A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients.

BACKGROUND: In sublingual immunotherapy, optimal doses are a key factor for therapeutic outcomes. The aim of this study with tablets containing carbamylated monomeric house dust mite allergoids was to determine the most effective and safe dose. METHODS: In this double-blind, placebo-controlled dose-finding study, 131 patients with house dust mite-induced allergic rhinoconjunctivitis were randomized to 12-week treatments with 300 UA/day, 1000 UA/day, 2000 UA/day, 3000 UA/day or placebo. Conjunctival provocation tests (CPT) were performed before, during and after treatment. The change in mean allergic severity (primary endpoint), calculated from the severity of the CPT reaction, and the proportion of patients with an improved CPT threshold (secondary endpoint) determined the treatment effect. RESULTS: The mean allergic severity decreased in all groups, including the placebo group. It was lower in all active treatment groups (300 UA/day: 0.14, 1000 UA/day: 0.15, 2000 UA/day: 0.10, 3000 UA/day: 0.15) than in the placebo group (0.30). However, this difference was not statistically significant (P < 0.1). The percentage of patients with an improved CPT threshold was higher in the active treatment groups (300 UA/day: 73.9%; 1000 UA/day: 76.0%; 2000 UA/day: 88.5%; 3000 UA/day: 76.0%) than in the placebo group (64.3%). The difference between placebo and 2000 UA/day was statistically significant (P = 0.04). In 13 (10%) exposed patients, a total of 20 treatment-related adverse events of mild severity were observed. CONCLUSIONS: The 12-week daily treatment using 2000 UA/day monomeric allergoid sublingual tablets is well tolerated and reduces the CPT reaction in house dust mite-allergic patients.

Drop the Likelihood Ratio. A Novel Non-electronic Tool for Interpreting Diagnostic Test Results.

OBJECTIVE: To present a geometric ruler to determine predictive values of binary diagnostic test results from prevalence, sensitivity and specificity without calculation. METHODS: On logarithmic scale the relationships between pre-/post-test odds and the likelihood ratio as well as sensitivity, specificity and the likelihood ratio appear as simple linear (additive) equations. RESULTS: Each of these additive equations can be solved geometrically in form of a ruler with three scales. By amalgamation we devise a novel non-electronic tool which omits the intermediate step of likelihood ratio determination. CONCLUSIONS: We propose a simple geometric method to aid in interpretation of diagnostic test results for both practical and educational purposes.

Propofol sedation for colonoscopy with a new ultrathin or a standard endoscope: a prospective randomized controlled study.

BACKGROUND AND STUDY AIMS: The majority of colonoscopies in Germany are performed under conscious sedation. Previous studies reported that pediatric colonoscopes reduce the demand for sedative drugs and may improve cecal intubation. The aim of this study was to compare a new ultrathin and a standard colonoscope in terms of propofol demand during colonoscopy. PATIENTS AND METHODS: A total of 203 patients were prospectively randomized to undergo colonoscopy with either a 9.5-mm ultrathin (UTC) colonoscope or a standard colonoscope of variable stiffness. Initially, 40 or 60 mg of propofol were administered according to body weight, followed by bolus injections of 20 mg as deemed necessary. Propofol was administered by a separate physician who was blinded to the endoscope used. Sedation levels were defined according to guidelines; pain and complaints were recorded on a numeric rating scale. RESULTS: Significantly less propofol was required to reach the cecum with the UTC (adjusted mean 94.9 mg [95 % confidence interval (CI) 85.7 - 105.0] vs. 115.3 mg [95 %CI 105.8 - 124.7]; P = 0.003). The level of sedation and pain score were lower with the UTC (sedation level 1 76 % vs. 61 %; P = 0.003; pain score adjusted mean 2.0 [95 %CI 1.7 - 2.4] vs. 2.8 [95 %CI 2.5 - 3.1]; P = 0.001). The rate of ileal and cecal intubation, time to reach the cecum, number of external compressions, withdrawal time, polyp and adenoma detection rate, and patient satisfaction were not different between the two colonoscopes. The time to intubate the ileum was longer with the UTC (1.73 minutes [95 %CI 1.42 - 2.04] vs. 1.22 minutes [95 %CI 0.91 - 1.52]; P = 0.020). CONCLUSIONS: Use of a new ultrathin colonoscope was associated with reduced propofol consumption, lower patient sedation levels, and less pain than the standard colonoscope, but ileal intubation time was longer.

