A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Abstract Background Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM. Methods Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored. Results The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK. Conclusions With personalised dosing, nabiximols had acceptable safety and tolerability with no drug–drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial. Clinical trial registration ClinicalTrials.gov: Part 1– NCT01812603; Part 2– NCT01812616.

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Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211682 ◽

2017 ◽

Vol 77 (2) ◽

pp. 212-220 ◽

Cited By ~ 111

Author(s):

Dinesh Khanna ◽

Christopher P Denton ◽

Celia J F Lin ◽

Jacob M van Laar ◽

Tracy M Frech ◽

...

Keyword(s):

Systemic Sclerosis ◽

Phase Ii ◽

Controlled Trial ◽

Safety Data ◽

Open Label ◽

Double Blind ◽

Skin Score ◽

Open Label Extension ◽

Registration Number ◽

Randomised Controlled

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

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Continuous bilateral thoracic paravertebral blockade for analgesia after cardiac surgery: a randomised, controlled trial

Perfusion ◽

10.1177/0267659117715507 ◽

2017 ◽

Vol 32 (7) ◽

pp. 591-597 ◽

Cited By ~ 5

Author(s):

Geoff G. Lockwood ◽

Leilani Cabreros ◽

Dorota Banach ◽

Prakash P. Punjabi

Keyword(s):

Cardiac Surgery ◽

Primary Outcome ◽

Controlled Trial ◽

Morphine Consumption ◽

Controlled Study ◽

Double Blind ◽

Clinical Trial Registration ◽

Subcutaneous Infusion ◽

Randomised Controlled Study ◽

Randomised Controlled

Background: Continuous bilateral thoracic paravertebral blockade has been used for analgesia after cardiac surgery, but its efficacy has never been formally tested. Method: Fifty adult patients were enrolled in a double-blind, randomised, controlled study of continuous bilateral thoracic paravertebral infusion of 0.5% lidocaine (1 mg.kg-1.hr-1) for analgesia after coronary surgery. Control patients received a subcutaneous infusion of lidocaine at the same rate through catheters inserted at the same locations as the study group. The primary outcome was morphine consumption at 48 hours using patient-controlled analgesia (PCA). Secondary outcomes included pain, respiratory function, nausea and vomiting. Serum lidocaine concentrations were measured on the first two post-operative days. Results: There was no difference in morphine consumption or in any other outcome measure between the groups. Serum lidocaine concentrations increased during the study, with a maximum of 5.9 mg.l-1. There were no adverse events as a consequence of the study. Conclusion: Bilateral paravertebral infusion of lidocaine confers no advantage over systemic lidocaine infusion after cardiac surgery. Clinical trial registration: ISRCTN13424423 ( https://www.isrctn.com )

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Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(15)00362-x ◽

2016 ◽

Vol 16 (1) ◽

pp. 31-42 ◽

Cited By ~ 120

Author(s):

Milagritos D Tapia ◽

Samba O Sow ◽

Kirsten E Lyke ◽

Fadima Cheick Haidara ◽

Fatoumata Diallo ◽

...

Keyword(s):

Virus Vaccine ◽

Ebola Virus ◽

Controlled Trial ◽

Phase 1 ◽

Randomised Trial ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Phase 1B ◽

Single Blind

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Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial

The Lancet ◽

10.1016/s0140-6736(16)31715-9 ◽

2017 ◽

Vol 389 (10070) ◽

pp. 709-717 ◽

Cited By ~ 98

Author(s):

Meike H van der Ree ◽

J Marleen de Vree ◽

Femke Stelma ◽

Sophie Willemse ◽

Marc van der Valk ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Randomised Controlled Trial ◽

Chronic Hepatitis C ◽

Controlled Trial ◽

Antiviral Effect ◽

Double Blind ◽

Phase 1B ◽

Randomised Controlled

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Efficacy of PCV vaccine is primarily mediated by controlling pneumococcal colonisation density

10.1101/547703 ◽

2019 ◽

Author(s):

E.L. German ◽

C. Solórzano ◽

S. Sunny ◽

F. Dunne ◽

J.F. Gritzfeld ◽

...

Keyword(s):

Controlled Trial ◽

Double Blind ◽

Clinical Trial Registration ◽

Herd Effect ◽

Vaccine Type ◽

Pneumococcal Serotype ◽

Classical Culture ◽

Randomised Controlled ◽

The Impact ◽

Quantitative Pcr Assay

AbstractWidespread use of Pneumococcal Conjugate Vaccines (PCV) has resulted in a reduction in nasopharyngeal colonisation and invasive pneumococcal disease caused by vaccine-types. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and a reduction in bacterial intensity (AUC) in experimentally colonised volunteers as measured by classical culture. In this study, we used a multiplex quantitative PCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the experimental colonisation status of the same trial volunteers. Increase in detection of low-density colonised volunteers by this molecular method led to a decrease of PCV efficacy against colonisation acquisition (29%), as compared to classical culture (83%). For subjects who were colonised following pneumococcal challenge, PCV had a pronounced effect on decreasing colonisation density. These results have implications for vaccine efficacy and surveillance studies as they indicate that the success of PCV vaccination could primarily be mediated by the control of vaccine-type colonisation density which results in decreased transmission and the reported herd effect of PCVs. Studies assessing the impact of PCV should account for density measurements in their design.Clinical trial registration with ISRCTN: 45340436

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Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension

Cephalalgia ◽

10.1177/0333102420973994 ◽

2020 ◽

pp. 033310242097399

Author(s):

Richard B Lipton ◽

Stewart J Tepper ◽

Stephen D Silberstein ◽

David Kudrow ◽

Messoud Ashina ◽

...

Keyword(s):

Confidence Interval ◽

Chronic Migraine ◽

Controlled Trial ◽

Treatment Phase ◽

Episodic Migraine ◽

Double Blind Study ◽

Open Label ◽

Double Blind ◽

Clinical Trial Registration

Objective To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. Methods A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1–12, 21–24, 37–40, and 49–52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. Results In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8–58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6–61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3–99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1–99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5–54.7]) patients; of these, 77.8% (95% confidence interval: 60.9–89.9) persisted in reversion through week 64. Conclusions Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine. Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02066415

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