A Double-blind, Randomized Trial to Evaluate Miltefosine and Topical Granulocyte Macrophage Colony-stimulating Factor in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;73(7):e2465-e2469
BACKGROUND The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. METHODS A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. RESULTS The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. CONCLUSIONS Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. CLINICAL TRIALS REGISTRATION NCT03023111.
Effect of intrauterine granulocyte-colony stimulating factor administration on in vitro fertilization outcome in women with moderate-to-severe endometriosis: An RCT
International journal of reproductive biomedicine. 2021;19(8):733-740
BACKGROUND Nearly 25-50% of infertile women have endometriosis. There are reports of disorders in the expression of granulocyte colony-stimulating factor (G-CSF) receptors in women with endometriosis. OBJECTIVE To examine the effect of intrauterine administration of G-CSF in in vitro fertilization (IVF) cycles on the fertility rate of infertile women with moderate-to-severe endometriosis. MATERIALS AND METHODS This clinical trial was conducted on 66 infertile women with moderate-to-severe endometriosis, undergoing IVF and intracytoplasmic sperm injection (ICSI). The participants were allocated into two groups via simple randomization: the G-CSF (n = 27) and control (n = 39) groups. In the G-CSF intervention group, on the oocyte pick-up day, immediately after an ovarian puncture, 300 μg of G-CSF was injected through a transcervical catheter under abdominal ultrasound guide to visualize flushing into the uterine cavity. Women in the control group received no intervention. The two groups were evaluated for clinical pregnancy. RESULTS No significant difference was noted in the demographic characteristics of the two groups. The rate of clinical pregnancy was 28.2% in the control group and 25.9% in the G-CSF group, indicating no significant difference (p = 0.83). CONCLUSION The results showed that the intrauterine injection of G-CSF had no effects on pregnancy in women with stage-3/4 endometriosis undergoing IVF.
Granulocyte-Colony Stimulating Factor (G-CSF) to treat acute-on-chronic liver failure, a multicenter randomized trial (GRAFT study)
Journal of hepatology. 2021
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with decompensated liver cirrhosis and which is characterized by organ failure and poor short-term prognosis. Based on positive results from small single center studies, Granulocyte-Colony Stimulating Factor (G-CSF) is being widely used in the treatment of ACLF patients. The aim of that study was to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS In this multicenter, prospective, controlled, open-label phase 2 study, 176 patients with ACLF defined by the EASL-CLIF criteria were randomized to receive G-CSF (at a dose 5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n=88) or SMT alone. The primary efficacy endpoint was the 90-day transplant free survival analysed by Cox regression modeling. The key secondary endpoints were the overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores (model of end-stage liver disease score (MELD) and CLIF-C OF score) during the entire observation period. RESULTS Patients treated with G-CSF had a 90-day transplant free survival of 34.1% compared to 37.5% in the SMT group with a hazard ratio (HR) of 1.05 (95%CI 0.711; 1.551) (p=0.805). The 360-day transplant free survival with a HR of 0.998 [95%CI 0.697; 1.430 (p=0.992)] and overall survival with a HR of 1.058 [95%CI 0.727; 1.548 (p=0.768)] also did not differ between groups. G-CSF did not improve the CLIF-C OF score (p=0.757), MELD score (p=0.884) or the occurrence of infections (p=0.251). In subgroups of patients without infections [p=0.883], with alcohol related ACLF [p=0.875], or with ACLF defined by the APASL criteria [p=0.405] G-CSF also failed to improve survival. Sixty-one serious adverse events (SAE) were reported in the G-CSF+SMT group and 57 SAEs in the SMT group. In total, seven drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS In contrast to previous findings, this first multicenter, controlled trial failed to show a significant beneficial effect of G-CSF in treating patients with ACLF, and therefore, suggests G-CSF should not be used as a standard treatment for ACLF. LAY SUMMARY G-CSF was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled trial phase 2 trial which showed that G-CSF in not improving survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies. CLINICALTRAILS. GOV NUMBER NCT02669680.
