CLINICAL TRIALS PROFILE FOR VERSED

505(b)(2) Clinical Trials for VERSED

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
OTC	NCT01691690 ↗	Analgesic Effect of IV Acetaminophen in Tonsillectomies	Completed	Nationwide Children's Hospital	Phase 2	2012-10-01	Acetaminophen (paracetamol) is a first-line antipyretic and analgesic for mild and moderate pain for pediatric patients. Its common use (particularly in oral form) is underscored by its wide therapeutic window, safety profile, over the counter accessibility, lack of adverse systemic effects (as compared with NSAIDS and opioids) when given in appropriate doses. Although the exact anti-nociceptive mechanisms of acetaminophen continue to be elucidated, these mechanisms appear to be multi-factorial and include central inhibition of the cyclo-oxygenase (COX) enzyme leading to decreased production of prostaglandins from arachidonic acid, interference with serotonergic descending pain pathways, indirect activation of cannabinoid 1 (CB1) receptors and inhibition of nitric oxide pathways through N-methyl-D-aspartate (NMDA) or substance P. Of the above mechanisms, the most commonly known is that of central inhibition of COX enzymes by which the decreased production of prostaglandins diminish the release of excitatory transmitters of substance P and glutamate which are both involved in nociceptive transmission (Anderson, 2008; Smith, 2011). To date, several studies have shown acetaminophen's opioid sparing effect in the pediatric population when given by the rectal or intravenous routes (Korpela et al, 1999; Dashti et al, 2009; Hong et al, 2010).