[Sound levels in nursery schools]. / Lärm in Kindertagesstätten.

INTRODUCTION: Children and teenagers often suffer from hearing loss because of exposure to sound levels above 100 dB generated by toys, portable music players and stereo equipment in discotheques. Even in nursery schools and schools, considerable noise levels are produced by children's voices. METHODS: Sound levels were measured in a nursery school in Cologne in four different rooms, each with 22 children aged between 3 and 6 years and two teachers. Sound dosimeters detected sound levels in each room for 5 days of the week. These were positioned in the room above the playing children as well as near the teachers' ears. The same measurements were repeated after the children had been instructed about noise and possible noise damage. In addition, the children were now able watch the "noise lights", an instrument resembling traffic lights which translated the sound levels actually measured in their room into optical signals. A questionnaire containing 13 questions about noise and sensitivity to noise was distributed to 35 teachers at nursery schools in the Cologne municipal area. RESULTS: Mean sound levels of an 8-h/day measuring period (L(eq)) were 80.1 ± 2.3 dB(A) near the ear of the teacher and 70.87 ± 2.5 dB(A) measured in the room. The maximal sound level for 1 s, L(max) dB(A), was 112.55 ± 2.3 dB(A) near the ear and 103.77 ± 8.1 dB(A) in the room. After the children had learned about noise and were able to check the sound level they produced with the help of the "noise lights", a tendency towards a reduction of sound levels in the room and near the teachers' ears could be seen. An evaluation of the questionnaire revealed the high physical strain and emotional stress the teachers were subjected to due to noise. CONCLUSIONS: Children and teachers in nursery schools are subjected to high sound levels. Therefore, the education and early sensitization of children to noise in order to prevent prospective hearing damage, e.g. using the "noise light", should be set as a goal. Soundproofing measures are also possible. Further investigations to assess the effects of these measures are planned.

Inconsistent trial assessments by the National Institute for Health and Clinical Excellence and IQWiG: standards for the performance and interpretation of subgroup analyses are needed.

OBJECTIVES: The methodology for the critical assessment of medical interventions is well established. Regulatory agencies and institutions adhere, in principle, to the same standards. This consistency, however, is not always the case in practice. STUDY DESIGN AND SETTING: Using the evaluation of the CAPRIE (Clopidogrel versus Aspirin in Patients at risk of Ischemic Events) trial by the British National Institute for Health and Clinical Excellence (NICE) and the German Institute for Quality and Efficiency in Health Care (IQWiG), we illustrate that there was no consensus for the interpretation of possible heterogeneity in treatment comparisons across subgroups. RESULTS: The NICE concluded that CAPRIE demonstrated clinical benefit for the overall intention-to-treat (ITT) population with sufficient robustness to possible sources of heterogeneity. The IQWiG interpreted the alleged heterogeneity as implying that the clinical benefit only applied to the subgroup of patients with a statistically significant result irrespective of the results of the ITT analysis. CONCLUSION: International standards for the performance and interpretation of subgroup analyses as well as for the assessment of heterogeneity between strata are needed.

[Should all patients with thyroid nodules > or = 1 cm undergo fine-needle aspiration biopsy?]. / Soll man alle Schilddrüsenknoten > or = 1 cm punktieren?

The prevalence of thyroid nodules > or = 1 cm is high in a previously iodine-deficient area. Under the hypothesis, that all patients with such nodules undergo fine-needle aspiration biopsy (FNAB) and that sensitivity and specificity of cytology are calculated with 85%, the positive predictive value of pathologic cytologic finding will reach 1.5% only according to Bayes-theorem. This is clinically unacceptable, as resection will be the consequence in all cases with suspect cytology. Even implementation of a second, independent test (e. g. moleculargenetic testing of thyreocytes, sensitivity to detect mutation 50%, specificity 95%) and application of sequential Bayes-theorem the positive predictive value of combined pathologic findings will increase to 13% only. Nevertheless, 58% out of all thyroid cancer remain undetected by such a sequential algorithm. As a consequence , pre-selection of thyroid nodules for FNAB is required to increase the pretest-probability to at least 5-10%. A combination of sonographic criteria and scintigraphy, even in patients with normal TSH-levels, is suited to selected thyroid nodules for FNAB.

Skin sclerosis is only of limited value to identify SSc patients with severe manifestations--an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register.

