Clinical Trials – New Horizons
~ Pharmacology News ~
FDA Approves Tafenoquine, Novel Antimalarial
July 20th, FDA: The FDA has approved the pre-erythrocytic-, erythrocytic-, and gametocyte-targeting novel antimalarial durg tafenoquine for the prevention of plasmodium vivax malaria relapse (not for acute treatment).
Many FDA Breakthrough Therapy Approvals Not Based on Rigorous Evidence
July 17th, JAMA: Between 2012 and 2017, 46 drugs approved by the FDA received Breakthrough Therapy designation, which facilitates expedited development and review. 41% of approvals were not based on randomized trials, 54% were not double-blinded, 46% were not active or placebo-controlled, and 78% did not use a clinical primary end point.
More than 1 in 3 Urgent Care and Retail Clinic Visits Results in Antibiotic Prescriptions
July 16th, JAMA Internal Medicine: 39% of urgent care visits and 36.4% of retail clinic visits resulted in antibiotic prescriptions, with 45.7 % of antibiotic-inappropriate urgent care clinic visits resulting in antibiotic prescriptions.
Retrospective cohort (9,911,900 office visits).
FDA Expands Somatropin Indication For Short-Stature Disorders
July 21st, FDA: The US FDA has expanded the indications of somatropin (somatotropin, Zomactin) to include short stature attributed to Turner syndrome, small for gestational age (SGA) with no catch-up growth by 2 to 4 years, homeobox-containing gene (SHOX) deficiency, or idiopathic origin.
FDA Expands Indication of Ribociclib Combo Drug for Breast Cancer Patients
July 19th, FDA Press Release: The US FDA has expanded the indications for the antineoplastic agent ribociclib (Kisqali), a cyclin-dependent cell cycle inhibitor. In combination with an aromatase inhibitor, it is now approved for the treatment of pre- and peri- and (previously only post-) menopausal women with hormone receptor+/HER2- breast cancer. In combination with fulvestrant it is now approved as endocrine therapy for post-menopausal women with hormone receptor+/HER2- breast cancer.
More Opioid Prescriptions Than Patients in Some Parts of Rural America
July 19th, American Journal of Public Health: Opioid prescription rates vary significantly between urban and rural areas in the United States. In a district in Alabama, nearly 167 opioid prescriptions per 100 persons were written compared to 23/100 in Brooklyn, New York.
FDA Approves Ivosidenib, 2nd IDH Inhibitor, for Acute Myeloid Leukemia
July 20th, FDA: The US FDA has approved ivosidenib, an inhibitor of isocitrate dehydrogenase-1 (IDH1) in patients with relapsed/refractory acute myeloid leukemia (r/rAML) with IDH1 mutations. The FDA approved enasidenib (Idhifa) last year for r/rAML with IDH2 mutations.
Many US Heart Failure Patients Not Receiving Recommended Medical Therapy
July 16th, JACC: Patients with heart failure with reduced ejection fraction (HFrEF) are overwhelmingly not receiving guideline-recommended pharmacologic therapy, with only 1% of patients eligible for simultaneous ACE/ARB/ARNI, beta-blocker, and MRA therapy receiving target doses of these medications. Observational cross-sectional, CHAMP-HF registry (3,518 patients).
Meat Products Containing Nitrates Associated with Increased Risk of Mania
July 18th, JAMA: Patients treated for mania or hypomania were more than 3 times more likely to have ingested nitrate-containing meat products (e.g., preserved meat like beef jerky) than patients without diagnoses of manic-spectrum disorders. This association was not observed for other meat products. Observational retrospective (1001 participants).
FDA Approves First Protease Inhibitor-Based Single-Tablet Regimen for HIV
July 18th, Medscape Coverage: The US FDA has approved the first single-tablet regimen that includes a protease inhibitor, darunavir. Clinical trials demonstrated comparable virologic suppression to established HIV antiretroviral therapies, with possible advantages in renal function and bone loss.
FDA Warns Synthetic Cannabinoid Contamination with Powerful Anticoagulant
July 19th, FDA: The United States FDA has issued a statement warning about the consumption of synthetic cannabis products following reports of contamination with the long-acting anticoagulant brodifacoum, a common rat poison.