All Clinical Trials for VERSED

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00109395 ↗	Lorazepam Sedation for Critically Ill Children	Completed	Case Western Reserve University	Phase 2/Phase 3	2004-09-01	This clinical trial is being performed under the Best Pharmaceuticals for Children Act, signed into law in 2002 in order to improve pediatric labeling for off-patent drugs. The purpose of this study is to make sure that lorazepam, when given to children who are very sick in the Intensive Care Unit and who are on a breathing machine, is safe and works as well as a drug called midazolam. Midazolam is already approved by the FDA for this use, but lorazepam is not, even though both drugs are commonly used for sedation.
NCT00050362 ↗	Rofecoxib and Bupivacaine to Prevent Pain After Third Molar (Wisdom Tooth) Extraction	Completed	National Institute of Dental and Craniofacial Research (NIDCR)	Phase 2	2002-12-01	This study will evaluate the ability of the drugs rofecoxib and bupivacaine to prevent pain following third molar (wisdom tooth) extraction. Rofecoxib is approved to treat pain of arthritis and menstrual cramps. Bupivacaine is a local anesthetic similar to lidocaine, but longer acting. Healthy normal volunteers between 16 and 35 years of age who are in general good health and require extraction of their two lower wisdom teeth may be eligible for this study. Participants will have their two lower wisdom teeth extracted, and a biopsy (removal of a small piece of tissue) will be taken from the inside of the cheek around the area behind one of the extraction sites. Ninety minutes before surgery, patients will take a dose of either rofecoxib, or a placebo (a pill with no active ingredient) by mouth. Just before surgery, they will receive an injection of either lidocaine or bupivacaine to numb the mouth and a sedative called midazolam (Versed® (Registered Trademark)) through an arm vein to cause drowsiness. After surgery, a small piece of tubing will be placed into one of the two extraction sites. Samples will be collected from the tubing to measure chemicals involved in pain and inflammation. Patients will remain in the clinic for up to 4 hours after surgery to monitor pain and drug side effects while the anesthetic wears off. During this time, they will complete pain questionnaires every 20 minutes. (Patients whose pain is unrelieved an hour after surgery may request and receive acetaminophen (Tylenol) and codeine.) The tubing then will be removed and they will be discharged with pain medicines (Tylenol, codeine and the study drug) and forms to record pain ratings. They will be given detailed instructions on how and when to take the medicines and how to record information in the pain diary. Patients will return to the clinic 48 hours after surgery with the pain diary and pain relievers. At this visit, another biopsy will be taken under local anesthetic (lidocaine).
NCT00050180 ↗	Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers	Completed	National Institutes of Health Clinical Center (CC)	Phase 4	2002-11-22	This study will examine whether a particular type of gene (MDR1) in the body can affect blood levels of two protease inhibitors, indinavir and saquinavir, which are used to treat people with HIV. If blood levels of these drugs are too low or too high, they may not work well or may cause side effects in patients. This study will determine how MDR1 genes might affect absorption of these medicines. Healthy normal volunteers between 18 and 50 years of age may be eligible for this study. Candidates will be screened with a medical history and blood and urine tests. The blood will be tested for: - Routine laboratory values for assessing general health - HIV - MDR1 gene type - Amount of P-glycoprotein (a protein made by the MDR1 gene) on T cells. Participants will have blood drawn three more times, as follows: - After one dose of the sedative midazolam (Versed(Registered Trademark)): Participants will take an 8-milligram dose of midazolam syrup by mouth. Four hours later, a single blood sample will be drawn through a needle in an arm vein. This part of the study will assess the efficiency of a certain enzyme involved in metabolizing (breaking down) indinavir and saquinavir. - After four doses of indinavir: About a week after taking the midazolam, participants will take 800 mg of indinavir (two capsules) 3 times a day (every 8 hours) for 1 day. The following morning they will come to the clinic, where a catheter (flexible plastic tube) will be placed in an arm vein for repeated blood draws. A blood sample will be drawn, and a fourth and final dose of indinavir will be given. Seven blood samples of about a teaspoon each will then be collected through the catheter over an 8-hour period to measure blood levels of the drug. - After 10 doses of saquinavir: About a week after the last dose of indinavir, participants will start taking 1,200 mg (6 capsules) of saquinavir soft-gelatin capsules 3 times a day for 3 days. On the fourth day, participants will come to the clinic. A catheter will be inserted into an arm vein and about 4 teaspoons of blood will be collected for routine laboratory tests and to measure saquinavir levels. A urine sample will also be collected for routine tests. Participants will then receive the tenth and final dose of saquinavir, and eight blood samples of about a teaspoon each will be collected through the catheter over an 8-hour period.
NCT00006070 ↗	Etanercept (Enbrel) to Treat Pain and Swelling After Third Molar Extraction	Completed	National Institute of Dental and Craniofacial Research (NIDCR)	Phase 2	2000-07-01	This study will evaluate the effects of the anti-inflammatory drug etanercept (Enbrel) on relieving pain and swelling after oral surgery. The Food and Drug Administration has approved Enbrel for treating symptoms of rheumatoid arthritis, including pain. Healthy volunteers 16 to 35 years of age who require third molar (wisdom teeth) extractions may be eligible for this study. Participants must not be allergic to aspirin or to non-steroidal anti-inflammatory drugs (NSAIDs). Candidates will be screened for eligibility with a medical history and oral examination, including X-rays if needed. Participation in the study requires four clinic visits: two for surgery and two for follow-up: Visit 1: Patients will have ultrasound pictures taken to measure cheek size. One hour before surgery, they will receive a dose of either 25 milligrams (mg) of Enbrel; 15 mg of the standard pain medicine Toradol; or a placebo (salt-water) through an arm vein. A local injection of an anesthetic (lidocaine) will be given before surgery to numb the mouth, and a sedative (Versed) will be infused through a vein to induce sleepiness. When the anesthetic takes effect, a small piece of tissue will be removed from the inside of the cheek, and then the upper and lower molars on one side of the mouth will be extracted. After surgery, a small piece of tubing will be placed in the lower extraction site, from which samples will be collected to measure chemicals involved in pain and inflammation. Patients will stay in the clinic for 4 hours after surgery while the anesthetic wears off and will complete pain questionnaires during that time. If, an hour after surgery, patients have pain that is not relieved by the treatment given before surgery, they may receive acetaminophen (Tylenol) and codeine for pain. Another biopsy will be taken (under local anesthetic) from the inside of the cheek when pain occurs or at the end of the 4-hour observation period. The tubing then will be removed and the patient discharged with Tylenol and codeine for pain. Visit 2: Patients will return to the clinic in the morning 48 hours after the oral surgery for a 1- to 2-hour visit. They will fill out questionnaires, undergo ultrasound imaging of both cheeks and have another biopsy taken from the inside of the cheek on the operated side. Visits 3 and 4: Three weeks after the first surgery patients will schedule extraction of the two wisdom teeth on the other side of the mouth, and the procedures for visits 1 and 2 will be repeated.
NCT00001724 ↗	Local Flurbiprofen to Treat Pain Following Wisdom Tooth Extraction	Completed	National Institute of Dental and Craniofacial Research (NIDCR)	Phase 2	1997-11-01	This study will evaluate the effectiveness of the non-steroidal anti-inflammatory drug flurbiprofen (Ansaid® (Registered Trademark)) in relieving pain following oral surgery. Flurbiprofen is approved by the Food and Drug Administration for treatment of arthritis pain. Patients 16 years of age and older requiring third molar (wisdom tooth) extraction may be eligible for this study. Patients will undergo oral surgery to remove two lower third molar teeth. Before surgery, they will be given a local anesthetic (lidocaine with epinephrine) injected in the mouth and a sedative (Versed) infused through a catheter (thin plastic tube) placed in an arm vein. At the time of surgery, patients will also be given flurbiprofen or a placebo formulation (look-alike substance with no active ingredient) directly into the extraction site and a capsule that also may contain flurbiprofen or placebo. One in seven patients will receive only placebo. All patients will fill out pain questionnaires and stay in the clinic for up to 6 hours for observation of bleeding and medication side effects. Patients who do not have satisfactory pain relief from the test medicine after surgery may request a standard pain reliever. A small blood sample will be collected during surgery and at 15 minutes, one-half hour and 1, 2, 3, 4, 5, 6, 24 and 48 hours after surgery to measure flurbiprofen blood levels. A total of 33 ml (about 2 tablespoons) of blood will be drawn for these tests. Samples collected on the day of surgery will be drawn from the catheter used to administer the sedative; the 24- and 48-hour samples will be taken by needle from an arm or hand vein. Urine samples will also be collected between 4 and 6 hours after surgery and again at 24 and 48 hours after surgery.

