared a similar adverse effect profile. A favourable effect on lipid profile was observed following nilvadipine treatment.

Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: The VAST study

Recent antihypertensive treatment guidelines recommend greater use of combination therapies. The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and > or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP <140 mm Hg or a reduction in mean sitting SBP of > or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP <90 mm Hg or a reduction in mean sitting DBP of > or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged > or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P < 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P < 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P < 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P < 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P < 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P < 0.05). In this group of patients with moderate hypertension and > or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.

The results of M-fact (metoprolol succinate-felodipine antihypertension combination trial)

The majority of hypertensive patients do not achieve blood pressure goals on antihypertensive medication monotherapy, thereby creating a need for combination therapies. This multicenter, randomized, double-blind, placebo-controlled, parallel group, unbalanced factorial study evaluated once-daily dosing of extended release (ER) metoprolol succinate (ER metoprolol; 25, 100, 400 mg), ER felodipine (2.5, 10, 20 mg), ER felodipine/ER metoprolol combination therapy (2.5/25, 2.5/100, 2.5/400, 10/25, 10/100, 10/400, 20/25, 20/100, 20/400 mg), and placebo in adults with essential hypertension. The study lasted 15–16 weeks, consisting of a 4–5 week placebo run-in period and a 9-week treatment phase. The primary efficacy endpoint was mean change in sitting diastolic blood pressure (SiDBP) from start of treatment to week 9. The treatment groups (N=1087) were well balanced with respect to demographic and clinical variables. Mean baseline BP was 152.6/99.9 mmHg. Both ER metoprolol 25 mg and ER felodipine 2.5 mg monotherapy showed significant placebo-subtracted SiDBP reductions of 3.7 mmHg (P<0.001). Incremental reductions in SiDBP were observed with increasing monotherapy doses. Overall, combination therapy was superior to monotherapy and placebo with generally additive effects (Figure). Of note, ER metoprolol 25 mg in combination with the lowest dose of ER felodipine (2.5 mg) gave approximately the same SiDBP reduction as the highest dose of ER felodipine (20 mg) alone. Most frequent adverse events leading to study drug discontinuation were edema (4%) and headache (2%). Higher rates of edema and fatigue were associated with felodipine doses ≥10 mg (alone or in combination). Low doses of ER metoprolol (25 mg) or ER felodipine (2.5 mg) are effective monotherapy; the antihypertensive effects of each are dose-related and additive. ER metoprolol and ER felodipine is an effective combination for the treatment of hypertension. Open in new tabDownload slide

Olmesartan medoxomil (OLM) reduces blood pressure (BP) load and improves goal rates more effectively than losartan potassium (LOS) and valsartan (VAL) in patients with essential hypertension

Total BP load is defined as the percentage of BP readings greater than the daytime (08:00–19:59) cut-off values of 90 mmHg for diastolic BP (DBP) and 140 mmHg for systolic BP (SBP) and nighttime (20:00–07:59) cut-off values of 85 mmHg for DBP and 130 mmHg for SBP. There is a direct relationship between BP load and target organ damage: the more time BP remains above the BP cutoff values, the greater the risk of organ damage. This was a randomized double-blind parallel-group efficacy study. Following a 4-week placebo run-in period, patients were randomized to 8 weeks’ treatment with starting doses of OLM 20 mg/day (n=147), LOS 50 mg/day (n=150), VAL 80 mg/day (n=145) or irbesartan (IRB) 150 mg/day (n=146). Analysis of the 24-hour ABPM data showed that OLM 20 mg/day was significantly more effective in reducing mean total BP load (DBP and SBP) vs LOS 50 mg/day and VAL 80 mg/day, and numerically greater vs IRB 150 mg/day in the intent-to-treat population at week 8 (Table). 1% = percent of patients’ BP readings above cut-off values; 2%DBP > daytime/nighttime cutoff value of 90/85 mmHg; 3%SBP > daytime/nighttime cutoff value of 140/130 mmHg; LOCF, last observation carried forward; *p = 0.0035 vs LOS; †p = 0.0011 vs VAL; ‡p = 0.0014 vs LOS; §p = 0.0002 vs VAL 1% = percent of patients’ BP readings above cut-off values; 2%DBP > daytime/nighttime cutoff value of 90/85 mmHg; 3%SBP > daytime/nighttime cutoff value of 140/130 mmHg; LOCF, last observation carried forward; *p = 0.0035 vs LOS; †p = 0.0011 vs VAL; ‡p = 0.0014 vs LOS; §p = 0.0002 vs VAL In addition to absolute BP reduction, the ability of an agent to decrease BP load is an important measure of antihypertensive efficacy. Decreasing BP load may reduce the risk of target organ damage and may therefore improve clinical outcomes.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

