Placebo Withdrawal Research Articles

P0807 Impact of Risankizumab on Patient-reported Outcomes and Biomarkers Over Time: Post-Hoc Analysis of Phase 3 INSPIRE and COMMAND Studies

Abstract Background Patients with ulcerative colitis (UC) may experience debilitating symptoms that impact their quality of life. This post hoc analysis evaluates changes in patient-reported outcomes (PROs) and biomarkers over time during maintenance treatment with risankizumab (RZB), a specific inhibitor of IL-23, among patients who responded to RZB induction treatment. Methods Patients with a clinical response to 12 weeks of intravenous (IV) RZB treatment from the Phase 2b and Phase 3 INSPIRE induction studies were randomised 1:1:1 to subcutaneous (SC) placebo (PBO) withdrawal, 180 mg RZB SC, or 360 mg RZB SC every 8 weeks during maintenance (COMMAND). Individual PROs were examined as no bowel urgency, no abdominal pain, no nocturnal bowel movements, no tenesmus, no faecal incontinence, no UC-related sleep interruption, and no fatigue (Functional Assessment of Chronic Illness-Fatigue [FACIT-F] ≥ 40). Biomarkers examined were faecal calprotectin (FCP) and high-sensitivity C-reactive protein (hs-CRP). Results were reported as the percentage of patients achieving each outcome for all PROs and median values for biomarkers at Week (wk) 0 of induction and every 8 wks from wk 0–52 of maintenance, unless otherwise stated for FACIT-F ≥ 40.1, hs-CRP and FCP. Non-responder imputation with no special data handling for missing data due to logistic restrictions (COVID-19 or the geo-political conflict in Ukraine and surrounding impacted regions) was used for missing data. Results In total, 548 patients (PBO SC, n=183; RZB 180 mg SC, n=179; RZB 360 mg SC, n=186) were randomised into the maintenance study. A higher proportion of patients achieved PROs at maintenance wk 0 compared to the induction baseline (Figures 1 and 2). Throughout maintenance, achievement of PROs persisted in patients receiving RZB, regardless of dosage, except for no nocturnal bowel movements, no fecal incontinence, and no UC-related sleep interruption, which showed a slight decrease in response for all treatment groups. A decline in achievement of all PROs in the PBO withdrawal arm was seen from wk 32 onwards. Both biomarkers showed a decrease in median levels from induction wk 0 to maintenance wk 0. During maintenance, median FCP levels were lower for both RZB doses compared to PBO. Lower median hs-CRP levels persisted during maintenance but were similar among all treatment groups. Conclusion Improvements in most PROs and biomarkers were sustained throughout maintenance, with declines seen in the PBO maintenance group likely due to the withdrawal of RZB from RZB induction treatment. These findings show that RZB may decrease common UC-related symptoms and may improve patients’ quality of life and inflammatory burden.

Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial

Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that targetaldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA. This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145-190mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate. In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n=32, 91.4%). The median ARR and the mean 24h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values-2.5, p<0.0001; aSBP: 142.6 vs 131.9mmHg, LSM change-10.7mmHg, p<0.0001). There were no safety concerns; all TEAEs were mild or moderate and there were no serious TEAEs. Dexfadrostat phosphate corrected the ARR and aSBP and was well tolerated in patients with PA, demonstrating the benefit of pharmacologically targeting the source of hyperaldosteronism. DAMIAN Pharma AG.

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort

BackgroundData assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. ObjectivesThe authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). MethodsAfter mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. ResultsBetween April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: −35.6 ± 32.6 mm Hg; Valsalva: −45.3 ± 35.9 mm Hg), N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (median: −480 ng/L; Q1-Q3: −1,104 to −179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. ConclusionsMavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men

Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.

Chloroquine Is Effective for Maintenance of Remission in Autoimmune Hepatitis: Controlled, Double-Blind, Randomized Trial.