Clinical Trial Conditions for VERSED

Condition Name

Condition Name for VERSED
Intervention	Trials
Pain	8
Anxiety	7
Critical Illness	5
Healthy	4

Condition MeSH

Condition MeSH for VERSED
Intervention	Trials
Anxiety Disorders	7
Pain, Postoperative	6
Critical Illness	5
Lacerations	4

Clinical Trial Locations for VERSED

Trials by Country

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−

Trials by Country for VERSED
Location	Trials
United States	131
Spain	1
United Kingdom	1
Korea, Republic of	1
Taiwan	1

Trials by US State

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−

Trials by US State for VERSED
Location	Trials
California	10
Pennsylvania	9
Ohio	8
Texas	8
Florida	8

Clinical Trial Progress for VERSED

Clinical Trial Phase

Clinical Trial Phase for VERSED
Clinical Trial Phase	Trials
Phase 4	36
Phase 3	11
Phase 2/Phase 3	4

Clinical Trial Status

Clinical Trial Status for VERSED
Clinical Trial Phase	Trials
Completed	64
Terminated	10
Withdrawn	10

Clinical Trial Sponsors for VERSED

Sponsor Name

Sponsor Name for VERSED
Sponsor	Trials
Yale University	5
Hospira, Inc.	4
Hospira, now a wholly owned subsidiary of Pfizer	4

Sponsor Type

Sponsor Type for VERSED
Sponsor	Trials
Other	106
Industry	32
NIH	12

Clinical Trials, Market Analysis, and Projections for Midazolam: A Comprehensive Update

Introduction

Midazolam, a benzodiazepine, has been a subject of significant clinical interest, particularly in the management of seizures and status epilepticus. This article will delve into the recent clinical trials, market analysis, and future projections for midazolam, highlighting its efficacy, adoption, and potential challenges.

Clinical Trials: The RAMPART Study

One of the landmark studies that has significantly impacted the use of midazolam is the RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial) study. This double-blind, randomized clinical trial compared the efficacy of intramuscular (IM) midazolam versus intravenous (IV) lorazepam in the pre-hospital treatment of status epilepticus by paramedics[3].

Key Findings

• The RAMPART study established IM midazolam as a standard of care in pre-hospital emergency management of epilepsy crises, showing it to be as effective as IV lorazepam.
• The study highlighted that midazolam is faster to administer, cheaper, and easier to use, particularly because it does not require refrigeration[1].