OBJECTIVES: In SSc, diagnosis and classification is based mainly on skin sclerosis. Herein, we investigated in a large multicentre cohort, to what extent skin sclerosis reflects organ involvement and additional clinical symptoms. METHODS: A total of 1200 SSc patients from the register of the German Systemic Sclerosis Network (DNSS), classified as either lcSSc or dcSSc, were analysed for their serological characteristics, clinical symptoms and organ manifestations in relation to skin involvement measured by the modified Rodnan skin score (mRSS). RESULTS: SSc patients with different mRSS did not differ significantly in their disease duration and in most of the clinical symptoms. They showed a similar distribution of most organ manifestations such as pulmonary arterial hypertension as well as cardiac, renal and nervous system involvement. More severe skin thickening was found to be associated with pulmonary fibrosis and gastrointestinal symptoms, as well as with digital ulcers and musculoskeletal involvement. CONCLUSIONS: In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Breast cancer patients' expectations in respect of the physician-patient relationship and treatment management results of a survey of 617 patients.

BACKGROUND: The following study was conducted to explore patients' information needs and preferences with a special focus on doctor-patient communication. PATIENTS AND METHODS: A 62-item questionnaire developed by a multidisciplinary team and validated in a phase-I study was given to breast cancer patients via the Internet (homepage) or in a hard copy version. RESULTS: A total of 617 patients responded, 552 on line and 65 via the hard copy questionnaire. The median age of the on-line group was 47 (21-85) and 55 (40-92) in the hard copy group. Sixty-five per cent of the patients were treated with the intention of achieving a cure and 35% of the patients had metastatic disease. The median length of the consultation communicating the information 'You have breast cancer' was 15 min (0-300). The most effective and patient-relevant source of information about the disease and the treatment options was consultation with the physician (84%). When asked to suggest areas for improvement, patients' most common answers were: more complementary therapies should be offered by the physician (54%); physicians should take more time to explain things (51%); and cooperation between the physicians involved in the patient's care should be improved (39%). The questions most relevant to patients were: 'Am I getting the right therapy?' (89%); 'How many patients with my condition does my doctor treat?' (46%) and 'Can I be enrolled into a trial?' (46%). An independent second opinion centre was desired by 94% of the respondents but only 20% knew of any such resource. CONCLUSIONS: This study underlines the need to give patients with breast cancer the full details on treatment options and cancer management. The results provide a suitable basis for a broader interdisciplinary discussion of the patient-physician relationship and should be useful in generating hypotheses for subsequent prospective studies.

Trapidil is as effective as isosorbide-dinitrate for treating stable angina pectoris: a multinational, multicenter, double-blind, randomized study.

OBJECTIVE: Nitrates have long been used in the treatment of stable angina pectoris. We set out to show that trapidil, a triazolo-pyrimidine with a mode of action different from that of nitrates, is not inferior to isosorbide-dinitrate (ISDN) in the treatment of this clinical syndrome. PATIENTS AND METHODS: We studied the efficacy of 200 mg trapidil (t.i.d.) vs. ISDN (20 mg b.i.d.) in patients with chronic stable angina treated for 12 weeks. The therapeutic effect was measured in terms of responder rate as change in total exercise time (TET) by at least 60 seconds using the bicycle ergometer test. RESULTS: A total of 648 patients were included in the study. Responder rates in the Per- Protocol (PP) population (n = 529) were 50.4% (n = 133) in the trapidil group and 52.5% (n = 139) in the ISDN group (p = 0.233). As the lower non-inferiority limit (-15%) was clearly excluded from the 95% CI (pp: -10.6%, +6.4%; ITT -9.7%, 5.7%), non-inferiority of trapidil compared to ISDN can be concluded. Trapidil 200 mg t.i.d. combined with short-acting NTG prn as rescue medication over 12 weeks in subjects with chronic stable angina pectoris proved to have similar effects on TET and on other clinical endpoints as ISDN 20 mg b.i.d. The secondary efficacy analyses did not reveal any clinically relevant differences between treatment groups, and were not in conflict with the non-inferiority claim. Patients in the ISDN group had significantly more headache (34.1%; n = 110) compared to those taking trapidil (19.3%, n = 62; p <0.0001). CONCLUSIONS: Overall results of this study show that both drugs are equally effective and safe for the short-term treatment of patients with chronic stable angina pectoris and that trapidil can be considered as therapeutically equivalent to ISDN.