A clinical study of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during concurrent chemoradiotherapy of cervical cancer
BMC cancer. 2021;21(1):661
PURPOSE To evaluate the effectiveness and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during chemoradiotherapy in patients with cervical cancer. METHODS From August 2018 to April 2020, 60 patients who were pathologically confirmed as cervical cancer were randomly divided into two groups at a ratio of 2:1: PEG-modified-rhG-CSF experimental group and control group. The primary endpoints were the incidence of grade 3-4 neutropenia. Secondary endpoints included the duration of grade 3-4 neutropenia, the incidence of grade 4 neutropenia, the incidence of febrile neutropenia (FN), delay rate of chemotherapy, prolonged time of chemotherapy, time to complete radiotherapy and safety. RESULTS The incidence of grade 3-4 neutropenia in the experimental group was significantly lower than the control group (10% vs. 77.78%, P < 0.001). However, there was no statistical significance between the two groups in the duration of grade 3-4 neutropenia (3.75 days vs. 5.07 days, P = 0.871). The experimental group was better than the control group in the incidence of grade 4 neutropenia, the incidence of FN and delay rate of chemotherapy, and the difference was statistically significant (P < 0.05). Besides, the prolonged time of chemotherapy and the time to complete radiotherapy in the experimental group were less than those in the control group, but the difference was not statistically significant (P > 0.05). The incidence of adverse events in the experimental group and control group were 55.00 and 94.44%, respectively, and the difference was statistically significant (P = 0.003). CONCLUSION PEG-rhG-CSF preventive treatment used in the course of chemoradiotherapy for patients with cervical cancer can reduce the incidence of neutropenia and improve the incidence of delayed chemotherapy cycles. TRIAL REGISTRATION ClinicalTrials.gov , NCT04542356 . Registered 9 September 2020 - Retrospectively registered.
Randomized trial of granulocyte colony-stimulating factor for spinal cord injury
Brain : a journal of neurology. 2021
Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.
What is the impact of granulocyte colony-stimulating factor (G-CSF) in subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles on recurrent implantation failure: a systematic review and meta-analysis?
Reproductive biology and endocrinology : RB&E. 2021;19(1):125
BACKGROUND Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients. METHOD The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I(2) index were analyzed. Stata 15 was used for statistical analysis. RESULTS A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27-2.37, I(2) = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14-1.81, I(2) = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33-2.23, I(2) = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09-1.78, I(2) = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28-2.68; I(2) = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25-5.21: I(2) = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86-2.36; I(2) = 52.5%; n = 372) when a random-effects model was employed. CONCLUSION The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.
A multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia
Breast (Edinburgh, Scotland). 2021;58:42-49
BACKGROUND Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. METHODS EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. RESULTS 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = -6.7%, 95%CI = -13.5%-0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained. CONCLUSION The primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective.
Eflapegrastim, a Long-Acting Granulocyte-Colony Stimulating Factor for the Management of Chemotherapy-Induced Neutropenia: Results of a Phase III Trial
BACKGROUND Eflapegrastim, a novel, long-acting recombinant human granulocyte-colony stimulating factor (rhG-CSF), consists of a rhG-CSF analog conjugated to a human immuglobulin G4 Fc fragment via a short polyethylene glycol linker. Preclinical and phase I and II pharmacodynamic and pharmacokinetic data showed increased potency for neutrophil counts for eflapegrastim versus pegfilgrastim. This open-label phase III trial compared the efficacy and safety of eflapegrastim with pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. MATERIALS AND METHODS Patients with early-stage breast cancer were randomized 1:1 to fixed-dose eflapegrastim 13.2 mg (3.6 mg G-CSF) or standard pegfilgrastim (6 mg G-CSF) following standard docetaxel plus cyclophosphamide chemotherapy for 4 cycles. The primary objective was to demonstrate the noninferiority of eflapegrastim compared with pegfilgrastim in mean duration of severe neutropenia (DSN; grade 4) in cycle 1. RESULTS Eligible patients were randomized 1:1 to study arms (eflapegrastim, n = 196; pegfilgrastim, n = 210). The incidence of cycle 1 severe neutropenia was 16% (n = 31) for eflapegrastim versus 24% (n = 51) for pegfilgrastim, reducing the relative risk by 35% (p = .034). The difference in mean cycle 1 DSN (-0.148 day) met the primary endpoint of noninferiority (p < .0001) and also showed statistical superiority for eflapegrastim (p = .013). Noninferiority was maintained for the duration of treatment (all cycles, p < .0001), and secondary efficacy endpoints and safety results were also comparable for study arms. CONCLUSION These results demonstrate noninferiority and comparable safety for eflapegrastim at a lower G-CSF dose versus pegfilgrastim. The potential for increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study in patients at higher risk for CIN. IMPLICATIONS FOR PRACTICE Chemotherapy-induced neutropenia (CIN) remains a significant clinical dilemma for oncology patients who are striving to complete their prescribed chemotherapy regimen. In a randomized, phase III trial comparing eflapegrastim to pegfilgrastim in the prevention of CIN, we discerned noninferiority and comparable safety for eflapegrastim and pegfilgrastim. Nevertheless, the risk of CIN remains a momentous concern for patients undergoing chemotherapy, as the condition frequently results in chemotherapy delays, dose reductions, and treatment discontinuations.
