scholarly journals Efficacy and Safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three doses combination

2021 ◽  
Author(s):  
Maria Eugenia Toledo-Romani ◽  
Mayra Garcia-Carmenate ◽  
Carmen Valenzuela Silva ◽  
Waldemar Baldoquin-Rodriguez ◽  
Marisel Martinez Perez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Placebo Group ◽  
Conjugate Vaccine ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Dose Schedule ◽  
T Cell Response ◽  
Group 14 ◽  
Phase 3 ◽  
Double Blinded

Background: SOBERANA 02 is a COVID19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phase 1 and 2 clinical trials demonstrated its high immunogenicity, promoting neutralizing IgG together with specific T-cell response. A third dose of SOBERANA Plus (SARS-CoV-2 RBD-dimer) further increased the specific anti-RBD neutralizing antibodies. Methods: In a randomized, double-blinded, placebo-controlled, phase 3 trial we randomly assigned 44 031 participants, aged 19-80 years to three groups in a 1:1:1 ratio to receive 28 days apart either a) two doses of 25 microg SOBERANA 02, or b) two doses of 25 microg SOBERANA 02 followed by a third dose of 50 microg SOBERANA Plus, or c) two doses of placebo. Reported study endpoints are vaccine efficacy (VE) evaluated through laboratory-confirmed symptomatic COVID-19 cases and safety. During the trial, the SARS CoV-2 isolates in Havana were predominantly (beta 74.0 %) and shift gradually to delta (100%). Results: Two doses of SOBERANA 02 protects against symptomatic COVID-19: 43 cases in the two-dose group (14 371) vs. 155 in the placebo group (14 403), VE 71.0%, adjusted (CI 95%58.9-79.1). The heterologous three dose combination with SOBERANA Plus protected against symptomatic COVID-19: 15 cases in the vaccine groups (13 833) vs. 155 in the placebo group (14 303), VE 92.4%, adjusted (CI 95% 86.9-95.6%). For two-dose schedule VE against severe COVID-19 was 63.0% and for death 59.0%; for heterologous three-dose schedule, 100% in both cases. Conclusions: This is the first phase 3 study of a three-dose, heterologous vaccine combination against SARS-CoV-2. Two doses of the conjugate vaccine SOBERANA 02 was safe and attained efficacy of 71.0% in adults population 19-80 y/o; incorporating SOBERANA Plus after two doses of SOBERANA 02, increased efficacy from 71.0 % to 92.4% (Clinical Trials IFV/COR/09 number, RPCEC00000354.)

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals The race for a coronavirus vaccine

Bionatura ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. 1290-1292
Author(s):  
Gerardo Ferbeyre ◽  
Nelson Santiago Vispo
Keyword(s):  
Clinical Trials ◽  
Viral Vectors ◽  
Phase 1 ◽  
Phase 3 ◽  
Antiviral Immune Response ◽  
Degree Of Protection ◽  
Advantages And Disadvantages ◽  
Phases Of Development ◽  
Vaccination Campaigns ◽  
Short Time

The international race to find a preventive vaccine and effective treatments against COVID 19 has been influenced by two fundamental factors. Firstly, by the molecular characterization of the causative virus and the pathology it produces, and secondly, by access to this information, mostly free of charge by the international scientific community causing a synergy to obtain results in such a short time. Several vaccines preparations against Covid19 have entered Phase 3 clinical trials. Although it is uncertain the degree of protection that they will achieve, preliminary data from Phase 1 and 2 trials and studies in animals indicate that they trigger an antiviral immune response without serious side effects. The current formulations include viral vectors, RNA vaccines, inactivated viruses, and recombinant proteins particles. They all have advantages and disadvantages, but only the results of Phase 3 clinical trials will ultimately decide the best candidates for vaccination campaigns. The tremendous impact of the SARS-CoV-2 in our society has triggered an unprecedented effort to find a vaccine to control the pandemic. Billions of dollars have already been invested in multiple vaccination schemes. According to the WHO, more than 170 vaccines were in different phases of development in August 2020. Here is a summary of the advantages and disadvantages of the front runner strategies categorized according to their delivery method.

scholarly journals Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study).