~ Clinical Trials: New Horizons ~
Novel Antiviral Drug Baloxavir Marboxil Shows Efficacy in Improving Flu Symptoms
July 17th, Roche Press Release: The novel antiviral baloxavir marboxil, an inhibitor of a cap-dependent endonuclease, has demonstrated efficacy over placebo and osetltamivir in reducing symptoms of influenza infection in high-risk individuals. Phase III RCT, CAPSTONE-2 trial.
Canagliflozin Effective in CKD + Type II Diabetes, Trial Ended Early
July 17th, Janssen: Canagliflozin appears to be effective in preserving renal function in patients with type II diabetes and chronic kidney disease. The CREDENCE trial was halted early when a scheduled interim analysis demonstrated that efficacy criteria had been achieved. Phase III RCT, CREDENCE Trial.
Fremanezumab Effective in Refractory Migraine
June 29th, AHS Meeting: One dose of anti-CGRP antibody fremanezumab decreased headache days by 4.4/month for 3 months in patients who were previously treated with topiramate. RCT (338 patients).
Botox 3 Times More Likely Than Topiramate Bring Major Headache Relief
June 30th, AHS Meeting: In a head-to-head trial, onabotulinumtoxin A was associated with greater than 50% reduction in headache days in 40% of patients compared to 12% of patients treated with topiramate. Randomized head-to-head trial (~300 patients).
Niraparib, Olaparib Improve Quality of Life in Patients with Recurrent Ovarian Cancer
July 16th, The Lancet: In addition to improving progression-free survival (same cohort, previously reported) the novel PARP1/2 inhibitor niraparib was associated with an improved quality of life in women with recurrent ovarian cancer treated with platinum-based chemotherapy. Similar results were observed in women with BRCA1/2 mutations and relapsed ovarian cancer receiving adjunctive olaparib, another PARP inhibitor. Phase III RCT, ENGOT-OV16/NOVA trial (533 patients) and SOLO/ENGOT Ov-21 trial (295 patients).
Adjunctive Complementary Medicine For Cancer Associated with Higher Mortality Risk
July 19th, JAMA Oncology: Patients who received complementary medical care (i.e., “Other-Unproven: Cancer treatments administered by nonmedical personnel” listed in patient record) in addition to at least one modality of conventional cancer treatment doubled their risk of death compared to individuals who received conventional care only. Observational retrospective (1,901,815 patients).
Checkpoint Blockade Associated Improved Survival in Brain-Metastatic Melanoma
July 12th, Cancer Immunology Research: Overall survival in patients with melanoma brain metastases (MBM) increased by 91 following approval of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted treatments. CBI was associated with an improved median survival of 12.4 months compared with patients who did not receive CBI. Observational retrospective (2,753 patients).
Post-Remission Continuation of Adalimumab Reduces Flares in Spondyloarthritis Patients
June 28th, The Lancet: Continuation of adalimumab after remission of symptoms in patients with non-radiographic spondyloarthritis (who responded to adalimumab induction therapy) resulted in a nearly 50% lower risk of experiencing a relapse after 68 weeks, compared with patients who received placebo maintenance. Extension of ABILITY-3 RCT (305 patients).
L-Glutamine Decreases Pain Crisis Frequency by 25% in Sickle Cell Patients
July 19th, NEJM: Twice-daily oral L-glutamine therapy (proposed to stimulate NAD production and subsequent reduction to NADH) decreased the median number of pain crises in children and adults with sickle cell anemia to a median of 3 over a 48-week period, compared to 4 in patients not receiving L-glutamine. RCT, Phase III (230 patients).
Tanezumab, Novel Pain Medication Demonstrates Efficacy in Osteoporosis
July 18th, Pfizer: Tanezumab, a novel nerve growth factor inhibitor, has shown efficacy and reasonable safety in the treatment of pain in osteoarthritis. Tanezumab is also under investigation for the treatment of chronic low back pain and cancer pain. RCT, Phase III Trial (698 patients).
~ Clinical Research ~
NSAIDs After Ovarian Cancer Associated with Better Outcomes
July 17th, The Lancet: Use of aspirin and other NSAIDs within 2 years after epithelial ovarian cancer diagnosis was associated with a 32% increased cancer-specific survival rate. Prospective observational Nurses’ Health Study I/II cohort (1143 participants).