24-hour ambulatory blood-pressure effects of valsartan + hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk

There is a lack of data on the effects of angiotensin-receptor blocker and diuretic combinations on ambulatory blood pressure (ABP) in hypertensive patients with additional cardiovascular risk factors.In a randomized, double-blind trial, the effects on 24-h ABP of the combination valsartan 160 mg od and hydrochlorothiazide 25 or 12.5 mg during 24 weeks of therapy were compared with the effects of amlodipine 10 mg monotherapy (group A10) in 474 stage-II hypertensive patients with additional cardiovascular risk factors. After a two-week single-blind placebo run-in period, patients were randomized to receive valsartan 160 mg od or amlodipine 5 mg od. At week 4, HCTZ 12.5 mg (group V160/HCTZ12.5) and 25 mg (group V160/HCTZ25) were added to the valsartan groups and in the A10 patients the amlodipine dose was force-titrated to 10 mg od.All three treatments reduced 24-h BP as well as night-time and daytime BP levels from baseline. Twenty-four hour systolic blood pressure (SBP) was reduced by 15.9+/-1.0 mmHg (least-squares mean change+/-SE), 19.3+/-1.0 mmHg and 16.1+/-1.1 mmHg in the V160/HCTZ12.5, V160/HCTZ25 and A10 groups, respectively and 24-h diastolic blood pressure (DBP) was reduced by 9.3+/-0.6 mmHg, 11.4+/-0.6 mmHg and 9.6+/-0.7 mmHg in the three groups. The differences between the V160/HCTZ25 group and the A10 group were significant (p<0.05) for the changes in 24-h systolic BP as well as for changes in daytime systolic BP and night-time diastolic BP. Control rates defined as ABPM < or =130/80 mmHg were: 48.4%, 60.8% and 50.9% in the V160/HCTZ12.5, V160/25 and A10 groups, respectively. The differences in control rates between the V160/HCTZ25 group and the other two treatment groups were significant at p<0.05.The fixed-dose combination of valsartan 160 mg+HCTZ 25 mg od is an attractive therapeutic option measured on the effects on 24-h ABPM, night-time and daytime BP reduction and control rates in hypertensive patients at additional cardiovascular risk.

Child Psychopharmacology, Effect Sizes, and the Big Bang

Back to table of contents Previous article Next article Letter to the EditorFull AccessChild Psychopharmacology, Effect Sizes, and the Big BangRÉMY P. BARBE, M.D., RÉMY P. BARBESearch for more papers by this author, M.D., Pittsburgh, Pa.Published Online:1 Apr 2005https://doi.org/10.1176/appi.ajp.162.4.817-bAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dr. Wagner and colleagues reported on a randomized clinical trial for the treatment of depressed children and adolescents with citalopram. The standard of randomized clinical trial reporting has been described in the CONSORT statement (1); one of its recommendations is to describe the flow of the subjects in the study (number screened, proportion randomly assigned, etc.). Dr. Wagner and colleagues did not report the proportion of subjects who were excluded from the random assignment after the single-blind period. This information is critical because a placebo run-in period might help to “wash out” nonspecific responders, allowing sharper evaluation of treatment-specific effects as shown in some pharmacotherapy studies (2).An additional concern is the elicitation method used for adverse events at a time when the safety of SSRIs in youth has been called into question (3). The adverse events were: “reported by patients or observed by investigators” (Wagner et al., p. 1080). The reliability of this practice is questionable because some adverse events, even very severe ones, could neither be reported by the patient nor observed by the investigator and would need to be specifically assessed (4).Finally, it is somewhat surprising that the authors do not compare their results with those of another trial, involving 244 adolescents (13–18-year-olds), that showed no evidence of efficacy of citalopram compared to placebo and a higher level of self-harm (16 [12.9%] of 124 versus nine [7.5%] of 120) in the citalopram group compared to the placebo group (5). Although these data were not available to the public until December 2003, one would expect that the authors, some of whom are employed by the company that produces citalopram in the United States and financed the study, had access to this information.