2021 ◽  
Author(s):  
Francisco Hernandez-Bernal ◽  
Maria del Carmen Ricardo-Cobas ◽  
Yenima Martin-Bauta ◽  
Zadis Navarro-Rodriguez ◽  
Marjoris Pinera-Martinez ◽  
...  
Keyword(s):  
Placebo Group ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Vaccination Schedule ◽  
Phase 2 ◽  
Igg Antibodies ◽  
Protein Vaccine ◽  
Double Blind ◽  
Double Blind Placebo ◽  
The Third

Aim: To evaluate the safety and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine (Abdala), administered intramuscularly in different strengths and vaccination schedules. Method: A phase 1-2, randomized, double-blind, placebo-controlled trial was done. Subjects were randomly distributed in 3 groups: placebo, 25 and 50 μg RBD. The product was applied intramuscularly, 0.5 mL in the deltoid region. During the first phase, two immunization schedules were studied: short (0-14-28 days) and long (0-28-56 days). In phase 2, only the short scheme was evaluated. The main endpoints were: safety and proportion of subjects with seroconversion of anti-RBD IgG antibodies to SARS-CoV-2. Blood samples were collected in several points according to the corresponding vaccination schedule to determine the level of RBD-specific IgG antibodies (seroconversion rates and geometric mean of the titers), the percentage of inhibition of RBD-ACE-2 binding and levels of neutralizing antibodies. Results: The product was well tolerated. Severe adverse events were not reported. Adverse reactions were minimal, mostly mild and local (from the injection site), resolved in the first 24-48 hours without medication. In phase 1, at day 56 (28 days after the third dose of the short vaccination schedule, 0-14-28 days) seroconversion of anti-RBD IgG was seen in 95.2 % of the participants (20/21) for the 50 μg group and 81 % of the participants (17/21) for the 25 μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 80 % of the participants (8/10) for the 50 μg group and 94.7% of the participants (18/19) for the 25 μg group. For the long schedule, at day 70 (14 days after the third dose) seroconversion of anti-RBD IgG was seen in 100% of the participants (21/21) for the 50 μg group and 94.7% of the participants (18/19) for the 25 μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 95 % of the participants (19/20) for the 50 μg group and 93.8% of the participants (15/16) for the 25 μg group In phase 2, at day 56 seroconversion of anti-RBD IgG was seen in 89.2% of the participants (214/240) for the 50 μg group, 77.7% of the participants (185/238) for the 25 μg group, and 4.6% in the placebo group (11/239); whereas neutralizing antibodies to SARS-CoV-2 were seen in 97.3% of the participants (146/150) for the 50 μg group and 95.1% of the participants (58/61) for the 25 μg group. Conclusion: Abdala vaccine against SARS-CoV-2 was safe, well tolerated and induced humoral immune responses against SARS-CoV-2 among adults from 19 to 80 years of age.

scholarly journals Assessing Sunscreen Protection Using UV Photography: Descriptive Study (Preprint)

2020 ◽  
Author(s):  
Caitlin Horsham ◽  
Helen Ford ◽  
Jeremy Herbert ◽  
Alexander Wall ◽  
Sebastian Walpole ◽  
...  
Keyword(s):  
Clinical Trials ◽  
New Zealand ◽  
Phase 1 ◽  
Sun Protection ◽  
Trial Registration ◽  
Phase 2 ◽  
Phase 3 ◽  
The Public ◽  
Uv Photography ◽  
Clinical Trials Registry

