Issues with Tissues: Trends in Tissue-Engineered Products in Clinical Trials in the European Union.

Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. TEPs make up <5% of all advanced therapeutic medicinal products (ATMPs) in clinical trials and received 5.1% of ATMP-designated funding in trials in the European Union (EU) in 2019, highlighting the relatively low proportion of TEPs being developed. The realization of TEPs being marketed has yet to be fulfilled, with few products being approved. Since 2009, 90 TEP-based clinical trials have been undertaken in the EU. Of these 90, 25 were Phase I/II trials, 35 were Phase II, 28 were Phase III, and two were Phase IV trials. This review provides an overview of TEPs in development, identifying musculoskeletal, cardiovascular, and skin/connective tissue disorders as the main therapeutic areas of interest. Commercial sponsors have funded most trials, and a significantly higher proportion of late-phase trials. Furthermore, this study has identified a shift toward the use of allogeneic cells in TEPs and increased activity in the proportion of early phase trials listed. This indicates a renewed interest in TEP development as sponsors adapt to the new regulation, with prospects of more TEP market authorization applications in the future. Impact Statement Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. This article evaluates the regulatory landscape of TEPs and identifies the trends in clinical trial activity in the European Union (EU) since the introduction of Regulation (EC) No 1394/2007. This article identifies trends in TEP development, highlighting the most active member states, commercial involvement, a shift toward the use of allogeneic cells and a renewed interest in TEP development in recent years.

CARE guidelines for case reports: explanation and elaboration document.

BACKGROUND: Well-written and transparent case reports (1) reveal early signals of potential benefits, harms, and information on the use of resources; (2) provide information for clinical research and clinical practice guidelines, and (3) inform medical education. High-quality case reports are more likely when authors follow reporting guidelines. During 2011-2012, a group of clinicians, researchers, and journal editors developed recommendations for the accurate reporting of information in case reports that resulted in the CARE (CAse REport) Statement and Checklist. They were presented at the 2013 International Congress on Peer Review and Biomedical Publication, have been endorsed by multiple medical journals, and translated into nine languages. OBJECTIVES: This explanation and elaboration document has the objective to increase the use and dissemination of the CARE Checklist in writing and publishing case reports. ARTICLE DESIGN AND SETTING: Each item from the CARE Checklist is explained and accompanied by published examples. The explanations and examples in this document are designed to support the writing of high-quality case reports by authors and their critical appraisal by editors, peer reviewers, and readers. RESULTS AND CONCLUSION: This article and the 2013 CARE Statement and Checklist, available from the CARE website [www.care-statement.org] and the EQUATOR Network [www.equator-network.org], are resources for improving the completeness and transparency of case reports.

Is autologous chondrocyte implantation (ACI) an adequate treatment option for repair of cartilage defects in paediatric patients?

Cartilage lesions in the knee of juvenile patients require an effective repair to regain life-long functional activity of the joint. Autologous chondrocyte implantation (ACI) is discussed to be advantageous over other methods for cartilage repair regarding long-term outcome. ACI has successfully been applied in juvenile patients, although currently recommended for patients ≥18 years of age. Only few controlled clinical trials present evidence of efficacy and safety of ACI in adolescent patients. ACI products have to undergo the process of a marketing authorisation application, including the submission of a paediatric investigation plan (PIP). Data from prospective clinical studies or retrospective collection of long-term data in paediatric patients should be submitted for risk-benefit evaluation by the Paediatric Committee (PDCO).

Proposal for publishing and parallel reporting of case reports on adverse drug reactions to authorities by physicians.

For the safe use of medicinal products, it is important that physicians publish adverse experiences with a medicinal product-particularly regarding side effects-in the scientific literature. However, when searching applicable publications, we determined that adverse drug reactions (ADRs) are often published several months after their occurrence. In the context of patient safety, this is rather questionable as new and important information on ADRs is not available quickly enough to be considered in pharmacovigilance systems. This delay is also not acceptable on the background of the timelines-eg, European Union (EU) legislation requires that marketing authorization holders (MAH) report serious ADRs (SADRs) within 15 calendar days. The legal basis for ADR reporting by physicians and other healthcare professionals is specified in article 102 of the EU Directive 2001/83/ EC as amended (2010/84/EU).

One-Year Clinical and Radiological Results of a Prospective, Investigator-Initiated Trial Examining a Novel, Purely Autologous 3-Dimensional Autologous Chondrocyte Transplantation Product in the Knee.