Presentiment or entanglement?: An alternative explanation for apparent entanglement in provings

A number of authors have recently discussed the possible role entanglement in homeopathy. Walach et al have published a homeopathic proving which they interpreted as demonstrating entanglement between placebo and verum groups in a proving. The lack of a 'run-in' period was a weakness of this trial. We present further results of our proving of Belladonna which show that subjects who reported symptoms during the placebo run-in period ('presentiment provers') were more likely to report symptoms during the treatment period. This data suggests and the observations of Walach et al may be explicable by conventional mechanisms including differential reporting and constitutional type.

LDL-C goal attainment with the addition of ezetimibe to on-going simvastatin treatment in coronary heart disease patients with hypercholesterolemia

ABSTRACTObjective: To evaluate the addition of ezetimibe or placebo to on-going simvastatin treatment on attaining the LDL‐C treatment target of ≤ 2.60 mmol/L (100 mg/dL) in coronary heart disease (CHD) patients with hypercholesterolemia.Methods: Patients with documented CHD were recruited if they were on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks, had LDL‐C > 2.60 mmol/L and ≤ 4.20 mmol/L (> 100 mg/dL and ≤ 160 mg/dL), triglycerides ≤ 4.00 mmol/L (355 mg/dL) and hepatic transaminases and creatine kinase ≤ 50% above the upper limit of normal. After a 4-week placebo and diet run-in period, eligible patients were randomized to a double-blind, placebo-controlled comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n = 208) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg for 6 weeks (n = 210).Results: When ezetimibe was added to on-going simvastatin therapy, a significantly greater percentage of patients attained the LDL‐C target of ≤ 2.60 mmol/L after 6 weeks of treatment compared to placebo added to on-going simvastatin (80.4% vs. 17.4%, respectively; p ≤ 0.001). When co-administered with on-going simvastatin therapy, mean percentage reduction in LDL‐C from baseline was significantly larger in the ezetimibe group compared to placebo (27.1% vs. 4.1%, respectively; p ≤ 0.001). The co-administration of ezetimibe or placebo to on-going simvastatin treatment was generally well tolerated.Conclusions: Ezetimibe co-administered with on-going simvastatin 10 mg or 20 mg treatment enabled more CHD patients with hypercholesterolemia to attain the LDL‐C treatment target of ≤ 2.60 mmol/L.

Botulinum Toxin Type A (BOTOX®) for the Prophylactic Treatment of Chronic Daily Headache: A Randomized, Double‐Blind, Placebo‐Controlled Trial

The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH). Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache. This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed. Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity. BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.

24-hour ambulatory blood-pressure effects of valsartan &amp; hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk: A VAST sub-study

There is a lack of data on the effects of angiotensin-receptor blocker and diuretic combinations on ambulatory blood pressure (ABP) in hypertensive patients with additional cardiovascular risk factors. In a randomized, double-blind trial, the effects on 24-h ABP of the combination valsartan 160 mg od and hydrochlorothiazide 25 or 12.5 mg during 24 weeks of therapy were compared with the effects of amlodipine 10 mg monotherapy (group A10) in 474 stage-II hypertensive patients with additional cardiovascular risk factors. After a two-week single-blind placebo run-in period, patients were randomized to receive valsartan 160 mg od or amlodipine 5 mg od. At week 4, HCTZ 12.5 mg (group V160/HCTZ12.5) and 25 mg (group V160/HCTZ25) were added to the valsartan groups and in the A10 patients the amlodipine dose was force-titrated to 10 mg od. All three treatments reduced 24-h BP as well as night-time and daytime BP levels from baseline. Twenty-four hour systolic blood pressure (SBP) was reduced by 15.9+/-1.0 mmHg (least-squares mean change+/-SE), 19.3+/-1.0 mmHg and 16.1+/-1.1 mmHg in the V160/HCTZ12.5, V160/HCTZ25 and A10 groups, respectively and 24-h diastolic blood pressure (DBP) was reduced by 9.3+/-0.6 mmHg, 11.4+/-0.6 mmHg and 9.6+/-0.7 mmHg in the three groups. The differences between the V160/HCTZ25 group and the A10 group were significant (p<0.05) for the changes in 24-h systolic BP as well as for changes in daytime systolic BP and night-time diastolic BP. Control rates defined as ABPM < or =130/80 mmHg were: 48.4%, 60.8% and 50.9% in the V160/HCTZ12.5, V160/25 and A10 groups, respectively. The differences in control rates between the V160/HCTZ25 group and the other two treatment groups were significant at p<0.05. The fixed-dose combination of valsartan 160 mg+HCTZ 25 mg od is an attractive therapeutic option measured on the effects on 24-h ABPM, night-time and daytime BP reduction and control rates in hypertensive patients at additional cardiovascular risk.