Between 50% and 86% of patients with autoimmune hepatitis (AIH) relapse after immunosuppression withdrawal; long‐term immunosuppression is associated with increased risk of neoplasias and infections. Chloroquine diphosphate (CQ) is an immunomodulatory drug that reduces the risk of flares in rheumatologic diseases. Our aims were to investigate the efficacy and safety of CQ for maintenance of biochemical remission of AIH in a double‐blind randomized trial and to define a subgroup that obtained a greater benefit from its use. A total of 61 patients with AIH in histologic remission (90.1% AIH type 1 [AIH‐1]) were randomized to receive CQ 250 mg/day or placebo for 36 months. Of the 61 patients, 31 received CQ and 30 placebo. At baseline, clinical, laboratory, histologic findings, and human leukocyte antigen (HLA) profile were similar between the two groups. Relapse‐free survival was significantly higher in the CQ group compared to the placebo group (59.3% and 19.9%, respectively P = 0.039). For those patients completing 3‐year treatment, relapse rates were 41.6% and 0% after CQ and placebo withdrawal, respectively. Factors associated with a higher risk of relapse in multiple Cox regression were placebo use (hazard ratio, 2.4; 95% confidence interval [CI], 1.055.5; P = 0.039) and anti‐soluble liver antigen/liver‐pancreas (anti‐SLA/LP) seropositivity (hazard ratio, 5.4; 95% CI, 1.91‐15.3; P = 0.002). Although it was not possible to define a subgroup that obtained a greater benefit from CQ according to anti‐SLA/LP reactivity or HLA profile, 100% of patients who were anti‐SLA/LP‐positive (+) relapsed with placebo compared to 50% with CQ (P = 0.055). In the CQ group, 54.8% had side effects and 19.3% interrupted the drug regimen. Conclusion: CQ safely reduced the risk of relapse of AIH, but it was not possible to define a subgroup that obtained a greater benefit with CQ use, probably because of sample size.

A Randomized Trial of Iloperidone for Prevention of Relapse in Schizophrenia: The REPRIEVE Study.

BackgroundThe purpose of this study was to evaluate the safety and effectiveness of iloperidone for the prevention of relapse in schizophrenia.MethodsStudy subjects were adults with schizophrenia who started on oral open-label iloperidone titrated to an initial target dose of 12 mg/day (6 mg twice daily) and then stabilized on a flexible-dose iloperidone regimen (range 8–24 mg/day) for up to 24 weeks. Subjects meeting stabilization criteria then entered the relapse-prevention phase and were randomized 1:1 in a double-blind fashion to continue with iloperidone or placebo withdrawal for up to 26 weeks or until meeting relapse or other withdrawal criteria.ResultsA total of 303 subjects were randomized to the relapse-prevention phase; 153 continued to receive iloperidone, and 150 were withdrawn to placebo. The modal total daily dose for iloperidone in all phases of the study was 12 mg/day. The pre-defined unblinded interim analysis upon reaching 68 relapse events confirmed the hypothesis that iloperidone (n = 97) was more effective than placebo (n = 96) in preventing relapse events, and the trial was stopped early. The estimated relapse rates were 63.4 % (Kaplan–Meier [KM] estimate) for placebo compared with 20.4 % (KM estimate) for those continuing to receive iloperidone (log rank test: p < 0.0001). The mean time to relapse was 71 days for placebo and 139 days for iloperidone (hazard ratio 4.7; 95 % confidence interval 2.7–8.3; p < 0.0001). The safety profile observed in previous short-term studies was also reaffirmed in this maintenance treatment setting. The most common treatment-emergent adverse events (TEAEs) in the stabilization phase were dizziness (11.6 %), somnolence (8.3 %), and dry mouth (6.8 %). Rates of reported extrapyramidal disorder or akathisia during stabilization were 2.5 and 3.7 %, respectively.ConclusionsFlexible dosing of iloperidone for maintenance-phase therapy, with a modal dose of 12 mg/day was effective in preventing relapse in subjects previously stabilized on iloperidone. The adverse event profile for iloperidone was consistent with other studies, and the low extrapyramidal symptom and akathisia burden during stabilization was sustained during the course of the study.ClinicalTrials.gov identifier: NCT01291511.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-016-0345-4) contains supplementary material, which is available to authorized users.

Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia

BackgroundThe aim of this study was to examine if gradual withdrawal of remifentanil infusion prevented opioid-induced hyperalgesia (OIH) as opposed to abrupt withdrawal. OIH duration was also evaluated. MethodsNineteen volunteers were enrolled in this randomized, double-blinded, placebo-controlled, crossover study. All went through three sessions: abrupt or gradual withdrawal of remifentanil infusion and placebo. Remifentanil was administered at 2.5 ng ml−1 for 30 min before abrupt withdrawal or gradual withdrawal by 0.6 ng ml−1 every five min. Pain was assessed at baseline, during infusion, 45–50 min and 105–110 min after end of infusions using the heat pain test (HPT) and the cold pressor test (CPT). ResultsThe HPT 45 min after infusion indicated OIH development in the abrupt withdrawal session with higher pain scores compared with the gradual withdrawal and placebo sessions (both P<0.01. Marginal mean scores: placebo 2.90; abrupt 3.39; gradual 2.88), but no OIH after gradual withdrawal compared with placebo (P+0.93). In the CPT 50 min after end of infusion there was OIH in both remifentanil sessions compared with placebo (gradual P+0.01, abrupt P<0.01. Marginal mean scores: placebo 4.56; abrupt 5.25; gradual 5.04). There were no differences between the three sessions 105–110 min after infusion. ConclusionsWe found no development of OIH after gradual withdrawal of remifentanil infusion in the HPT. After abrupt withdrawal OIH was present in the HPT. In the CPT there was OIH after both gradual and abrupt withdrawal of infusion. The duration of OIH was less than 105 min for both pain modalities. Clinical trial registrationNCT 01702389. EudraCT number 2011-002734-39.

Detection of Clinically Relevant Pain Relief in Cats with Degenerative Joint Disease Associated Pain

BackgroundDetection of clinically relevant pain relief in cats with degenerative joint disease (DJD) is complicated by a lack of validated outcome measures and a placebo effect.Hypothesis/ObjectivesTo evaluate a novel approach for detection of pain relief in cats with DJD.AnimalsFifty‐eight client‐owned cats.MethodsProspective, double‐masked, placebo‐controlled, stratified, randomized, clinical study. Enrolled cats were 6–21 years of age, with owner‐observed mobility impairment, evidence of pain in at least 2 joints during orthopedic examination, and overlapping radiographic evidence of DJD, and underwent a 2‐week baseline period, 3‐week treatment period with placebo or meloxicam, and 3‐week masked washout period. Outcome measures were evaluated at days 0, 15, 36, and 57.ResultsBoth groups significantly improved after the treatment period (day 36) on client‐specific outcome measures (CSOM) and feline musculoskeletal pain index (FMPI) (P < .0001 for both); there was no difference between the groups on CSOM or FMPI score improvement. After the masked washout period, more cats that received meloxicam during the treatment period had a clinically relevant decrease in CSOM score (P = .048) and FMPI score (P = .021) than cats that received placebo.Conclusions and Clinical ImportanceUsing both a client‐specific and a general clinical metrology instrument, owners of cats with DJD were able to detect evident recurrence of clinical signs after withdrawal of active medication than after withdrawal of placebo, and that this study design might be a novel and useful way to circumvent the placebo effect and detect the efficacy of pain‐relieving medications.

Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial

ObjectivesThis 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with...

Efficacy and safety of valsartan in hypertensive children 6 months to 5 years of age

To evaluate a dose-dependent reduction in blood pressure (BP) and overall safety of valsartan in hypertensive children. In a multicenter, randomized, double-blind, parallel-group study, 75 patients with a documented history of hypertension were randomized (2 : 1 : 2) to receive valsartan (0.25, 1 or 4 mg/kg per day) for 6 weeks, then rerandomized (1 : 1) to receive placebo or valsartan for 2 weeks. This followed the 18-week extension study in which all patients received open-label valsartan (1 mg/kg initial dose, titratable up to 4 mg/kg). The primary endpoint was the slope analysis of the dose-response curve for mean sitting SBP (MSSBP) derived through MSSBP reduction over the first 6 weeks. Safety was assessed in terms of adverse events and serious adverse events (SAEs). At Week 6, significant reductions in MSSBP (P < 0.05) from baseline were observed for all three valsartan doses. Greater reductions were observed with the medium and high doses, although the dose-response trend was not statistically significant (P = 0.099). At Week 8, a greater increase in BP was observed in patients who switched from valsartan to placebo; the difference was not significant. At the extension endpoint, MSSBP was comparable to that observed at Week 6 of the core study. Overall, valsartan was well tolerated with no dose-dependent increase in adverse events during the dose-ranging period (Week 0-6) and a comparable incidence of adverse events to placebo during the placebo withdrawal period (Week 7-8). Although a dose-response trend was observed, statistical significance was not achieved during the dose ranging (primary endpoint) or the placebo-withdrawal periods of the study. However, valsartan demonstrated significant reductions in BP compared with baseline and provided consistent reductions over 26 weeks.