A randomized, double-blind, placebo-controlled, clinical dose-response trial of an extract of Baptisia, Echinacea and Thuja for the treatment of patients with common cold.

The aim of this study was to verify the efficacy and safety of an herbal medication containing an extract of a mixture of Baptisiae tinctoriae radix, Echinaceae pallidae/purpureae radix and Thujae, occidentalis herba (SB-TOX) in the treatment of upper respiratory tract infections (URIs), and to test whether SB-TOX's clinical efficacy is dose dependent. A total of 91 adults (mean age 42.1 +/- 13.0 years) were randomised to receive 19.2 mg of SB-TOX (n=31), 9.6 mg SB-TOX (n=29) or placebo (n=31) three times daily for 3-12 days. Since a "running nose" is the main symptom of a common cold, the total number of facial tissues used throughout the clinical duration of their cold was the primary efficacy parameter. In the intention-to-treat analysis, this total number of tissues decreased with increasing extract dose. The slope across groups according to the Jonckheere test was significant (p = 0.0259). In the high-dose group, the standardised effect size delta/SD was 0.46 compared with placebo. Time to relevant improvement in cold symptoms (measured as the time until less than 30 tissues per day were used) was 1.1 days (95% CI 0.52; 1.67), 0.76 days (95% CI 0.28; 1.24) and 0.52 days (95% CI 0.22; 0.82) in the placebo, low-dose and high-dose groups, respectively (p(LogRank) = 0.0175). No adverse events were reported. This study demonstrates the efficacy and safety of SB-TOX in the treatment of URIs, and that its efficacy is dose dependent.

Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation.

OBJECTIVE: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. MATERIAL AND METHOD: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 x 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 x 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. RESULTS: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C(max) to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t(max) for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. CONCLUSIONS: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.

A ruler for interpreting diagnostic test results.

OBJECTIVES: Bayes' rule formalizes how the pre-test probability of having a condition of interest is changed by a diagnostic test result to yield the post-test probability of having the condition. To simplify this calculation a geometric solution in form of a ruler is presented. METHODS: Using odds and the likelihood ratio of a test result in favor of having the condition of interest, Bayes' rule can succinctly be expressed as "the posttest odds equals the pre-test odds times the likelihood ratio". Taking logarithms of both sides yields an additive equation. RESULTS: The additive log odds equation can easily be solved geometrically. We propose a ruler made of two scales to be adjusted laterally. A different, widely used solution in form of a nomogram was published by Fagan. CONCLUSIONS: Whilst use of the nomogram seems more obvious, the ruler may be easier to operate in clinical practice since no straight edge is needed for precise reading. Moreover, the ruler yields more intuitive results because it shows the change in probability due to a given test result on the same scale.

Closure procedures for monotone bi-factorial dose-response designs.

Two goals of multiple-dose factorial trials are (i) demonstrating improved effectiveness of a fixed combination over each of its components as well as (ii) identifying a safe and effective dose range. The authors address both goals though with focus on the second by closure procedures that guarantee strong control of the familywise error rate. Two different families of null hypotheses are investigated for bi-factorial dose-response designs that are monotone with respect to the matrix partial order. One is suitable to find the minimum effective dose(s) and the other one is large enough to identify the highest effective dose step(s). Likelihood ratio tests and appropriate multiple contrast tests are applied to an unbalanced clinical trial example taken from Hung (2000, Statistics in Medicine 19, 2079-2087). Full computer code written in the R language is available from the Internet.