BACKGROUND: The 3-dimensional autologous chondrocyte transplantation (ACT3D) comprises isolation of chondrocytes from cartilage biopsies, cultivation to spheroids, and transplantation into the cartilage defect. OBJECTIVES: To evaluate the patients' general health and functionality and to assess the defect repair after ACT3D with spheroids by MRI and MOCART scoring. METHODS: Thirty-seven patients with isolated chondral lesions of the knee underwent ACT3D with spheroids through medial arthrotomy. Patient-administered scores were assessed at baseline (day before transplantation), at 6 weeks, and at 3, 6, and 12 months. MRI and MOCART scoring were performed at 3 and 12 months after ACT3D. RESULTS: Patients were diagnosed with full-thickness patellofemoral (n = 16), femoral condylar (n = 18), or both defect types (n = 3), International Cartilage Repair Society (ICRS) grade 3 or 4, with defect sizes between 1.0 and 12.0 cm(2). On average, 59.5 spheroids/cm(2) in defect size were transplanted. An overall statistically significant improvement from baseline to 12 months was observed for all assessment scores (Lysholm, International Knee Documentation Committee [IKDC], SF-36, Tegner) combined with a significant reduction in the visual analog scale (VAS) for pain and an advanced defect filling. Subgroup analyses revealed a positive clinical outcome independent on defect size, defect locations, spheroid dosage, age, duration of symptoms, and severity of complaints at baseline. Seven patients experienced in total 8 adverse events, of which knee joint effusion and blocking were assessed as possibly or probably related to ACT3D. CONCLUSIONS: The patient-administered assessment scores along with the fast defect filling with ACT3D using spheroids demonstrated an increase in activity level and quality of life after a 1-year follow-up.

Case reports on cancer therapies: the urgent need to improve the reporting quality.

Current guidelines for certain cancer therapies mainly provide recommendations for therapy options treating the primary tumors. However, first-choice treatments for advanced or metastasizing tumors are described only rarely if at all. In such cases, one or more individual treatment options are chosen by the physician depending on the medical need of the patient and considering the acceptance of this treatment by the patient. Often, well-known drugs are selected with a different dosing than is indicated in the drug information leaflet. In other cases, drugs not yet approved for this particular type of cancer are used off label or certain therapies are used in combination or consecutively in a manner not reported before. With the increasing research on personalized medicine, particularly in treating cancer, case reports on innovative drug therapies or newly developed surgical interventions may provide extremely valuable information in instances where randomized controlled trials may not be feasible (eg, because of a low patient number or ethical considerations).

A Homeopathic Arnica Patch for the Relief of Cellulitis-derived Pain and Numbness in the Hand.

OBJECTIVES: Arnica montana, belonging to the Compositae family, is a plant with a longstanding tradition of relieving pain and/or inflammation in muscles and joints and may thus represent an alternative to nonsteroidal antiinflammatory drugs, which are often ineffective or lead to a number of adverse effects. A homeopathic arnica patch (3X dilution according to the Homeopathic Pharmacopoeia of the United States) was developed to alleviate pain symptoms in the back and neck muscles and joints. CASE PRESENTATION: The present case report describes the treatment outcome after administration of the arnica patch in a 55-year-old female patient with pain in the right hand and numbness in the fourth finger after cellulitis in the palmar area. The cellulitis was treated with antibiotics, but pain symptoms remained at 7 points on a 0-to-10-point visual analog scale (VAS) for pain despite intake of oral ibuprofen and oral and topical application of an arnica-containing complex homeopathic ointment. Ten arnica patches were dispensed to the patient. She cut the patch into strips to cover all painful areas of the hand and applied them at night. After 3 days, she reported a substantial decrease in pain symptoms (VAS = 1) and a marked decrease in numbness and in the size of a tender nodule on the third metacarpal area. Moreover, the patient was able to sleep through the night without being awakened by the pain. The symptoms declined further during the next 2 days. CONCLUSION: This case demonstrates that after a relatively short period of time, the administration of the arnica patch on the hand provided a marked reduction of pain and recovery of functionality of the hand.

Coherence and health care cost--RCA actuarial study: a cost-effectiveness cohort study.