Su1633 Placebo Effects in Functional Dyspepsia: A Preliminary Analysis on Symptoms in an Ongoing Randomized Placebo Controlled Trial

Background: Functional dyspepsia (FD) is a common disorder; however no currently available therapy is highly effective and most treatments provide only minimal gain over placebo. Due to the spontaneous fluctuation of disease activity, a considerable proportion of patients experience sufficient relief of symptoms even if treated with medications that are effective in a small subgroup of patients. We examined the efficacy of the herbal preparation STW5 (Iberogast®), esomeprazole and placebo in patients with FD. Methods: In a double-blind, double dummy, randomized study, FD patients (Rome III criteria) received either; esomeprazole (Nexium® 20mg/daily) + placebo; STW5 (20 drops/TID) + placebo; dual therapy or double placebo (“active treatment”) for 4 weeks. Thereafter, clinical responders all received placebo (“placebo treatment”) for 2 weeks. Ongoing responders were reassessed after 2 weeks of “no treatment”. Symptoms and severity (Nepean Dyspepsia Index [NDI-S], Gastrointestinal Symptom Score [GIS] and Leeds Dyspepsia Questionnaire [LDQ]), quality of life (Nepean Dyspepsia Index [NDI-QoL]) and anxiety and depression (Hospital Anxiety and Depression Scale) were assessed. Visceral hypersensitivity was assessed with a nutrient challenge test before and after the 4 weeks of “active treatment”. Blinded data was divided into “nonresponder” and “responder” groups. Results: 70 FD patients (44 females; 48±2 years) have completed the study. 51 (73%) were responders to “active treatment”. Of 51 responders, 18 relapsed during “placebo treatment” (35% treatment withdrawal relapsers) and 20 relapsed on visible treatment cessation (39% placebo withdrawal relapsers); 13 continued with sufficient control of symptoms (26% sustained responders) after 2 weeks of “no treatment”. There were no baseline differences between non-responders and responders in regards to their initial symptom occurrence and severity, quality of life or anxiety or depression. In addition, there were no baseline differences between those that responded or relapsed after “treatment withdrawal” and/or “placebo-withdrawal”. After “active treatment” symptoms and severity decreased in responders, when compared with non-responders and this was matched by an improved quality of life (see table). Anxiety, depression and volume consumed during the nutrient challenge test were not different after “active treatment” between the nonresponders and responders. Conclusions: Thus far, 73% of FD patients respond symptomatically to “active treatment” and report an improved quality of life. However, the treatment(35%) and placebo-withdrawal relapse (39%) rates are also high. Baseline patient characteristics thus far have not been shown to predict response.

A meta-analysis to estimate the “real” placebo effect in juvenile idiopathic arthritis (JIA) trials

Methods This study was developed according to the PRISMA statement and pre-specified study selection, eligibility criteria, data extraction, quality assessment, and statistical analysis. Studies with parallel, cross-over or withdrawal design (open label followed by a double-blind placebo withdrawal period) were included in the analysis. Publications were retrieved from MEDLINE, Web of Science, EMBASE, and the Cochrane Controlled Trials Register from 1960 to May 2010, with literature search carried out from February to December 2010. Estimates of the placebo response rate and estimates of the placebo flare rate for the withdrawal trials with 95% Confidence Intervals (CI) were calculated.

