Clinical trial NCT01339156: Study of P3914 to Evaluate the Safety, Tolerability, Food Effect & Pharmacokinetics in Healthy Male Subjects and Efficacy & Safety of P3914 in Patients With Acute Dental Pain
Official title: Randomized, Double-blind, Placebo-controlled Phase I-Ib Study of P3914 to Evaluate the Safety, Tolerability, Food Effect & Pharmacokinetics in Healthy Male Subjects and Efficacy & Safety of P3914 in Patients With Acute Dental Pain
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Dental Pain
Keywords: Safety
Tolerability
Food Effect
Pharmacokinetics
Lead sponsor: Piramal Enterprises Limited
Sponsor class: INDUSTRY
First posted: 2011-04-20
Enrollment: 46
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: P3914 a pro-drug of Naproxen, characterized by naproxen (COX inhibiting moiety) linked to a NO moiety is intended for the treatment of pain and inflammation. The rationale behind development of P3914 is to maintain the analgesic, antipyretic and anti-inflammatory activity of naproxen and enhance GI safety by virtue of release of NO besides with no major effect on blood pressure on long-term administration.


Eligibility criteria: Inclusion Criteria:

* for Part A, Part B and Part C

  1. Male subjects aged between 18 and 45 years (including both) with Body Mass Index between 18 to 25 kg/m2 (including both).
  2. Subjects with normal health as determined by personal medical history, clinical examination and laboratory examinations within the clinically acceptable normal range.
  3. Subjects having clinically acceptable 12-lead electrocardiogram (ECG).
  4. Subjects having clinically acceptable X-Ray chest (P/A view).
  5. Subjects having clinically acceptable endoscopy.
  6. Have a negative urine screen for drugs of abuse (including amphetamines, barbiturates, benzodiazepines, marijuana, cocaine, and morphine).
  7. Have negative alcohol breath test.
  8. Subjects willing to adhere to the protocol requirements and to provide written informed consent.

Part D:

Patients with acute postoperative dental pain (at least moderate in severity or score of 40 mm on VAS) after removal of an impacted third mandibular molar will be selected for study participation, if they meet the following criteria:

1. Male patients aged between 18 and 60 years (including both).
2. Patients with acute postoperative dental pain (at least moderate in severity or score of 40 mm on Visual Analogue Scale)
3. Patients with otherwise normal health as determined by personal medical history, clinical examination and laboratory examinations within the clinically acceptable normal range.
4. Patients having clinically acceptable 12-lead electrocardiogram (ECG).
5. Patients having clinically acceptable chest X-Ray (P/A view).
6. Patients having clinically acceptable endoscopy.
7. Have a negative urine screen for drugs of abuse (including amphetamines, barbiturates, benzodiazepines, marijuana, cocaine, and morphine).
8. Have negative alcohol breath test.
9. Patients willing to adhere to the protocol requirements and to provide written informed consent.

Exclusion Criteria:

* Part A, Part B and Part C:

  1. Hypersensitivity to NSAIDs or nitrodonating drugs.
  2. History or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder.
  3. Any treatment which could bring about induction or inhibition of hepatic microsomal enzyme system within one month of the study starting.
  4. History or presence of significant gastric and/or duodenal ulceration including the last three months or gastroduodenal bleeding including the last six months prior to the screening visit.
  5. History of peptic ulceration or significant dyspepsia as judged by the investigator.
  6. Endoscopy finding of gastric or duodenal ulcer at baseline. Erosive esophagitis or other endoscopic appearance that constitutes a risk to the subject, if included in the study, as judged by the investigator.
  7. Have positive test for Helicobacter pylori infection.
  8. Orthostatic hypotension with a systolic blood pressure drop of ≥ 25 mm Hg and/or a diastolic blood pressure drop of ≥ 15 mm Hg within 5 minutes of standing when changing from supine to erect position.
  9. A history of renal impairment, or a glomerular filtration rate (GFR) \<60 mL/min or, at visit 1, a serum creatinine value \>140 mol/L.
  10. Use of aspirin, H2 antagonists, antacids, misoprostol, proton pump inhibitors, sucralfate including two weeks prior to the screening visit.
  11. Subjects currently taking sildenafil, anticoagulants or ticlopidine, nitrates, nitrovasodilating drugs (e.g. nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, glycerin trinitrate), diuretics (in a dose potentially leading to volume depletion).
  12. Use of any prescribed medication during last two weeks or OTC medicinal products (including herbal/traditional medicine preparations) during the last one week prior to initiation of study.
  13. History or presence of significant alcoholism or drug abuse in the past one year.
  14. Positive screening test for any one or more: HIV, Hepatitis B and Hepatitis C.
  15. History or presence of smoking or use of other tobacco, pan, gutkha products since last six months.
  16. History or presence of significant asthma, urticaria or other allergic reactions.
  17. History or presence of significant thyroid disease, adrenal dysfunction, organic intracranial lesion such as pituitary tumour.
  18. Difficulty in swallowing solids like tablets or capsules.
  19. History or presence of cancer.
  20. Difficulty with donating blood.
  21. Major illness during three months before screening.
  22. Participation in a drug research study within past three months.
  23. Donation of blood in the past three months before screening.