Chronic stress is among the most costly health problems in terms of direct health costs, absenteeism, disability, and performance standards. The Reformed Church in America (RCA) identified stress among its clergy as a major cause of higher-than-average health claims and implemented HeartMath (HM) to help its participants manage stress and increase physiological resilience. The 6-week HM program Revitalize You! was selected for the intervention including the emWave Personal Stress Reliever technology. From 2006 to 2007, completion of a health risk assessment (HRA) provided eligible clergy with the opportunity to participate in the HM program or a lifestyle management program (LSM). Outcomes for that year were assessed with the Stress and Well-being Survey. Of 313 participants who completed the survey, 149 completed the Revitalize You! Program, and 164 completed the LSM. Well-being, stress management, resilience, and emotional vitality were significantly improved in the HM group as compared to the LSM group. In an analysis of the claims costs data for 2007 and 2008, 144 pastors who had participated in the HM program were compared to 343 non-participants (control group). Adjusted medical costs were reduced by 3.8% for HM participants in comparison with an increase of 9.0% for the control group. For the adjusted pharmacy costs, an increase of 7.9% was found compared with an increase of 13.3% for the control group. Total 2008 savings as a result of the HM program are estimated at $585 per participant, yielding a return on investment of 1.95:1. These findings show that HM stress-reduction and coherence-building techniques can reduce health care costs.

A series of case reports: clinical evaluation of a complex homeopathic injection therapy in the management of pain in patients after breast cancer treatment.

OBJECTIVE: In breast cancer patients, posttreatment pain often appears after several months and strongly impairs health-related quality of life. Conventional methods of pain reduction are often ineffective. Injection therapy with Traumeel (Heel GmbH, Baden-Baden, Germany), a medication with analgesic properties used in homotoxicology for treatment of the pain associated with trauma as well as a mediator of inflammation, was proposed as an innovative approach for pain relief after breast cancer treatment. DESIGN: Nine patients, still suffering from a high level of pain after breast cancer therapy despite use of postoperative treatment with conventional analgesics, were invited to participate. A Traumeel and procaine injection was administered once a week for three to 10 sessions. The level of pain was assessed by a pain score and physical and psychological status by a questionnaire before and directly after injection and again at follow-up visits after 3 and 6 months. RESULTS: After the last injection, all patients experienced a marked reduction of their level of pain on average from 7.6 +/- 1.5 to 2.4 +/- 1.4 points on a scale from 1 to 10 points. After a followup observational phase of 3 and 6 months, pain score ratings increased slightly again in some patients but remained consistently low in others. In any case, the ratings of pain levels did not reach the values assessed before the start of Traumeel injection. Similarly, health-related quality of life improved with this injection therapy. The perception of pain relief with Traumeel injection was high in 8 of 9 patients, reflecting an overall perceived positive outcome and tolerability of this treatment. CONCLUSIONS: This case series represents a first encouraging approach to using this complex homeopathic injection for pain relief in breast cancer patients.

Effects of the special extract ERr 731 from Rheum rhaponticum on estrogen-regulated targets in the uterotrophy model of ovariectomized rats.

A recent clinical study with a two-year application of the extract ERr 731 from Rheum rhaponticum demonstrated its efficacy and potentially suggested it safety regarding unwanted endometrial side effects. The aim of the present study is to provide experimental proof for the latter observation in a preclinical experimental animal model by assessing dose-dependent effects of ERr 731 - either alone or in combination with estradiol (E2) - on growth and proliferation in the uterus of ovariectomized (ovx) rats. ERr 731 was given in a dose corresponding to human therapeutic application and additionally in three pharmacologically relevant doses. In addition to uterine wet weight, this study examines the effects of ERr 731 on the uterine mRNA expression of the proliferation marker Ki67, proliferating cell nuclear antigen (PCNA), insulin-like growth factor-1 (IGF-1), type 1 IGF receptor (IGF-1R), the two estrogen receptor (ER) subtypes alpha and beta (ERalpha and ERbeta) and the estrogen-responsive gene complement C3 (C3). ERr 731 did neither stimulate an uterotrophic response in the uterotrophic assay with ovx rats nor stimulate or modulate the expression of genes associated with proliferation. In combination with E2, ERr 731 reduced the E2-induced uterine growth stimulation. These observations were further substantiated by the expression pattern of genes related to proliferation control, in view of the fact that the E2-induced elevation of Ki67 mRNA and PCNA protein levels in the uterus were counteracted by simultaneous treatment of the animals with ERr 731. In conclusion, the experimental findings presented here provide further evidence for the safety of ERr 731 towards unwanted uterine and endometrial proliferative events in response to ERr 731 and support observations from recent clinical trials.

Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms.

OBJECTIVE: In a previous study, the special extract ERr 731 of Rheum rhaponticum significantly reduced vasomotor and other menopausal symptoms associated with perimenopause. This trial was conducted to confirm the efficacy of ERr 731. DESIGN: A multicenter, randomized, placebo-controlled, clinical trial with 112 perimenopausal women with menopausal symptoms receiving either 1 enteric-coated tablet of ERr 731 (n = 56) or placebo (n = 56) daily for 12 weeks. Primary outcome criterion for efficacy of ERr 731 compared to placebo was the change of the Menopause Rating Scale (MRS) total score from day 0 to day 84. Other efficacy assessments analyzed included the number and severity of hot flushes, individual symptoms of the MRS, treatment outcome, and various safety parameters. RESULTS: By 12 weeks, ERr 731 caused a highly significant reduction of the MRS total score from 27.0 +/- 4.7 points to 12.4 +/- 5.3 points when compared to the placebo-induced decrease from 27.0 +/- 5.3 points to 24.0 +/- 6.2 points (P < .0001). A significant reduction in each individual MRS item score, in hot flushes and the hot flush weekly weighted score, together with a marked improvement in treatment outcome were also observed (P < .0001). These results confirm the efficacy of ERr 731 in alleviating menopausal symptoms in perimenopausal women. Fourteen adverse events were reported in total: 11 by 5 women receiving ERr 731 and 3 by 3 women receiving placebo. ERr 731 was well tolerated by the majority of the women. CONCLUSION: ERr 731 was confirmed to be effective for the treatment of menopausal symptoms in perimenopause.

Long-term efficacy and safety of the special extract ERr 731 of Rheum rhaponticum in perimenopausal women with menopausal symptoms.

OBJECTIVE: To investigate the long-term efficacy and safety of ERr 731 in perimenopausal women with menopausal symptoms. DESIGN: This was a multicenter, prospective, 48-week observational study (OS) (OS I) followed by a 48-week OS II in perimenopausal women with menopausal symptoms taking ERr 731. Of 109 women participating in a previous randomized, placebo-controlled trial (RCT), 39 women receiving ERr 731 and 41 women receiving placebo participated in OS I. Fifty-one women continued to take ERr 731 in OS II (23 women from the ERr 731 group and 28 women from the placebo group). The primary outcome criterion for long-term efficacy of ERr 731 was the change in the Menopause Rating Scale II score after 48 and 96 weeks. Several efficacy and safety parameters were also assessed. RESULTS: Women in the ERr 731 group in the RCT experienced a further decrease in their symptoms during OS I. Women who received placebo during the RCT and started taking ERr 731 in OS I reported a significant decrease in menopausal symptoms. After 18 weeks in OS I, their symptom scores were comparable to those of women who had taken ERr 731 for 12 weeks during the RCT. The symptom scores further decreased slightly in all women during OS II. At the end of OS II, all women had on average less than 1.4 slight hot flushes per day. There was no clinically relevant change in safety parameters, and no adverse events were observed with relation to the long-term use of ERr 731. CONCLUSIONS: ERr 731 is effective and safe in the long-term treatment of menopausal symptoms in perimenopausal women.

Efficacy of the special extract ERr 731 from rhapontic rhubarb for menopausal complaints: a 6-month open observational study.

BACKGROUND: The special extract ERr 731 from the roots of rhapontic rhubarb has been in widespread use in Germany since 1993, and the current regulations have required an evaluation of its risk:benefit ratio in daily use. OBJECTIVE: To demonstrate the efficacy and tolerability ofERr 731 in menopausal women in everyday practice. DESIGN: Three hundred sixty-three menopausal women with menopausal symptoms were enrolled at 70 German gynecological practices and received ERr 731 for 6 months. Women visited the practices for a baseline assessment and after 3 and 6 months. MAIN OUTCOME MEASURES: Primary outcome criterion was the change of the Menopause Rating Scale (MRS) total score after 6 months. Other assessments included compliance, tolerability, health-related quality of life, and occurrence of adverse events. RESULTS: After 6 months of treatment with ERr 731 in 252 women, there was a significant decrease of the MRS total score from 14.5 points at baseline to 6.5 points (P<.0001). The reduction of the MRS score was more pronounced in women with a score of > or =18 points at baseline. One tablet per day was sufficient to reduce the symptoms significantly in the majority of women. The health-related quality of life improved markedly. A good or very good treatment outcome was reported by the majority of the participating women. One adverse event was reported that was assessed as having no relation to ERr 731 intake. CONCLUSION: ERr 731 is a well-tolerated and safe medication for the successful treatment of menopausal symptoms in peri- and postmenopausal women.

Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells.

The special extract ERr 731 from the roots of Rheum rhaponticum is the major constituent of Phytoestrol N which is used for the alleviation of menopausal symptoms. Recently, we demonstrated that ERr 731 and its aglycones trans-rhapontigenin and desoxyrhapontigenin as single test substances do not activate the estrogen receptors-alpha (ERalpha) in human endometrial adenoarcinoma cells. However, these substances together with the structurally related hydroxystilbenes cis-rhapontigenin, resveratrol and piceatannol activated the ERbeta-dependent reporter gene activity. To investigate if these substance are tissue selective ER activators, ERr 731 and the single test substances were examined in bone-derived U2OS cells stably expressing ERalpha or transiently expressing ERbeta. In the ERalpha expressing U2OS cells, a weak, but statistically significant ERalpha-coupled luciferase activity was detected with ERr 731 and desoxyrhapontigenin which was 10-times lower than with 10(8) M 17 beta-estradiol. In the ERbeta test system, all test substances significantly induced the luciferase activity in a magnitude comparable to 17beta-estradiol. All effects were abolished with the pure ER antagonist ICI 182 780, indicating an ER-specific effect. Intracellular actions were also examined with the glycosylated ERr 731 constituents rhaponticin and desoxyrhaponticin. Treatment of U2OS cells with defined mixtures of both glycosides resulted in a reporter gene activity comparable to that of ERr 731, thereby providing evidence for the existence of cellular uptake mechanisms for glycosylated hydroxystilbenes. This report confirms the strong ERbeta-dependent activity of ERr 731 and provides evidence for a tissue selective ER agonistic activity by ERr 731 and its aglycones, as demonstrated by the activation of ERalpha in bone cells but not in endometrial cells.

Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds.

The special extract ERr 731 from the roots of Rheum rhaponticum is the major constituent of Phytoestrol N which is used for the treatment of climacteric symptoms in menopausal women. However, the molecular mode of action of ERr 731 was unknown. For the first time, ERr 731 and its aglycones trans-rhapontigenin and desoxyrhapontigenin were investigated with regard to the activation of the estrogen receptor-alpha or estrogen receptor-beta (ERalpha, ERbeta). The related hydroxystilbenes cis-rhapontigenin, resveratrol and piceatannol were studied as comparators. As controls, 17beta-estradiol or the selective ERalpha-(propylpyrazoltriol) or ERbeta-agonists (diarylpropionitril) were used. Neither in ERalpha-expressing yeast cells, in the ERalpha-responsive Ishikawa cells, nor in human endometrial HEC-1B cells transiently transfected with the ERalpha an activation of ERalpha by ERr 731 or the other single compounds was detected. Furthermore, an antiestrogenic effect was not observed. In contrast in human endometrial HEC-1B cells transiently transfected with the ERbeta, 100 ng/ml ERr 731 and the single compounds significantly induced the ERbeta-coupled luciferase activity in a range comparable to 10(-8)M 17beta-estradiol. All effects were abolished with the pure ER antagonist ICI 182780, indicating an ER-specific effect. The ERbeta agonistic activity by ERr 731 could be of importance for its clinical use, as central functions relevant to climacteric complaints are proposed to be mediated via ERbeta activation.

Efficacy of a complex homeopathic medication (Sinfrontal) in patients with acute maxillary sinusitis: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial.