Adoption and Impact

Following the publication of the RAMPART study, there was a substantial increase in the use of midazolam by EMS agencies.

Increased Usage

• After adjusting for various factors, the odds of a patient receiving midazolam were found to be 24 percent higher after the RAMPART study's publication[1].
• This increase indicates that EMS agencies are embracing clinical trial results and integrating them into their practices.

Secondary Analysis

• A secondary analysis showed little change in rates of airway interventions and rescue therapy for patients treated with midazolam, suggesting that midazolam does not significantly increase these complications[1].

Market Analysis

Midazolam's market presence is influenced by several factors, including its efficacy, ease of use, and regulatory environment.

Market Traction

• Midazolam has gained traction in the seizure community due to its proven efficacy and practical advantages. However, its use is also affected by its association with lethal injections, which can impact public perception and market dynamics[1].

Competitive Landscape

• Crossject's ZEPIZURE®, a needle-free auto-injector for midazolam, has shown bioequivalence with traditional IM injections and offers a rapid and easy two-step application. This product is poised to further enhance midazolam's market position by providing a more user-friendly and consistent delivery method[3].

Future Projections

The future of midazolam looks promising, but it is not without challenges.

Regulatory and Market Gate

• ZEPIZURE® is expected to gain regulatory approval and enter the market, potentially becoming the most rapid-to-use and lowest variability tool for pre-hospital midazolam administration[3].

Public Perception and Supply

• Despite its benefits, midazolam faces challenges related to public perception due to its use in lethal injections. There is a concern that drug companies may not find it profitable enough to continue production, given the negative publicity[1].

Clinical and Practical Advantages

• Midazolam's advantages, such as ease of administration and lack of need for refrigeration, are expected to continue driving its adoption in emergency medical services (EMS)[1].

Challenges and Considerations

While midazolam has several clinical and practical benefits, there are challenges that need to be addressed.

Public Perception

• The association with lethal injections could impact public and medical community perception, potentially affecting its market viability[1].

Supply Chain and Production

• The profitability of midazolam for pharmaceutical companies is a concern. If companies do not see sufficient financial returns, production might be reduced or discontinued, similar to what happened with sodium thiopental[1].

Conclusion

Midazolam has established itself as a critical drug in the management of seizures and status epilepticus, particularly in pre-hospital settings. The RAMPART study and subsequent bioequivalence studies have solidified its position as a standard of care. However, the drug faces challenges related to public perception and supply chain dynamics.

Key Takeaways

• Midazolam's efficacy in treating seizures has been significantly validated by the RAMPART study.
• There has been a substantial increase in the adoption of midazolam by EMS agencies following the RAMPART study.
• ZEPIZURE®, a needle-free auto-injector, is expected to enhance midazolam's market position with its ease of use and consistency.
• Public perception and supply chain issues remain significant challenges for the continued availability of midazolam.

FAQs

1. What was the main finding of the RAMPART study regarding midazolam? The RAMPART study found that intramuscular (IM) midazolam is as effective as intravenous (IV) lorazepam in the pre-hospital treatment of status epilepticus by paramedics[3].

2. How has the use of midazolam changed since the RAMPART study? The use of midazolam has increased significantly since the RAMPART study, with a 24 percent higher odds of patients receiving midazolam after the study's publication[1].

3. What are the advantages of midazolam over other benzodiazepines? Midazolam is faster to administer, cheaper, and easier to use because it does not require refrigeration[1].

4. What is ZEPIZURE®, and how does it enhance midazolam's delivery? ZEPIZURE® is a needle-free auto-injector for midazolam that offers a rapid and easy two-step application, providing a more user-friendly and consistent delivery method[3].

5. What challenges does midazolam face in terms of public perception and supply? Midazolam faces challenges related to its association with lethal injections, which can impact public perception and potentially reduce its market viability and production by pharmaceutical companies[1].

Sources

1. Michigan Medicine: "After a Clinical Trial on Midazolam for Seizures, Emergency Use of Drug Rises"[1]
2. Biospace: "Crossject elaborates on ZEPIZURE® potential in light of landmark RAMPART study and its own recently published bioequivalence study"[3]
3. Astrazeneca Clinical Trials: "A Study to Investigate the Pharmacokinetics of Midazolam after Repeated Oral Doses of Camizestrant"[4]