scholarly journals Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost–utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study)

BMJ Open ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. e055351
Author(s):  
Ariadna Colomer-Carbonell ◽  
Juan P Sanabria-Mazo ◽  
Halbert Hernández-Negrín ◽  
Xavier Borràs ◽  
Carlos Suso-Ribera ◽  
...  
Keyword(s):  
Pain Intensity ◽  
Low Dose ◽  
Cost Utility ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Trial ◽  
Life Years ◽  
Double Blinded ◽  
Ecological Momentary ◽  
Low Dose Naltrexone

IntroductionThere is evidence that low-dose naltrexone (LDN; <5.0 mg/day) reduces pain and improves the quality of life of people with fibromyalgia syndrome (FMS). However, no randomised controlled trials with long-term follow-ups have been carried out. The INNOVA study will evaluate the add-on efficacy, safety, cost–utility and neurobiological effects of LDN for reducing pain in patients with FMS, with a 1-year follow-up.Methods and analysisA single-site, prospective, randomised, double-blinded, placebo-controlled, parallel design phase III trial will be performed. Eligibility criteria include being adult, having a diagnosis of FMS and experiencing pain of 4 or higher on a 10-point numerical rating scale. Participants will be randomised to a LDN intervention group (4.5 mg/day) or to a placebo control group. Clinical assessments will be performed at baseline (T0), 3 months (T1), 6 months (T2) and 12 months (T3). The primary endpoint will be pain intensity. A sample size of 60 patients per study arm (120 in total), as calculated prior to recruitment for sufficient power, will be monitored between January 2022 and August 2024. Assessment will also include daily ecological momentary evaluations of FMS-related symptoms (eg, pain intensity, fatigue and sleep disturbance), and side effects via ecological momentary assessment through the Pain Monitor app during the first 3 months. Costs and quality-adjusted life years will be also calculated. Half of the participants in each arm will be scanned with MRI at T0 and T1 for changes in brain metabolites related to neuroinflammation and central sensitisation. Inflammatory biomarkers in serum will also be measured.Ethics and disseminationThis study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and community engagement activities.Trial registration numberNCT04739995.

scholarly journals Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Andrea DeCensi ◽  
Harriet Johansson ◽  
Thomas Helland ◽  
Matteo Puntoni ◽  
Debora Macis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Low Dose ◽  
Cancer Recurrence ◽  
Phase Iii ◽  
Cyp2d6 Genotype ◽  
Phase Iii Trial ◽  
Reactive Protein ◽  
Non Invasive ◽  
Tamoxifen Metabolites ◽  
Dose Trial

AbstractLow-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

scholarly journals Postoperative topical analgesia of hemorrhoidectomy with policresulen and cinchocaine: a prospective and controlled study

2014 ◽  
Vol 41 (2) ◽  
pp. 92-98 ◽  
Author(s):  
Ilario Froehner Junior ◽  
Paulo Gustavo Kotze ◽  
Juliana Gonçalves Rocha ◽  
Eron Fábio Miranda ◽  
Maria Cristina Sartor ◽  
...  
Keyword(s):  
Pain Intensity ◽  
Bowel Movement ◽  
Controlled Study ◽  
Control Group ◽  
Oral Medications ◽  
Average Pain Intensity ◽  
Average Pain ◽  
The Mean ◽  
Double Blinded ◽  
Topical Analgesia

OBJECTIVE: To evaluate the effects of topical policresulen and cinchocaine in the postoperative pain behavior of open hemorrhoidectomy.METHODS: We conducted a prospective, double-blinded, controlled study. The control group received the usual guidelines with oral medications. The topical treatment group received, in addition, the application of the ointment and was comprised of two subgroups (policresulen + cinchocaine, and placebo). Pain intensity was recorded with the visual analogue scale.RESULTS: 43 patients were operated on: control group - n = 13, one excluded; placebo - n = 15; and policresulen + cinchocaine - n = 15. The mean age was 45.98 years and 37.2% were men. The average pain intensity was 4.09 (immediate postoperative), 3.22 (hospital discharge), 5.73 (day 1) , 5.77 (day 2), 5.74 (day 3), 5.65 (day 7), 5.11 (day 10), 2.75 (day 15) and 7.70 (first bowel movement), with no difference between groups in all periods.CONCLUSION: This study showed no reduction in pain after hemorrhoidectomy with the use of topical policresulen and cinchocaine.

scholarly journals The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial

1998 ◽  
Vol 9 (5) ◽  
pp. 535-541 ◽  
Author(s):  
M.M. Borner ◽  
M. Castiglione ◽  
M. Bacchi ◽  
W. Weber ◽  
R. Herrmann ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Low Dose ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Advanced Colorectal Carcinoma ◽  
The Impact

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p &lt; 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p &lt; 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p &lt; 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p &lt; 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p &lt; 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p &lt; 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p &lt; 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2506-2506 ◽  
Author(s):  
Matthias Ritgen ◽  
C. Schweighofer ◽  
Günther Fingerle-Rowson ◽  
Barbara Eichhorst ◽  
Raimunde Busch ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Late Stage ◽  
Clinical Remission ◽  
Lymphocytic Leukaemia ◽  
Phase Iii ◽  
Remission Induction ◽  
Control Group ◽  
Consolidation Therapy ◽  
Phase Iii Trial