Treatment of acute bronchitis in adults with a pelargonium sidoides preparation (EPs 7630): a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Acute bronchitis is a widespread medical problem, and, although predominantly caused by viruses, antibiotics are still prescribed unnecessarily. Therefore, it is of utmost importance to evaluate the use of alternative treatments for acute bronchitis. OBJECTIVE: To evaluate the efficacy and safety of a Pelargonium sidoides preparation (EPs 7630 is a registered trademark of Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany) compared with placebo in patients with acute bronchitis. DESIGN: Randomized, double-blind, placebo-controlled trial using a design with planned interim analyses. SETTING: Six outpatient clinics. PATIENTS: One hundred twenty-four adults with acute bronchitis present /=five points, and informed consent. INTERVENTION: EPs 7630 or placebo (30 drops three times daily) for seven days. MEASUREMENTS: The primary outcome criterion was the change of BSS on day seven. RESULTS: The decrease of BSS from baseline to day seven was 7.2 +/- 3.1 points with EPs 7630 (n = 64) and 4.9 +/- 2.7 points with placebo (n = 60). The 95% confidence interval for the difference of effects between the two treatment groups (EPs 7630 minus placebo) was calculated as (1.21, 3.56) showing a significant improvement of EPs 7630 compared with placebo on day seven (P < .0001). For each of the five individual symptoms, rates of complete recovery were considerably higher in the EPs 7630 group. Within the first four days, onset of treatment effect was recognized in 68.8% of patients in the EPs 7630 group compared with 33.3% of patients in the placebo group (P < .0001). Health-related quality of life improved more in patients treated with EPs 7630 compared with placebo-treated patients. Adverse events occurred in 25 of 124 patients (EPs 7630: 15/64 patients, placebo: 10/60 patients). All adverse events were assessed as nonserious. CONCLUSIONS: EPs 7630 was superior in efficacy compared with placebo in the treatment of adults with acute bronchitis. It may therefore offer an effective alternative for acute bronchitis unless antibiotics are clearly indicated.

Meta-analysis of randomised controlled prostaglandin E1 studies in peripheral arterial occlusive disease stages III and IV.

BACKGROUND: The relevance of Prostaglandin El (PGE,) in the treatment of peripheral arterial occlusive disease stage III and IV was to be evaluated for the first time by a meta-analysis. PATIENTS AND METHODS: Altogether, 643 patients were analyzed from seven randomized, controlled PGE1 studies that were comparable with regard to patient selection, study design and endpoints. Of these, only placebo-controlled studies (n = 254) were included in the formal meta-analysis using the method of DerSimonian and Laird. Additionally, the response rate and the rate of adverse events were determined for the pooled groups of all studies. RESULTS: At the end of treatment, PGE1 showed a significantly better response (ulcer healing and/or pain reduction) as compared to placebo (47.8% for PGE1, vs. 25.2% for placebo, p = 0.0294). A significant difference in favor of PGE1 was also seen for the combined endpoint "major amputation or death" after 6-month follow-up (22.6% for PGE1 vs. 36.2% for placebo, p = 0.0150). The response rate (ulcer healing and/or pain relief) of the pooled treatment groups was 60.2% for PGE1, 25.2% for placebo, and 53.6% for iloprost. The adverse events rate of the pooled treatment groups showed good tolerability for PGE, with a rate of 39.6% in comparison to 73.9% for iloprost and 15.4% for placebo. CONCLUSION: For patients with peripheral arterial occlusive disease stage III or IV not eligible for arterial reconstruction, PGE1 therapy not only has significant beneficial effects over placebo on ulcer healing and pain relief but also increases the rate of patients surviving with both legs after 6-months follow-up.

The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

Patients with breast cancer receiving adjuvant chemotherapy frequently suffer from a restricted quality of life (QoL) due to the side-effects of chemotherapy and the consequences of coping with the diagnosis. Therefore, the objective of this clinical study was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to the galactoside-specific mistletoe lectin, on QoL by performing a placebo-controlled trial. Overall, 272 patients with breast cancer receiving adjuvant CMF chemotherapy (cyclophosphamide-methotrexate-fluorouracil) were enrolled and randomised to groups receiving placebo or PS76A2 at concentrations of 10, 30 or 70 ng mistletoe lectin (ML) per ml. The patients received 0.5 ml study medication twice weekly subcutaneously for 15 consecutive weeks (4 CMF cycles). Primary variables were the self-assessment QoL scores GLQ-8 (Global Life Quality) and Spitzer's uniscale. As a result, statistically significant effects on QoL were obtained with the medium dose (15 ng ML/0.5 ml). The treatment difference between the medium dose and placebo with regard to the GLQ-8 sum was 60.8 mm (95% confidence interval: 19.3 to 102.0 mm). The treatment effect for Spitzer's uniscale between the medium dose and placebo was 16.4 mm (95% confidence interval: 6.3 to 26.6 mm). The results on QoL were supported by an increase of T helper lymphocytes (CD4+) and the CD4+/CD8+ ratio (p<0.05). Overall, PS76A2 was well tolerated. Local reactions at the injection sites occurred dose-dependently, but were mild at the low and medium dose levels.