Telmisartan in patients with mild/moderate hypertension and chronic kidney disease

This study assessed the clinical efficacy and safety of telmisartan, an angiotensin II receptor blocker with a long terminal elimination half-life and almost exclusively excreted in bile, in patients with varying severity of chronic kidney disease (CKD). Adults with diastolic blood pressure (DBP) 90 - 109 mmHg and stable CKD were enrolled: mild/moderate (creatinine clearance (CrCl) 30 - 74 ml/ min/1.73 m2), severe (CrCl < 30 ml/min/1.73 m2) or requiring maintenance hemodialysis. A two- to four-week single-blind, placebo run-in period preceded once-daily telmisartan 40 mg administration for four weeks. Telmisartan 80 mg was given after four- or eight-week treatment ifDBP > or = 85 mmHg. After 12-week treatment, trough DBP/systolic blood pressure (SBP), DBP and SBP control rates, renal function and tolerability were recorded. Mean changes in DBP/SBP were 10.5/-10.7 mmHg for mild/moderate CKD (n = 27), -11.2/-14.9 mmHg for severe CKD (n = 27) and -15.0/-21.1 mmHg for hemodialysis patients (n = 28). DBP control rates (< 90 mmHg)/SBP responses (< 140 mmHg or > 10 mmHg reduction) occurred in 59.3%/66.7%, 63.0%/70.4% and 71.4%/92.9% of mild/moderate CKD, severe CKD and hemodialysis patients, respectively. Incidences of drug-related adverse events were low, and all were known adverse events of telmisartan and common to other angiotensin II receptor blockers. At the end of treatment, a decrease in 24-h urine creatinine occurred in 5/53 (9.4%) patients. Two patients discontinued treatment prematurely due to the worsening of CKD and one due to aggravated proteinuria. Once-daily telmisartan provided effective and well-tolerated treatment of mild/moderate hypertension in CKD patients, with no worsening of renal function.

Manidipine versus enalapril monotherapy in patients with hypertension and type 2 diabetes mellitus: A multicenter, randomized, double-blind, 24-week study