BACKGROUND Photography using a UV transmitting filter allows UV light to pass and can be used to illuminate UV blocking lotions such as sunscreens. OBJECTIVE The aim of this study is to compare currently available UV photography cameras and assess whether these devices can be used as visualization tools for adequate coverage of sun protection lotions. METHODS This study was conducted in 3 parts: in phase 1, 3 different UV cameras were tested; in phase 2, we explored whether UV photography could work on a range of sun protection products; and in phase 3, a UV webcam was developed and was field-tested in a beach setting. In phase 1, volunteers were recruited, and researchers applied 3 sun protection products (ranging from sun protection factor [SPF] 15 to 50+) to the participants’ faces and arms. UV photography was performed using 3 UV cameras, and the subsequent images were compared. In phase 2, volunteers were recruited and asked to apply their own SPF products to their faces in their usual manner. UV photographs were collected in the morning and afternoon to assess whether the coverage remained over time. Qualitative interviews were conducted to assess the participants’ level of satisfaction with the UV image. In phase 3, a small portable UV webcam was designed using a plug-and-play approach to enable the viewing of UV images on a larger screen. The developed webcam was deployed at a public beach setting for use by the public for 7 days. RESULTS The 3 UV camera systems tested during phase 1 identified the application of a range of sun protection lotions of SPF 15 to 50+. The sensitivity of the UV camera devices was shown to be adequate, with SPF-containing products applied at concentrations of 2 and 1 mg/cm<sup>2</sup> clearly visible and SPF-containing products applied at a concentration of 0.4 mg/cm<sup>2</sup> having lower levels of coverage. Participants in phase 2 reported high satisfaction with the UV photography images, with 83% (29/35) of participants likely to use UV photography in the future. During phase 2, it was noted that many participants used tinted SPF-containing cosmetics, and several tinted products were further tested. However, it was observed that UV photography could not identify the areas missed for all tinted products. During phase 3, the electrical components of the UV webcam remained operational, and the camera was used 233 times by the public during field-testing. CONCLUSIONS In this study, we found that UV photography could identify the areas missed by sun protection lotions with chemical filters, and participants were engaged with personalized feedback. CLINICALTRIAL Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000975190; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377089 ; Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000145101; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376672.

Reversal of Drug/TRAIL-Resistant B-NHL Cells to Apoptosis by the Combination of Rituximab (anti-CD20) and Either Mapatumumab or Lexatumumab

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4931-4931
Author(s):  
Mario I. Vega ◽  
Sara Huerta-Yepez ◽  
Melisa Martinez-Paniagua ◽  
Stavroula Baritaki ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Death Receptor ◽  
Hematologic Malignancies ◽  
Direct Role ◽  
Induced Apoptosis ◽  
Anti Cd20