Role of Granulocyte Colony Stimulating Factor on the Short-Term Outcome of Children with Acute on Chronic Liver Failure
J Clin Exp Hepatol. 2020;10(3):201-210
Background: Acute-on-chronic liver failure (ACLF) results in very high mortality in children. We aimed to evaluate the role of granulocyte colony-stimulating factor (GCSF) on short-term outcome of children with ACLF in a nontransplant unit. Methods: Children (aged > 1 year) diagnosed with ACLF over a 15 month period were randomised. Group A was given GCSF therapy along with standard medical care (SMC - details in supplementary data) and group B was given only SMC. The outcome was evaluated as survival at 30 and 60 days of therapy. Result: Thirty-one children with ACLF were enrolled, with a mean age of 6.92 +/- 4.3yrs. A total of 15 patients were randomised to group A and 16 to group B. The overall mortality was 54.83%. The intervention group showed survival rates of 80%, 66.67% and 53.3%, whereas the control group had survival rates of 43.75%, 37.5% and 37.5% at 14, 30 and 60 days, respectively. A significant survival benefit was noted on day 14 (p = 0.043) of therapy in group A with significant difference in Child-Turcotte-Pugh (CTP) and pediatric end-stage liver disease (PELD) scores in the two groups. After an initial rise in group A, the granulocyte counts fell to become comparable in the two groups by day 30 and 60, indicating that the effect of GCSF therapy wears off over time. There was no significant difference in the overall survival, median/mean CTP, PELD and MCS (Modified Cliff sequential organ failure assesment (SOFA)) scores on day 30 and 60. Mean (%) CD 34 + cells level showed a rise on day 7 in group A but was statistically insignificant. Conclusion: The present study shows that GCSF therapy at 5 mcg/kg/day for 5 days seems to be ineffective in improving the survival outcome on day 30 and 60 of therapy. Studies with larger number of children enrolled and longer duration of therapy are required. (CTRI/2017/11/010420).
Association of Miltefosine with Granulocyte and Macrophage Colony Stimulating Factor (GM-CSF) in the Treatment of Cutaneous Leishmaniasis in the Amazon Region: a randomized and controlled trial
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2020
OBJECTIVES To compare topical GM-CSF and miltefosine (G + M) versus placebo and miltefosine (P + M) or parenteral meglumine antimoniate (MA) in the treatment of 150 patients with cutaneous leishmaniasis (CL) caused by Leishmania guyanensis in the Amazon. DESIGN A randomized and double-blinded clinical trial. RESULTS At 90 days after initiation of therapy the cure rates were 66%, 58% and 52% for the groups P + M, G + M, and MA respectively (p > 0.05). Cure rates at 180 days did not differ. Healing time was similar in the 3 groups, but faster in the MA group compared to the G + M group (p = 0.04). Mild and transitory systemic adverse events were frequent in all groups (above 85%). Nausea (85%) and vomiting (39%) predominated in the miltefosine groups; arthralgia (51%) and myalgia (48%) in the MA group. One patient (group MA) stopped treatment after presenting fever, exanthema, and severe arthralgia. CONCLUSIONS Miltefosine did not present a higher cure rate than MA, and the association of GM-CSF did not improve the therapeutic response. Nevertheless, due to its less toxicity, easier administration, and a similar cure rate when compared with MA, miltefosine should remain as one of the main drugs for treating CL due to L. guyanensis. (Clinicaltrials.gov Identifier NCT03023111).