Widespread Unsafe Use of Zolpidem
July 16th, JAMA Internal Medicine: Zolpidem, a GABA agonist commonly prescribed as a sleep aid, was found to be used unsafely by the majority of patients for whom it is prescribed. Despite safety and efficacy issues, 68% of zolpidem use was sustained over months and years, and 41% of patients reported simultaneous use of other CNS-depressants including opioids and benzodiazepines. Observational retrospective (MEPS database, 3.8 million adults with zolpidem prescriptions).
Parenteral N-3 Fatty Acids Associated with Faster Recovery in Post-Surgical Jaundice
July 13th, EJCN: Intravenous lipid emulsion enriched in n-3 fatty acids was associated with a shorter recovery period from post-surgical obstructive jaundice in patients receiving parenteral nutrition, shortening recovery time by approximately 3 days compared those who received other lipid emulsion formulations. Prospective observational (226 patients).
Link to study
IBD Associated with Higher Likelihood of Erectile Dysfunction Prescriptions
AJG, July 10th: In a nationwide Danish cohort, men with a history of ulcerative colitis or Crohn’s disease were between 19-31% (depending on history of bowel surgery) more likely to fill an erectile dysfunction medication prescription than men without IBD. Observational retrospective (346,478 participants).
Tofacitinib Improves Ulcerative Colitis Symptoms Within 3 Days
July 13th, Journal CGH: Twice daily tofacitinib, a small-molecule JAK inhibitor, decreases stool frequency and rectal bleeding severity more signifantly than placebo within 3 days of starting therapy. Post-hoc analysis of OCTAVE Induction ½ RCTs (1139 participants).
Link to study
Methotrexate May not Be Effective in Ulcerative Colitis
June 29th, Journal Gastroenterology: Parenteral methotrexate, a DHFR inhibitor, was not associated with improved outcomes in ulcerative colitis compared with placebo. RCT (179 patients).
Closed-Loop System More Effective than SubQ Insulin
June 25th, NEJM: An automated, closed-loop insulin delivery system resulted in measured blood glucose levels in the target range 24.3% more often than patients receiving traditional subcutaneous insulin in an inpatient setting. Randomized, open-label (136 patients).
Epinephrine Improves Survival in Out-of-Hospital Cardiac Arrest, May Worsen Neurological Outcomes
July 25th, NEJM: A UK trial involving paramedic administration of either epinephrine or placebo to patients experiencing out-of-hospital cardiac arrest found that the epinephrine group experienced a 39% increased chance of survival, but nearly doubled the risk of severe neurological impairment at the time of hospital discharge. RCT, double-blind (8014 patients).
Link to study
DOACs Associated with Lower Bleed Risk and Lower Mortality than Warfarin in Women
July 17th, JACC: Women with atrial fibrillation treated with direct-acting oral anticoagulants (e.g., apixaban (Eliquis®). dabigatran (Pradaxa®), rivaroxaban (Xarelto®), edoxaban (Savaysa™)) had a 45% lower all cause mortality than women taking warfarin, as well as a significantly lower rate of intracerebral hemorrhage. No significant difference was observed in men taking either drug. Observational retrospective (9,806 patients).
Rivaroxaban Associated with More Adverse Events than Warfarin in Anti-Phospholipid Syndrome
July 12th, Journal Blood: In a study of patients with thrombotic anti-phospholipid syndrome, once-daily rivaroxaban was associated with more thromboembolic and major bleeding events than warfarin (INR target 2.5). RCT (120 patients).
Link to study
Direct Oral Anticoagulants Associated with Higher Bleeding Risk Than Warfarin in CKD Patients with Atrial Fibrillation
July 6th, CJAN: Patients with chronic kidney disease and atrial fibrillation who received direct oral anticoagulants (e.g., apixaban (eliquis®), dabigatran (Pradaxa®), rivaroxaban (Xarelto®), edoxaban (Savaysa™) experienced comparable thromboembolic risk reducation to patients receiving warfarin, but had a 23% higher risk of bleeding. Observational retrospective (6,412 patients).