Abstract Abstract 4931 Conventional treatments of non-Hodgkin's lymphoma (B-NHL) consist primarily of chemotherapy. Currently, rituximab is used alone or in combination with chemotherapy. However, there are subsets of patients who do not respond initially or develop resistance to further treatment. Therefore, there is an urgent need to develop other immunotherapies with less toxicities. At present, both TRAIL and agonist antibodies directed against TRAIL-R1 and -R2 have been explored for various cancer treatments in various phase 1 and phase 2 clinical trials. We have recently demonstrated that rituximab sensitizes TRAIL-resistant B-NHL cells to TRAIL-induced apoptosis. Sensitization was the result of rituximab-induced inhibition of the constitutively activated NF-κB pathway and downstream the DR5 transcription repressor Yin Yang 1 (YY1). The direct role of YY1 in the regulation of resistance to TRAIL was demonstrated in cells transfected with YY1 siRNA and that became sensitive to TRAIL- apoptosis. Treatment with rituximab did not have any observed effects on the expression of DR4. Based on these findings, it was possible that rituximab-mediated sensitization to TRAIL may invoke either TRAIL-R1 (DR4) or TRAIL-R2 (DR5), or both; thus, this possibility is currently being examined by the use of either neutralizing antibodies against each death receptor or by the use of silencing RNA. Currently, clinical trials are being conducted with both mapatumumab (anti-TRAIL-R1,) and lexatumumab (anti-TRAIL-R2) against a variety of cancers. These agonist antibodies have been evaluated clinically as single agents and in combination with standard therapy in solid and hematologic malignancies. It is not clear whether tumors can develop resistance to agonism of either one or both death receptors and thus, may not respond to monotherapy alone. Combination therapies may be required and we have hypothesized that the combination treatment of rituximab and agonist antibodies may be complementary or synergistic. This hypothesis was based on our findings that rituximab inhibits survival pathways and downregulates anti-apoptotic gene products and, thus, significantly reducing the threshold of resistance. Thus, this rituximab-mediated effect will facilitate the direct cytotoxicity of the agonist death receptor antibodies. The present study investigated whether rituximab can sensitize TRAIL-resistant tumor cells by either agonist TRAIL-R1 or TRAIL-R2 antibodies To address this question, we have examined the effect of agonist antibodies directed against either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumamab). Treatment of the TRAIL-resistant Ramos B-NHL cells with rituximab for 24h and followed with treatment with non-toxic concentrations of mapatumumab (12 μg/ml) or lexatumumab (12 μg/ml) for 18h resulted in significant sensitization to apoptosis as assessed by activation of caspase 3. The mechanism of the sensitization by rituximab for each antibody was also examined. These findings demonstrated that rituximab sensitizes tumor cells to apoptosis by activation of either DR4 or DR5. Although there is heterogeneous expression of TRAIL-R1 and TRAIL-R2 in B-NHL cells, such cells may still be sensitive to rituximab-mediated sensitization to apoptosis by the corresponding agonist death receptor antibody. Recent findings demonstrated that some tumors expressing both DR4 and DR5 were shown to respond to TRAIL by preferential activation of DR4 and not DR5. Therefore, preclinical findings obtained with the use of TRAIL may not be predictive of outcome compared to the use of TRAIL-receptor specific agonist antibodies; mapatumumab or lexatumumab. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Effects of Alum Adjuvant or a Booster Dose on Immunogenicity during Clinical Trials of Group B Streptococcal Type III Conjugate Vaccines