Abstract The monoclonal antibody alemtuzumab is known to be effective in combination or alone in patients with late stage chronic lymphocytic leukaemia. Flow cytometric studies on minimal residual disease (MRD) showed the high potency beyond clinical response criteria even in late stage chronic lymphocytic leukaemia (CLL). The aim of the phase III trial of the GCLLSG was to investigate the role of alemtuzumab as consolidation therapy in CLL patients in first clinical remission after fludarabin (F) or F plus cyclophosphamide (FC). Patients in partial or complete clinical remission were randomized to either arm A (alemtuzumab 3 x 30 mg i.v. for up to 12 wks) or no further treatment (arm B). From 21 eligible patients 11 (1CR, 1 nPR, 9PR) were randomized to arm A. All patients received standard infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Before, at 6 and 12 weeks after start of consolidation therapy and regulary during follow up blood and bone marrow samples were send for molecular MRD assessment by allele specific real time PCR. The PCR allowed MRD assessment with a sensitivity of at least 10E-4 in 11 eligible cases. Results: MRD analysis showed clear reduction of CLL content by first line treatment to a median MRD level of 2.2E-3. Short after alemtuzumab treatment all treated patients showed pronounced MRD reduction to a median MRD level of 5.0E-5. During molecular follow-up median MRD level remained below 1E-4 for one year with a tendency to increase afterwards. After a median follow-up of 31.3 months from start of initial treatment occurred one relapse in the treatment arm compared to 7 of 10 in arm B. The median progression free survival (PFS) calculated from start of consolidation therapy was significantly shorter in the control group versus the treatment group (pfs 25.2; p= 0.04). Nevertheless due to severe acute infections (CTC III and IV) this study had to be stopped prematurely. Conlusion: The addition of alemtuzumab as a consolidation regimen after remission induction by F or FC is highly effective and leads to sustained MRD reduction below 10E-4. This translates into significant improved clinical outcome even in this small patient cohort compared to the control group. Encouraged by the molecular responses the GCLLSG initiated a new phase I/II trial as a dose finding study in CLL patients after F based induction of clinical remission.

A Randomized Prospective Multicenter Phase III Trial Comparing Standard GvHD Prophylaxis with Cyclosporine and Methotrexate with Additional Pretransplant ATG Fresenius (ATG-F) in Allogeneic Stem Cell Transplantation from Matched Unrelated Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 57-57 ◽  
Author(s):  
Jürgen Finke ◽  
Wolfgang Andreas Bethge ◽  
Claudia Schmoor ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Group Versus ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Trial ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Treatment Comparisons ◽  
Grade Iii

Abstract Graft versus host disease is a major cause of morbidity and mortality after allogeneic stem cell transplantation from unrelated donors. Strategies using intensified GvHD prophylaxis including T cell depletion did not result in better outcome due to increased risks of infection and relapse. The use of ATG in the conditioning regimen for in vivo-Tcell depletion for GVHD prophylaxis has been reported by several groups but not been tested in a large prospective randomized trial. Here we report on results from the first large prospective, randomized, multicenter, open-label, phase III trial comparing standard GvHD prophylaxis with cyclosporine A (CyA) and short course methotrexate (Mtx) days +1, +3, +6, +11 (15/10/10/10 mg/m2) with or without 3×20mg/kg ATG-Fresenius (ATG-F) after a median follow-up time of two years. Between 2003 and 2007, 201 patients, median age 40 (range 18–60) years with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94), were transplanted from HLA-A and -B (2 digit), DRB1, DQB1 (4 digit) identical unrelated donors after highdose myeloablative conditioning with marrow (n=37) or PBSC (n=164) grafts. Median follow up time was 732.5 (25%-quartile 604, 75%-quartile 1097) days. For treatment comparisons with regard to the occurrence of aGvHD grade III-IV or death within 100 days post Tx, logistic regression adjusted for status of disease, source of stem cells, and center was used. For treatment comparisons with regard to time-to-event variables, cumulative incidence rates considering relapse and death as competing events were estimated, and Cox regression modelling the event-specific hazard rates and adjusting for status of disease and source of stem cells was used. Engraftment with WBC &gt; 1000/μl was achieved in 97% in the ATG-F group after median 26 days, and in 95% in the control group after median 19 days (p&lt;0.0001). At day +100, the rate of patients experiencing the primary efficacy endpoint-severe aGvHD (grade III–IV) or death - was 21.4% in the CyA/Mtx/ATG-F arm versus 33.7% in the CyA/Mtx only arm (p=0.1286). Incidence of grade III–IV acute GvHD was 11.7% in the ATG-F arm and 24.5% in the control group (p=0.054), grade II–IV aGvHD was 33.0% vs. 51.0% (p=0.0108), and grade I–IV aGvHD was 56.3% vs. 74.5% (p=0.0073). Incidence of chronic GvHD (limited and extensive) after two years was 30.8% in the ATG-F group versus 58.8% in the control group (p&lt;0.0001). Incidence of extensive chronic GvHD after two years was 12.2% in the ATG-F group versus 42.6% in the control group (p&lt;0.0001). Disease-free survival (DFS) after two years was 51.6% in the ATG-F and 47.5% in the control group (p=0.65). Incidence of relapse/progression after two years was 28.9% in the ATG-F and 23.6% in the control group (p=0.55). Incidence of death without former relapse/progression (TRM) after two years was 19.6% in the ATG-F and 28.9% in the control group (p=0.198). Overall survival (OS) after two years was 59.2% in the ATG-F and 51.9% in the control group (p=0.47). Number of infections per follow up year was 4.54 in the ATG-F and 4.76 and in the control group. The addition of ATG-F to standard CyA/Mtx prophylaxis results in decreased incidence of acute and chronic GvHD without increase of relapse or TRM rates. This is the first randomized trial answering the long-standing question regarding the beneficial effect of additional ATG-F to a standard GvHD prophylaxis. A reduction of GvHD without compromising survival could be demonstrated.

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