Effects of Montelukast Treatment and Withdrawal on Fractional Exhaled Nitric Oxide and Lung Function in Children With Asthma

Leukotriene receptor antagonists (LTRAs) reduce fractional exhaled nitric oxide (Feno) concentrations in children with asthma, but the effect of LTRA withdrawal on Feno and lung function is unknown. We aimed to study the effect of treatment and withdrawal of montelukast, a LTRA, on airway inflammation as reflected by Feno and lung function in children with asthma. A double-blind, randomized, placebo controlled, parallel group study was undertaken in 14 atopic children with mild persistent asthma who were treated with oral montelukast (5 mg/d for 4 weeks) and 12 atopic children with mild persistent asthma who received matching placebo. A follow-up visit was performed 2 weeks after montelukast or placebo withdrawal. Montelukast reduced Feno concentrations by 17% (p = 0.067), an effect that was more pronounced (35%) [p = 0.0029] when children with seasonal atopy who were exposed to relevant allergens during the treatment phase were excluded from analysis (n = 3). Compared to those at the end of treatment, Feno concentrations were increased 2 weeks after montelukast withdrawal (p = 0.023) concomitant with a reduction in absolute FEV(1) values (p = 0.011), FEV(1) percentage of predicted values (p = 0.006), FEV(1)/FVC ratio (p = 0.002), and forced expiratory flow at 25% to 75% of FVC values (p = 0.021). These changes were not observed in the placebo group. LTRAs reduce Feno concentrations in children with asthma, and withdrawal can result in increased Feno values and worsening of lung function in children with asthma.

Some Surprises, Some Answers, and More Questions About Hormone Therapy

IN JULY 2002, INITIAL RESULTS FROM THE WOMEN’S HEALTH Initiative (WHI) randomized trial of combined estrogen plus progestin hormone therapy (CEE MPA) and follow-up data from the Heart Estrogen/progestin Replacement Study (HERS) were published within weeks of each other. The increased risks associated with CEE MPA therapy for postmenopausal women drew wide attention not only among the clinical professions, but also among the media, including front-page articles in major newspapers, feature stories in major weekly news magazines, and coverage by virtually all major television news programs. Neither women taking hormones nor their physicians could escape the media message: postmenopausal hormone therapy is dangerous. Many women taking hormones were urged by their physicians to stop taking these medications immediately or decided to stop taking them on their own. At the time, anecdote, not evidence, answered women’s question, “What can I expect?” In this issue of JAMA, Ockene et al report the results of a systematic collection of data on symptoms after discontinuing CEE MPA or placebo pills from 8405 of the 9351 participants in WHI who were still taking their assigned study drug on the stop date of the intervention (July 8, 2002). The WHI data and safety monitoring board had concluded in May 2002 that the risks of CEE MPA treatment outweighed the benefits and recommended early stopping of the study. These data should be of great interest both for counseling women currently taking hormones who may be reluctant to stop, and for providing information about symptoms commonly attributed to the decline in ovarian hormones that occurs with the menopausal transition. After discontinuing use of CEE MPA or placebo, women most commonly reported hot flashes or night sweats, pain and stiffness, and fatigue and difficulty sleeping, but nearly 36.7% of women reported neither moderate nor severe symptoms after they stopped taking CEE MPA. Among women who did not have a history of vasomotor symptoms at baseline, only 6.4% reported symptoms after discontinuing use of CEE MPA. Among the 63.3% of the WHI participants who reported at least 1 moderate or severe symptom after discontinuing use of CEE MPA, a wide range of strategies—many of them lifestyle changes, such as drinking more fluids, starting or increasing exercise, practicing yoga, meditation or breathing exercises, and using fans or air conditioners—were perceived to be quite helpful in relieving or coping with symptoms. So what can women who stop taking hormone therapy expect? Many will not experience unbearable symptoms, and those women whose symptoms are troubling may find relief with self-initiated, nonhormonal remedies. Symptom reports from the women in the WHI study who stopped taking placebo were also relatively common. Prior studies have shown that women who are randomized to the placebo group of trials investigating a variety of treatments for menopausal symptoms often improve. This is true not only for hormone therapies but also for treatments that are classified as complementary or alternative. In the WHI study, 40.5% of women who had been assigned to the placebo group reported a moderate or severe symptom after ceasing placebo use. Among women who had the symptom at baseline, 21.3% reported vasomotor symptoms, and 38.3% reported pain or stiffness after they stopped taking the placebo. This “placebo withdrawal effect”—combined with the data suggesting that simple lifestyle changes relieve some symptoms in at least some women—raises questions about the physiological basis of some of the symptoms that have always been associated with the estrogen-deficient state. Which of these are true consequences of cessation of estrogen production by the ovary? Accumulating evidence suggests many symptoms commonly attributed to estrogen deficiency are not. For example, in an examination of evidence for a causal association between ovarian aging and senescence and symptoms commonly attributed to menopause, including vasomotor symptoms (hot flashes and night sweats), vaginal dryness, sleep disturbances, mood symptoms (depression,