2001 ◽  
Vol 69 (11) ◽  
pp. 6696-6701 ◽  
Author(s):  
L. C. Paoletti ◽  
M. A. Rench ◽  
D. L. Kasper ◽  
D. Molrine ◽  
D. Ambrosino ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Phase 1 ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Conjugate Vaccines ◽  
Type Iii ◽  
Specific Igg ◽  
Group B

ABSTRACT Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-μg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 μg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-μg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 μg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.

scholarly journals LB7. Ad26.COV2.S-Elicted Neutralizing Activities Against SARS-CoV-2 Variants of Concern in Phase 1/2a and Phase 3 Clinical Trials

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S804-S805
Author(s):  
Mathieu Le Gars ◽  
Jerald Sadoff ◽  
Mandy Jongeneelen ◽  
Dirk Heerwegh ◽  
Georgi Shukarev ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Single Dose ◽  
Phase 1 ◽  
Geometric Mean ◽  
Wild Type Virus ◽  
Original Strain ◽  
Wild Type ◽  
Serum Samples ◽  
Phase 3 ◽  
Neutralizing Activity

Abstract Background In a Phase 3 trial, the Janssen COVID-19 vaccine, Ad26.COV2.S, showed robust efficacy against severe–critical COVID-19 in countries where different SARS-CoV-2 variants were circulating. We evaluated Ad26.COV2.S-elicited antibody neutralizing activity against variants of concern (VOC) B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) in sera from participants in clinical trials following a single dose of Ad26.COV2.S. Methods Neutralizing activities of Ad26.COV2.S (given at a dose level of 5 x 1010 viral particles [vp]) against VOC were assessed by wild-type virus neutralizing (wtVNA) and pseudovirion neutralization (psVNA) assays in sera from participants in Phase 1/2a and Phase 3 clinical trials, respectively. Geometric mean titers (GMTs) were determined at Days 29 and 71 after vaccination. Results In serum samples from Phase 1/2a participants (n = 6), at Day 29 after 1 dose of Ad26.COV2.S, wtVNA titers against VOC were lower than for the original strain (GMT = 573), with GMT = 65, 14, and 15 for Alpha, Beta, and Delta, respectively, representing 8.8-, 40.9-, and 37.7-fold decreases. By Day 71 after vaccination (n = 14), fold differences between the original strain (GMT = 375) and VOC (GMT = 113, 27, and 28) were smaller (3.3-, 13.9-, and 13.4-fold) than at Day 29, suggestive of B-cell maturation (Figure 1). Day 71 titers against the Delta variant were maintained for at least 8 months following a single dose of Ad26.COV2.S (5 x 1010 vp). In serum samples from Phase 3 participants (n = 8), psVNA titers against VOC were lower than the original strain at Day 71 after vaccination, with the lowest titers observed for the Beta variant (3.6-fold decrease vs original strain). Smaller reductions in Nab titers for VOC were observed in the psVNA assay compared to wtVNA. Figure 1. Neutralization of B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) lineages in serum samples from participants who received Ad26.COV2.S. n = 6 samples at Day 29 and n = 14 (n = 14 for Alpha and Beta; n = 6 for Delta, comprising the same 6 participants at Day 29) samples at Day 71 after vaccination with a single dose of Ad26.COV2.S (5 x 10^10 vp dose level) were analyzed in wild-type virus neutralization assays against the SARS-CoV-2 Victoria strain (D614, black dots), the B.1.1.7 (Alpha; green dots) the B.1.351 (Beta; blue dots), and the B.1.617.2 (Delta; purple dots) lineages. Dots represent the IC50 (inhibitory concentration) titers per participant. Geometric mean titers (GMTs) and fold decrease in neutralizing activity between the original Victoria strain and each lineage are shown. Conclusion Ad26.COV2.S-elicited serum neutralizing activity against VOC showed an overall decrease in titers relative to the original strain that was largest for the Beta variant, even though vaccine efficacy against severe–critical COVID-19 was maintained in countries where these variants were circulating versus in countries where they were not circulating. Over time, titers against variants increased, suggesting B-cell affinity maturation leading to increasing coverage of VOC. Disclosures Mathieu Le Gars, n/a, Johnson & Johnson (Employee, Shareholder) Jerald Sadoff, MD, Johnson & Johnson (Employee, Shareholder) Mandy Jongeneelen, n/a, Johnson & Johnson (Employee, Shareholder) Dirk Heerwegh, n/a, Janssen Research and Development (Employee) Georgi Shukarev, MD, Janssen (Employee) Carla Truyers, n/a, Janssen Research and Development (Employee) Anne Marit de Groot, n/a, Johnson & Johnson (Employee) Gert Scheper, n/a, Johnson & Johnson (Employee, Shareholder) Jenny Hendriks, n/a, Johnson & Johnson (Employee, Shareholder) Boerries Brandenburg, n/a, Johnson & Johnson (Employee, Shareholder) Frank Struyf, n/a, Johnson & Johnson (Employee, Shareholder) Johan Van Hoof, n/a, Johnson & Johnson (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Hanneke Schuitemaker, PhD, Johnson & Johnson (Employee, Shareholder)

scholarly journals Safety and Efficacy of Thrombopoietin Analogs in the Treatment of Chronic Thrombocytopenic Purpura in Children: A Systematic Review

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4215-4215
Author(s):  
Usman Ali Akbar ◽  
Vivek Soorya Sathya Moorthy ◽  
Sudeep Yadav ◽  
Saman Bahram ◽  
Adnan Mehboob Qureshi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Placebo Group ◽  
Observational Study ◽  
Immune Thrombocytopenic Purpura ◽  
Research Funding ◽  
Pediatric Population ◽  
Platelet Response ◽  
Thrombocytopenic Purpura ◽  
Double Blinded

