Safety of Intranasal Ketamine for Reducing Uncontrolled Cancer-Related Pain: Protocol of a Phase I/II Clinical Trial (Preprint)

BACKGROUND Approximately 12 million Americans are affected with cancer. Of these, 53% experience pain at all stages of cancer. Pain may remain uncontrolled despite high-dose opioid therapy, and opioids have many well-documented harmful side effects. Intranasal ketamine has been shown to be effective in controlling breakthrough noncancer pain in a double-blind randomized control trial (DBRCT) by Carr et al in 2003 as well as to help with depression in a DBRCT by Lapidus et al in 2014. We seek to obtain preliminary data on the safety, feasibility, and utility of this novel technique for the treatment of uncontrolled cancer pain. OBJECTIVE This study aimed to obtain preliminary data via a clinical trial addressing the safety, feasibility, pharmacokinetics, and pharmacodynamics of intranasal ketamine. These initial findings will be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients and to address the compelling need to identify new, successful management therapies for cancer pain. METHODS This is an institutional review board– and investigational new drug–approved, prospective phase I/II trial to investigate the safety and use of intranasal ketamine in patients with uncontrolled pain related to cancer or cancer treatment. Informed consent will be obtained prior to all study procedures. All patients will be assigned to the same investigational treatment arm. After patient selection via inclusion/exclusion criteria, patients will be seen over 5 visits, with each visit conducted 2-7 days apart. Patients will be administered ketamine on visits 1-4 and monitored for 240 minutes with continuous pulse oximetry and regular blood pressure checks. Blood samples as well as patient-reported outcomes will be collected at set time points at baseline and after drug delivery. Patients will receive 10 mg intranasal ketamine on visit 1, 10 mg intravenous ketamine on visit 2, 30 mg intranasal ketamine on visit 3, and 50 mg intranasal ketamine on visit 4. On visit 5, an addition blood sample will be drawn. RESULTS As of March 2019, enrollment is in progress, and a total of 7 subjects have completed the study. Enrollment is expected to be completed by April 2019. Final data analysis will commence soon after, and the results are expected to be submitted for publication in 2019. CONCLUSIONS If intranasal ketamine can be utilized for pain control in cancer patients, it could provide superior analgesia and better quality of life, without the risk of significant respiratory depression and constipation associated with opioid medications. These findings will be an important initial step toward testing the effectiveness of intranasal ketamine as a nonopioid medication for cancer pain and as potential maintenance outpatient therapy. CLINICALTRIAL ClinicalTrials.gov NCT03146806; https://clinicaltrials.gov/ct2/show/NCT03146806. INTERNATIONAL REGISTERED REPOR DERR1-10.2196/12125

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Continuous intravenous vitamin C in the cancer treatment: re-evaluation of a Phase I clinical study

Functional Foods in Health and Disease ◽

10.31989/ffhd.v9i3.590 ◽

2019 ◽

Vol 9 (3) ◽

pp. 180

Author(s):

Nina Mikirova ◽

Joseph Casciari ◽

Ronald Hunninghake

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Vitamin C ◽

Phase I ◽

Cancer Patients ◽

Phase 1 ◽

Cancer Prognosis ◽

Sodium Ascorbate ◽

High Dose ◽

Treatment Schedule

Background: Intravenous high-dose vitamin C (IVC) therapy is widely used in naturopathic and integrative oncology. A number of Phase I and Phase II clinical trials were launched to prove the benefits of the IVC therapy. Many case studies demonstrated the effectiveness of IVC, with various degrees of success. Clinical trials using IVC to treat cancer have, to date, demonstrated its safety without conclusively proven its efficacy. One difficulty in administering IVC is determining the optimal treatment schedule. To this end, data from a previous Phase 1 clinical trial conducted in 1998 using continuous vitamin C infusions was analyzed to examine the effects of this regimen on key prognostic parameters. Method: Twenty-four subjects were given continuous IVC at doses between 150 and 710 mg/kg/day. Most of the patients had colon cancer with liver and lung metastasis and three patients had pancreatic or liver cancer. All patients had several chemotherapy/radiation treatments before entering the study. Patients were treated by pharmaceutical grade sodium ascorbate diluted in Lactated Ringers solution with the rate of infusion of 20 ml/hr or 10 ml/hr for lower doses. This diluted solution was administered by continuous infusion.Results: Prior to treatment, serum lymphocyte counts and ascorbate concentrations tended to be low while serum levels of lactate dehydrogenase (LDH), neutrophils, and glucose tended to be high. Improvements were seen during IVC therapy. In patients with initially elevated neutrophil levels, numbers tended to decrease. In contrast, increased absolute neutrophil and lymphocyte numbers were seen in patients with initially low counts. Neutrophil to lymphocyte ratios (NLR) proved to be a good indicator of cancer patients’ survival times (high NLR, low survival). This was also true of LDH, creatinine, and glucose concentrations. In patients with the highest pre-treatment NLR, rate of growth of this ratio decreased significantly during therapy. IVC treatments were also associated with decreases in glucose concentrations, restoration of vitamin C levels, and, in about 40% of cases, reductions in LDH levels. Conclusions: As the result of the study we found that continuous IVC infusions improved several parameters associated with poor cancer prognosis. The data suggests a strategic benefit to using lower IVC doses in continuous infusions: raising the dose above 300 mg/kg/day (20 grams in 70 kg human) increased the frequency of side effects without noticeably increasing plasma ascorbate levels. Moreover, improvements in lymphocyte counts at low IVC doses tended to decrease at the higher doses. In conclusion, continuous infusions had benefits to cancer patients and further research in this area is warranted.Keywords: ascorbic acid; continuous infusion; cancer patients; clinical trial; lymphopenia; neutrophil to lymphocyte ratio; hyperglycemia; safety.