Background: Blood pressure reduction is associated with a reduced risk for cardiovascular events and death, particularly in patients with both hypertension and type 2 diabetes mellitus. Objective: The aim of this study was to compare theantihypertensive efficacy, tolerability, and effect on metabolic risk factors of manidipine, a new dihydropyridine calcium channel antagonist, and enalapril, a widely used angiotensin-converting enzyme inhibitor, in patients with mild to moderate essential hypertension and type 2 diabetes. Methods: This multicenter, double-blind trial compared manidipine and enalapril in patients with type 2 diabetes and hypertension (diastolic blood pressure [DBP] 90–104 mm Hg, systolic blood pressure [SBP] ≤190 mm Hg). Following a 3-week, single-blind placebo run-in period, eligible patients were randomized to receive either manidipine 10 mg or enalapril 10 mg once daily for 24 weeks. The dose was doubled after 3 weeks in patients who had not responded to treatment (DBP ≥90 mm Hg). The primary efficacy end point was change in DBP from baseline to the end of the study. Secondary outcomes were the responder rate (DBP <90 mm Hg and/or a DBP reduction of ≥10 mm Hg) at the end of the study. Other secondary measures were changes from baseline to the end of the study in heart rate and in the following measures obtained by ambulatory blood pressure monitoring (ABPM): 24-hour, daytime, and nighttime mean DBP and SBP, and the trough:peak ratio. Blood glucose, glycosylated hemoglobin (HbA 1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine were measured at the end of the placebo run-in period and the end of treatment. The study had 80% power to detect a between-treatment difference in mean sitting DBP of >3 mm Hg. Results: One hundred twenty-four patients were enrolled in the study. After the placebo run-in period, 13 patients were excluded from the study: 4 for DBP values outside the specified limits, 7 at their request, and 2 for adverse events. Thus, 111 patients met the eligibility criteria and were randomized to treatment (53 manidipine, 58 enalapril). The population consisted of 61 men and 50 women with a mean (SD) age of 62 (11) years and a body mass index of 28.2 (2.4) kg/m 2. Among patients who completed the study, drug doses were doubled in 67.6% (25/37) of patients in the manidipine group and 60.0% (24/40) of patients in the enalapril group ( P = NS). Similar reductions in blood pressure were observed in both groups, from a mean (SD) of 164 (12)/97.5 (5) mm Hg at baseline to 141 (12)/84.5 (6) mm Hg at the end of the study in the manidipine group ( P < 0.01), and from 159 (12)/98 (4) mm Hg to 139 (12)/86 (8) mm Hg in the enalapril group ( P < 0.01). The proportion of responders was 66.7% (32/48) in the manidipine group and 60.0% (30/50) in the enalapril group; the difference between groups was not significant. Twenty-four-hour ABPM revealed significant ( P < 0.01) and similar reductions in blood pressure in both groups, with a trough:peak ratio of ∼-50%. Neither drug affected heart rate. Among the statistically significant changes in metabolic parameters, significant reductions in HbA 1c (from 6.7% [1.4%] to 6.2% [1.1%]) and blood glucose concentrations (from 152 [44] to 143 [44] mg/dL) were observed only in the manidipine group ( P < 0.05). The incidence of adverse events was similar between groups. Conclusions: In the present study, manidipine wasas metabolically neutral and as effective as enalapril in reducing blood pressure in hypertensive patients with type 2 diabetes, providing a sustained 24-hour antihypertensive effect.

Efficacy and safety of controlled-release isosorbide-5-mononitrate for patients with stable effort angina pectoris: A randomized, double-blind, placebo-controlled study

Background A major limitation of the use of nitrates is the development of “nitrate tolerance”. The widely accepted treatment of preventing tolerance is to provide a period of “low nitrate interval”. Then, a new controlled-release isosorbide-5-mononitrate (I-CR) has been developed. Methods We conducted a randomized, double-blind, placebo-controlled study, which investigated the efficacy and safety of I-CR for 30 outpatients with stable angina pectoris. After consecutive exercise tests (ETs) for ascertaining the reproducibility of exercise tolerance during the placebo run-in period, patients were randomly assigned to either I-CR (40 mg once daily) or placebo groups (2:1) for 2 weeks. ETs were performed at 5, 12 and 24 hours after dosing on the final day. The primary efficacy variable was the change in exercise time to moderate angina from the baseline. Results The changes of exercise time to moderate angina were prolonged at 5 hours but not shortened at 24 hours. The subgroup analysis suggested that presence of concomitant use of insulin affected on this result. Headaches were the most frequent adverse effect but self-control levels in the I-CR group. The plasma concentration of I-CR at 24 hours was less than 100ng/mL. Conclusion These results suggest that I-CR improves exercise tolerance during the daytime and can be well tolerated in patients with stable effort angina without increasing adverse effect. (see Table) Clinical Pharmacology & Therapeutics (2005) 77, P53–P53; doi: 10.1016/j.clpt.2004.12.095 Table 1. Change in exercise time to moderate angina from baseline (seconds) Treatment N 5 hours 12 hours 24 hours I-CR 21 39.1 −7.5 27.5 All patients 14.7~63.6 −29.7~14.8 4.2~50.9 placebo 9 26.8 −17.2 65.4 −16.6~70.1 −61.7~27.3 26.1~104.8 Without insulin concomitant I-CR 16 52.9 5.0 38.8 28.0~77.9 −19.2~29.2 13.7~63.9 placebo 8 21.9 −24.5 65.4 −26.8~70.5 −72.4~23.4 19.7~111.1 Data are presented as mean values (95% confidence interval).