Abstract Introduction Immune thrombocytopenic purpura (ITP) is an autoimmune disorder consisting of low platelet count, purpura, and hemorrhagic episodes, caused by antiplatelet autoantibodies. Children who develop chronic or refractory ITP are at risk of bleeding after failing first-line therapies. Thrombopoietin analogs -Eltrombopag and romiplostim are safe and effective treatment options. Thrombopoietin receptor agonists (TPO-Ras) improve platelet production by activating the thrombopoietin pathway. They also stimulate megakaryocytes and hematopoietic stem cells. We analyzed the efficacy and toxicity of romiplostim and eltrombopag in chronic immune thrombocytopenic purpura in the pediatric population (1-17 years). Materials/Methods Following the PRISMA guidelines, we performed a comprehensive literature search on Pubmed, Embase, Cochrane Library, Web of Science, and Clinicaltrials.gov. We used the following keywords, "Thrombopoitein analogs", "TPOs", "Immune thrombocytopenic purpura", "Eltrombopag" and "Romiplostim" MeSh terms from the inception of data till 06/17/2021. We screened initial results from the search of 358 articles focusing on the pediatric population and finally included 9 clinical trials and 1 observational study. We excluded all case reports, case series, preclinical trials, review articles, and meta-analyses. We extracted the data for efficacy (platelet response, baseline platelet count, and Platelet count at first response) and safety (Bleeding or Grade ≥ 3 Adverse Events). Results: Romiplostim A total of 185 patients were analyzed in five clinical trials and 1 observational study employing Romiplostim in the treatment group. Platelet response (PR) (platelet count &gt;50 × 109/L) has been reported in all the studies. In 3 randomized double-blinded control trials by Bussel 2011, Elfaly 2011, and Tarantino 2016, Romiplostim achieved a platelet response of 81.69% vs 12.9% in the placebo group. The other three studies reported substantial platelet response as stated in table 1. In all the studies 25 participants had a prior splenectomy. The most common side effects reported in the studies were bleeding (56.75%), headache (58.64%), contusion (50.76%), and epistaxis (49.23%). Clinically significant bleeding (grade 2-4) was reported by 2 studies in Romiplostim vs placebo group (71.08% vs 96%). Eltrombopag A total of 246 patients were analyzed in five clinical trials and 1 observational study. In a randomized double-blinded multicenter study by Grainger et al., Eltrombopag achieved a PR of 39.68% vs 3.4% in the placebo group. Other clinical trials reported a PR of 55.85% whereas the observational study by Neuner et al. reported a PR of 72% in the patient population. Clinically significant bleeding was reported by Grainger et al. and was 47 % in the eltrombopag group vs 7% in the placebo group. Fifteen patients in all the studies had a prior splenectomy. Conclusion: Thrombopoietin analogs such as romiplostim and eltrombopag show substantial platelet response and are associated with minimal side effects. However, more randomized clinical trials are needed to compare their head-to-head efficacy and safety in the treatment of chronic immune thrombocytopenic purpura in pediatric patients. Figure 1 Figure 1. Disclosures Anwer: Janssen pharmaceutical: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Allogene Therapeutics: Research Funding; BMS / Celgene: Honoraria, Research Funding.

scholarly journals An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Corrado Campochiaro ◽  
Yannick Allanore
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Targeted Therapies ◽  
Observational Studies ◽  
Phase 1 ◽  
Phase 2 ◽  
Inclusion Criteria ◽  
Phase 3 ◽  
Trial Drug

AbstractNew molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

scholarly journals GRAd-COV2, a gorilla adenovirus based candidate vaccine against COVID-19, is safe and immunogenic in young and older adults

2021 ◽  
Author(s):  
Simone Lanini ◽  
Stefania Capone ◽  
Andrea Antinori ◽  
Stefano Milleri ◽  
Emanuele Nicastri ◽  
...  
Keyword(s):  
Older Adults ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Age Groups ◽  
T Cell Response ◽  
Open Label ◽  
Younger Age ◽  
Open Label Trial ◽  
Older Subjects ◽  
Further Development

Safe and effective vaccines against coronavirus disease 2019 (COVID-19) are urgently needed to control the ongoing pandemic. Although impressive progress has been made with several COVID-19 vaccines already approved, it is clear that those developed so far cannot meet the global vaccine demand. We have developed a COVID-19 vaccine based on a replication-defective gorilla adenovirus expressing the stabilized pre-fusion SARS-CoV-2 Spike protein, named GRAd-COV2. We aimed to assess the safety and immunogenicity of a single-dose regimen of this vaccine in healthy younger and older adults to select the appropriate dose for each age group. To this purpose, a phase 1, dose-escalation, open-label trial was conducted including 90 healthy subjects, (45 aged 18-55 years and 45 aged 65-85 years), who received a single intramuscular administration of GRAd-CoV2 at three escalating doses. Local and systemic adverse reactions were mostly mild or moderate and of short duration, and no serious AE was reported. Four weeks after vaccination, seroconversion to Spike/RBD was achieved in 43/44 young volunteers and in 45/45 older subjects. Consistently, neutralizing antibodies were detected in 42/44 younger age and 45/45 older age volunteers. In addition, GRAd-COV2 induced a robust and Th1-skewed T cell response against the S antigen in 89/90 subjects from both age groups. Overall, the safety and immunogenicity data from the phase 1 trial support further development of this vaccine.

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