Prevention of Relapse Following Cognitive Therapy vs Medications in Moderate to Severe Depression

Antidepressant medication prevents the return of depressive symptoms, but only as long as treatment is continued. To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication. Patients who responded to CT in a randomized controlled trial were withdrawn from treatment and compared during a 12-month period with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal. Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a subsequent 12-month naturalistic follow-up. Outpatient clinics at the University of Pennsylvania and Vanderbilt University. A total of 104 patients responded to treatment (57.8% of those initially assigned) and were enrolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to severe depression. Patients withdrawn from CT were allowed no more than 3 booster sessions during continuation; patients assigned to continuation medication were kept at full dosage levels. Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression or Hamilton Depression Rating Scale scores of 14 or higher during the continuation phase. Recurrence was defined in a comparable fashion during the subsequent naturalistic follow-up. Patients withdrawn from CT were significantly less likely to relapse during continuation than patients withdrawn from medications (30.8% vs 76.2%; P = .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%; P = .20). There were also indications that the effect of CT extends to the prevention of recurrence. Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication.

Tegaserod: a review of its use in the management of irritable bowel syndrome with constipation in women.

The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm, Zelmac) is the first selective serotonin 5-HT(4) receptor partial agonist to be approved for the treatment of this syndrome. Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established. Three large well designed clinical trials of tegaserod 6 mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4-46.8% with tegaserod 6 mg twice daily and 28.3-38.8% with placebo (p < 0.05-0.0001 vs placebo). The relative increases in response rates with tegaserod 6 mg twice daily over the already high responses in the placebo groups ranged from 12-65% after 4-12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time. Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (</=12 months). In conclusion, oral tegaserod 6 mg twice daily for 12 weeks is effective and well tolerated in the treatment of IBS-C in women. Data on long term and comparative efficacy, cost-effectiveness and quality-of-life effects would be beneficial; however, in light of the fact that very few alternatives for the treatment of IBS-C have proven efficacy, tegaserod appears to be a promising option in women not responding to increased dietary fibre or osmotic laxative therapy.

Darusentan: An effective endothelin A receptor antagonist for treatment of hypertension

Background The antihypertensive efficacy and safety of darusentan, a new selective endothelin A antagonist was investigated. Methods In a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients). Results Darusentan significantly reduced diastolic (mean difference to placebo: 10 mg: −3.7 mm Hg, 95% confidence interval (CI): −6.6, −0.9, P = .009; 30 mg: −4.9 mm Hg, 95% CI: −7.7, −2.2, P = .0005; 100 mg: −8.3 mm Hg, 95% CI: −11.1, −5.5, P = .0001) and systolic BP (mean difference to placebo: 10 mg: −6.0 mm Hg, 95% CI: −11.0, −0.9, P = .02; 30 mg: −7.3 mm Hg, 95% CI: −12.3, −2.4, P = .004; 100 mg: −11.3 mm Hg, 95% CI: −16.3, −6.2, P = .0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Héadache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only. Conclusion These data, the first, suggest the therapeutic benefit of selective endothelin A receptor antagonism in human hypertension.

Effects of Chronic Nitrate Therapy on Left-Ventricular Volume in Patients with Heart Failure Secondary to Coronary Disease Already Treated with Captopril: A Withdrawal Study