No Rebound Risk Observed Following D/C of Dual Antiplatelet Therapy
July 20th, Journal Heart: Patients who discontinued dual antiplatelet therapy following a hospitalization event for acute coronary syndrome did not experience a higher rate of cardiovascular events in the first 90 days post-discontinuation compared with the following 90 days (event rate ~16% for both periods). Observational retrospective (1340 patients).
Sulfonureas Associated with Increased Risk of Cardiovascular Events, Hypoglycemia
July 18th, BMJ: Patients with type II diabetes who initiated metformin therapy and were later switched to a sulfonurea medication, or received a sulfonurea as an add-on to metformin were at 26-28% higher risk of myocardial infarction and all-cause mortality after a median of 1.1 years, and at more than 4-fold higher risk of severe hypoglycemic events. Retrospective observational (77,138 patients).
Zolendronate Better for Bone Density Than Switching ART Agent in HIV Patients
June 20th, AIDS: Patients who experienced tenofovir disoproxil fumarate (TDF) related bone mineral density (BMD) loss experienced more substantial improvements in BMD following addition of the zolendronate than patients whose anti-retroviral therapy (ART) was altered to exclude TDF. RCT, ZEST Study (87 patients).
Isopropanol Aromatherapy Superior to Ondansetron Alone in ED Nausea
Feburary 17th/July 18th, Annals of Emergency Medicine: Inhaled isopropyl alcohol +/- ondansetron was more effective than ondansetron alone in treating patients presenting to the emergency department with a chief complaint of vomiting. Nearly twice as many patients treated with ondansetron alone eventually required administration of a rescue antiemetic. RCT (120 patients).
~ Reviews ~
Antibiotic Prophylaxis for UTI Associated with Increased Risk of Multi-Drug Resistance
June 28th, Pediatrics: Children with vesicoureteral reflux were 6.4 times more likely to develop a multi-drug resistant UTI than children who were treated with placebo or no treatment. Meta-analysis (6 RCTs, 1299 patients).
Fish-Derived Omega-3 Fatty Acids Not Associated with Improved Cardiovascular Health
July 18th, Cochrane: An review has determined that supplements of oily fish-derived omega-3 fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with a beneficial effect on mortality or cardiovascular health. The plant-based omega-3 fat alpha-linolenic acid (ALA) may slightly decrease cardiovascular disease risk. Systematic review and meta-analysis (79 RCTs, 112,059 participants).
Resveratrol Intake Associated with Lower CRP Levels
July 16th, EJCN: Resveratrol intake is linked to decreased serum CRP levels in adults, but is not associated with significantly lower IL-6 or TNF-alpha levels. Children and obese individuals did experience a mild decrease in TNF-alpha levels associated with resveratrol supplementation. Systematic review and meta-analysis (15 trials, 658 participants).
Budesonide Most Effective Pharmacologic Therapy for Eosinophilic Esophagitis
July 11th, JCG: Viscous budesonide, a synthetic glucocorticoid, was associated with better outcomes compared with suspension budesonide, viscous or suspension fluticasone, esomeprazole, prednisone, and mepolizumab, or placebo. Meta-analysis, 11 RCTs (456 patients).
Fidaxomicin Associated with Better C. Difficile Cure Rates than Vancomycin, Metronidazole
July 16th, The Lancet: Fidaxomicin, an RNA polymerase inhibitor, and the glycopeptide antibiotic teicoplanin (not approved in USA) were associated with significantly better sustained symptomatic cure rates of non-recurrent C. Difficile infections than other antibiotics, including vancomycin. Metronidazole was among the least effective antibiotics for C. Difficile infections. Meta-analysis, 24 RCTs (5361 patients).
Probiotics Associated with Lower Risk of Antibiotic-Related C. Difficile
July 19th, JAMA: Co-administration of probiotics and antibiotics in children and adults was associated with a 60% decreased risk of clostridium difficile infection compared to individuals who received antibiotics alone. Meta-analysis (31 RCTs, 8,672 patients).
NSAIDs As Effective as Opioids in Acute Renal Colic, with Better Safety Profile
April 30th/July 18th, Annals of Emergency Medicine: NSAIDs administered to emergency department patients presenting with acute renal colic were as or more effective than opioids or acetaminophen, but offered associated with approximately half of the risk of vomiting and other adverse events. Meta-analysis (36 RCTs, 4,887 patients).