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Faculty Opinions recommendation of Effect of high-dose erythropoietin on graft function after kidney transplantation: a randomized, double-blind clinical trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717950013.793455216 ◽

2012 ◽

Author(s):

Steven Coca

Keyword(s):

Clinical Trial ◽

Kidney Transplantation ◽

Graft Function ◽

High Dose ◽

Double Blind ◽

Double Blind Clinical Trial

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Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: A randomized, placebo-controlled, double-blind, Phase I clinical trial

Vaccine ◽

10.1016/j.vaccine.2012.03.010 ◽

2012 ◽

Vol 30 (22) ◽

pp. 3295-3303 ◽

Cited By ~ 71

Author(s):

Yan-Ping Li ◽

Zheng-Lun Liang ◽

Qiang Gao ◽

Li-Rong Huang ◽

Qun-Ying Mao ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Enterovirus 71 ◽

Phase I Clinical Trial ◽

Human Enterovirus ◽

Double Blind ◽

Human Enterovirus 71

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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Prostate high dose-rate brachytherapy as monotherapy for prostate cancer: Late toxicity and patient reported outcomes from a randomized phase II clinical trial

Radiotherapy and Oncology ◽

10.1016/j.radonc.2020.12.021 ◽

2021 ◽

Vol 156 ◽

pp. 160-165

Author(s):

Mark Corkum ◽

Andrew Loblaw ◽

Yaser Hasan ◽

Hans T. Chung ◽

Chia-Lin Tseng ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Dose Rate ◽

Phase Ii ◽

Patient Reported Outcomes ◽

Late Toxicity ◽

High Dose Rate ◽

High Dose ◽

Randomized Phase Ii ◽

Patient Reported

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Immunogenicity and Safety of Inactivated Sabin-Strain Polio Vaccine “PoliovacSin”: Clinical Trials Phase I and II

Vaccines ◽

10.3390/vaccines9060565 ◽

2021 ◽

Vol 9 (6) ◽

pp. 565

Author(s):

Anastasia Piniaeva ◽

Georgy Ignatyev ◽

Liubov Kozlovskaya ◽

Yury Ivin ◽

Anastasia Kovpak ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Phase I ◽

Safety Profile ◽

Neutralizing Antibody ◽

Polio Eradication ◽

Controlled Clinical Trial ◽

Double Blind ◽

Good Tolerability ◽

Poliomyelitis Vaccine

Global polio eradication requires both safe and effective vaccines, and safe production processes. Sabin oral poliomyelitis vaccine (OPV) strains can evolve to virulent viruses and result in poliomyelitis outbreaks, and conventional inactivated poliomyelitis vaccine (Salk-IPV) production includes accumulation of large stocks of neurovirulent wild polioviruses. Therefore, IPV based on attenuated OPV strains seems a viable option. To increase the global supply of affordable inactivated vaccine in the still not-polio free world we developed an IPV made from the Sabin strains–PoliovacSin. Clinical trials included participants 18–60 years of age. A phase I single-center, randomized, double-blind placebo-controlled clinical trial included 60 participants, who received one dose of PoliovacSin or Placebo. A phase II multicenter, randomized, double-blind, comparative clinical trial included 200 participants, who received one dose of PoliovacSin or Imovax Polio. All vaccinations were well tolerated, and PoliovacSin had a comparable safety profile to the Placebo or the reference Imovax Polio preparations. A significant increase in neutralizing antibody levels to polioviruses types 1–3 (Sabin and wild) was observed in PoliovacSin and Imovax Polio vaccinated groups. Therefore, clinical trials confirmed good tolerability, low reactogenicity, and high safety profile of the PoliovacSin and its pronounced immunogenic properties. The preparation was approved for clinical trials involving infants.

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Solumedrol Treatment for Severe Sepsis in Humans with a Blunted Adrenocorticotropic Hormone-Cortisol Response: A Prospective Randomized Double-Blind Placebo-Controlled Pilot Clinical Trial

Journal of Intensive Care Medicine ◽

10.1177/08850666211038883 ◽

2021 ◽

pp. 088506662110388

Author(s):

Divya Birudaraju ◽

Sajad Hamal ◽

John A. Tayek

Keyword(s):

Blood Pressure ◽

Clinical Trial ◽

Adrenocorticotropic Hormone ◽

Serum Cortisol ◽

High Dose ◽

Cortisol Response ◽

Acth Stimulation ◽

Double Blind ◽

Significant Difference ◽

To Receive

Purpose To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13 µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250 µg of ACTH, and serum cortisol was measured at times 0, 30, and 60 min. Eleven patients failed to increase their cortisol concentration above 19.9 µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1 µg/dL increased to 38 ± 3 µg/dL at 30 min and 40 ± 3 at 60 min. All cortisol responses were <12.9 µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20 mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8 h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P < .05 as significant. Results Results: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20 mg every 8 h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.

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