Objective: This randomized, double-blind, placebo-controlled study with treatment lasting 16 weeks and withdrawal lasting 6 weeks tried to determine whether stopping nitrates has an effect on left-ventricular end-systolic volume in patients with heart failure who were chronically treated with captopril and diuretics. Patients and Methods: The study group comprised 29 patients with previous myocardial infarction, symptoms of mild-to-moderate heart failure, ejection fraction below 40%, no exercise-induced angina and no electrocardiographic signs of ischemia. After all patients had been treated with captopril (target dose: 25 mg twice daily), diuretics and the study drug (target dose: 40 mg isosorbide dinitrate twice daily or placebo) for 16 weeks, the study drug was withdrawn. The patients were then maintained on captopril and diuretics at constant doses for a 6-week withdrawal period. Radionuclide ventriculography with right-heart catheterization was performed at rest and during supine bicycle exercise after 16 weeks of double-blind treatment and at the end of the 6-week withdrawal period. Results: The changes in resting parameters following the withdrawal of the study drug were not different between the groups. At comparable maximum workload (placebo group 68 ± 15 W, nitrate group 68 ± 20 W), nitrate withdrawal caused a decrease in ejection fraction (placebo withdrawal: +0.8 ± 4.0%; nitrate withdrawal: –2.7 ± 4.3%, p < 0.02) and increases in left-ventricular end-diastolic volume (–9 ± 35 vs. 23 ± 48 ml, p < 0.02) and end-systolic volume (–9 ± 33 vs. +24 ± 47 ml; p < 0.01). Conclusion: The addition of nitrates to a baseline therapy with captopril and diuretics might reduce exercise-induced left-ventricular dilatation in patients with heart failure from coronary disease.

Doxepin in the treatment of primary insomnia — A placebo-controlled, double-blind, polysomnographic study

BACKGROUND Over recent years, the use of antidepressants for the symptomatic treatment of insomnia has grown substantially, but controlled studies are still lacking. Our study is the first investigation to prove objective efficacy and tolerability of low doses of a sedating antidepressant in a randomized, double-blind, and placebo-controlled manner in patients with primary insomnia. METHOD Forty-seven drug-free patients meeting DSM-IV criteria for primary insomnia (mean +/- SD duration of complaints = 11.2+/-9.7 years) received either 25-50 mg of the tricyclic antidepressant doxepin or placebo for 4 weeks followed by 2 weeks of placebo withdrawal. Sleep was measured by polysomnography at baseline and the first night of application, at 4 weeks of treatment and the first to third night of withdrawal, and after 2 weeks of withdrawal. RESULTS In the doxepin-treated patients who completed the study (N = 20, 47.6+/-11.3), medication significantly increased sleep efficiency after acute (night 1, p < or = .001) and subchronic (night 28, p < or = .05) intake compared with the patients who received placebo (N = 20, 47.4+/-16.8 years of age). Latency to sleep onset was not affected since the patients had normal baseline sleep latencies. Investigators found doxepin to cause significantly (p < or = .05) better global improvement at the first day of treatment. Patients rated sleep quality (p < or = .001) and working ability (p < or = .005) to be significantly improved by doxepin during the whole treatment period. Overall rebound in sleep parameters was not observed, but patients with severe rebound insomnia were significantly more frequent in the doxepin group (night 29, p < .01, night 30, p < or = .01; night 31, p < or = .05). No significant group differences in side effects were found, but 2 doxepin-treated patients dropped out of the study due to specific side effects (increased liver enzymes, leukopenia, and thrombopenia). CONCLUSION The results support the effectiveness of low doses of doxepin to improve sleep and working ability in chronic primary insomniacs, although subjective effects were light to moderate, and in some patients, rebound insomnia and specific side effects have to be considered.

The influence of trazodone treatment on cognitive functions in outpatients with major depressive disorder

Eight patients suffering from major depression were treated with trazodone 150 or 200 mg bid (non-responders) over 5 weeks, preceded and followed by a placebo week. Cognitive functioning was tested in the morning at the end of each treatment week. Before trazodone treatment commenced, patients' cognitive performance was compared with non-depressed controls. The depressed group showed significantly slower reaction times on the memory scanning test, but did not differ from the control group on five other tests including word learning, Critical Flicker/Fusion frequency (CFF), vigilance, tracking and divided attention. CFF threshold decreased significantly during trazodone treatment. CFF returned to its initial baseline level at the end of the placebo withdrawal. During the trazodone treatment period, recall from long-term memory of a previously learnt word list significantly improved, but at the end of the placebo withdrawal period memory performance returned to its initial baseline level. These results indicated that the subchronic influence of trazodone on cognitive functions is at least of a two-dimensional nature: decreased CFF threshold can be interpreted in terms of lowered CNS arousal, whereas a higher cognitive function, memory, improved, possibly related to the relief of depressive symptoms. Copyright © 1999 John Wiley & Sons, Ltd.