BACKGROUND: There is a demand for clinical trials that demonstrate homeopathic medications to be effective and safe in the treatment of acute maxillary sinusitis (AMS). OBJECTIVE: The objective of this clinical trial was to demonstrate the efficacy of a complex homeopathic medication (Sinfrontal) compared with placebo in patients with AMS confirmed by sinus radiography. DESIGN: A prospective, randomized, double-blind, placebo-controlled, phase III clinical trial was conducted for a treatment period of 22 days, followed by an eight-week posttreatment observational phase. SETTING: The clinical trial was conducted at six trial sites in the Ukraine. PARTICIPANTS: One hundred thirteen patients with radiography-confirmed AMS participated in the trial. INTERVENTIONS: Fifty-seven patients received Sinfrontal and 56 patients received placebo. Additionally, patients were allowed saline inhalations, paracetamol, and over-the-counter medications, but treatment with antibiotics or other treatment for sinusitis was not permitted. MAIN OUTCOME MEASURES: Primary outcome criterion was change of the sinusitis severity score (SSS) from day zero to day seven. Other efficacy assessments included radiographic and clinical cure, improvement in health state, ability to work or to follow usual activities, and treatment outcome. RESULTS: From day zero to day seven, Sinfrontal caused a significant reduction in the SSS total score compared with placebo (5.8 +/- 2.3 [6.0] points vs 2.3 +/- 1.8 [2.0] points; P < .0001). On day 21, 39 (68.4%) patients on active medication had a complete remission of AMS symptoms compared with five (8.9%) placebo patients. All secondary outcome criteria displayed similar trends. Eight adverse events were reported that were assessed as being mild or moderate in intensity. No recurrence of AMS symptoms occurred by the end of the eight-week posttreatment observational phase. CONCLUSION: This complex homeopathic medication is safe and appears to be an effective treatment for acute maxillary sinusitis.

The special extract ERr 731 of the roots of Rheum rhaponticum decreases anxiety and improves health state and general well-being in perimenopausal women.

OBJECTIVE: To investigate the efficacy of the special extract ERr 731 from the roots of Rheum rhaponticum compared with placebo on anxiety, health state, and general well-being in perimenopausal women. DESIGN: This study is a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial, in which 109 perimenopausal women with climacteric complaints and anxiety received either 1 enteric coated tablet of ERr 731 (n=54) or placebo (n=55) daily for 12 weeks. The Hamilton Anxiety Scale, the Menopause Rating Scale II, the Women's Health Questionnaire, and the Psychological General Well-Being Index were used to measure anxiety, health state, and subjective psychological well-being. RESULTS: The results demonstrate that ERr 731 is highly effective in reducing anxiety in perimenopausal women compared with placebo. After 12 weeks, the Hamilton Anxiety Scale total score decreased significantly with ERr 731 (from 27.5+/-6.8 to 9.4+/-4.2 points) compared with placebo (from 25.1+/-6.0 to 21.6+/-8.6 points). ERr 731 also reduced the Hamilton Anxiety Scale factor scores for somatic and psychic anxiety. After 12 weeks, a reduction in the severity of anxiety from "moderate" or "severe" to "slight" was observed in 33 of 39 ERr 731 women completing the double-blind phase, which correlated well with the reduction in number and severity of hot flushes. This was reflected by a high rate of ERr 731 women reporting a marked improvement in health state and general well-being. CONCLUSIONS: ERr 731 is an effective medication for women with menopause-related anxiety and improves their health state and general well-being.

Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12-week randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the efficacy and safety of the special extract ERr 731 from the roots of Rheum rhaponticum compared to placebo in perimenopausal women with climacteric complaints. DESIGN: A multicenter, prospective, randomized, double-blind, placebo-controlled, clinical trial in which 109 women with climacteric complaints received either one enteric-coated tablet of ERr 731 (n = 54) or placebo (n = 55) daily for 12 weeks. Primary outcome criterion for efficacy was the change in Menopause Rating Scale II (MRS II) total score after 12 weeks. Other efficacy assessments analyzed number and severity of hot flushes, menopause-specific quality of life, number of bleeding/spotting days, and treatment outcome. RESULTS: By 12 weeks, the MRS II total score and each MRS II symptom significantly decreased in the ERr 731 group compared to the placebo group (P < 0.0001). After 4 weeks, ERr 731 also significantly decreased the number and severity of hot flushes (P < 0.0001). After 12 weeks, the overall menopause-specific quality of life was significantly better in women treated with ERr 731 compared with placebo (P < 0.05). Treatment outcome assessed by investigators and participants was better in the ERr 731 group, and ERr 731 was better tolerated than placebo. There were no differences in gynecological findings including endometrial biopsies, bleeding, weight, blood pressure, pulse, and laboratory safety parameters between the treatment groups. No adverse events were classified as being related to the investigational medication. CONCLUSIONS: Compared to placebo, ERr 731 significantly reduces the occurrence and severity of climacteric complaints in perimenopause. It is also safe and well tolerated.