For Part D:

1. Hypersensitivity to NSAIDs or nitrodonating drugs.
2. History or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder.
3. Any treatment which could bring about induction or inhibition of hepatic microsomal enzyme system within 1 month of the study starting.
4. History or presence of significant gastric and/or duodenal ulceration including the last three months or gastroduodenal bleeding including the last six months prior to the screening visit.
5. History of peptic ulceration or significant dyspepsia as judged by the investigator.
6. Endoscopy finding of gastric or duodenal ulcer at baseline. Erosive esophagitis or other endoscopic appearance that constitutes a risk to the subject, if included in the study, as judged by the investigator.
7. Have positive test for Helicobacter pylori infection.
8. Orthostatic hypotension with a systolic blood pressure drop of ≥ 25 mm Hg and/or a diastolic blood pressure drop of ≥ 15 mm Hg within 5 minutes of standing when changing from supine to erect position.
9. A history of renal impairment, or a glomerular filtration rate (GFR) \<60 mL/min or, at visit 1, a serum creatinine value \>140 mol/L.
10. Use of aspirin, H2 antagonists, antacids, misoprostol, proton pump inhibitors, sucralfate including two weeks prior to the screening visit.
11. Patients currently taking sildenafil, anticoagulants or ticlopidine, nitrates, nitrovasodilating drugs (e.g. nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, glycerin trinitrate), diuretics (in a dose potentially leading to volume depletion).
12. Use of analgesics in the 48 hrs preceding the day of dental surgery except use of acetaminophen until midnight on the day before surgery.
13. Patients with oral surgery in the 30 days before the pre-study visit.
14. Use of any prescribed medication during last two weeks or OTC medicinal products (including herbal preparations) during the last one week prior to initiation of study.
15. History or presence of significant alcoholism or drug abuse in the past one year.
16. Positive screening test for any one or more: HIV, Hepatitis B and Hepatitis C.
17. History or presence of smoking or use of other tobacco, pan, gutkha products since last 06 months.
18. History or presence of significant asthma, urticaria or other allergic reactions.
19. History or presence of significant thyroid disease, adrenal dysfunction, organic intracranial lesion such as pituitary tumour.
20. Difficulty in swallowing solids like tablets or capsules.
21. History or presence of cancer.
22. Difficulty with donating blood.
23. Major illness during three months before screening.
24. Participation in a drug research study within past three months.
25. Donation of blood in the past three months before screening.

Primary outcomes:
measure: Vital signs- systolic and diastolic blood pressure, pulse rate and oral body temperature.
timeFrame: Defined in description
Secondary outcomes:
measure: Pain intensity using 100 mm Visual analog scale
timeFrame: immediately before administration of study drug and at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 7.00, and 8.00 hrs post-dose, and immediately before administration of rescue analgesia (if any).
measure: Pharmacokinetic assessment for Part A
timeFrame: within 15 min prior to dosing. Post-dose blood samples will be drawn at 0.25, 0.50, 1, 2, 3, 3.50, 4, 4.50, 5, 5.50, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 & 120 hrs following drug administration.
measure: Pharmacokinetic assessment for Part C
timeFrame: within 15 min prior to dosing. Post-dose samples will be drawn at 0.25, 0.50, 1, 2, 3, 3.50, 4, 4.50, 5, 6, 8, 10, 12, 24, 48, 72, 96 & 120 hrs following drug administration.
measure: Pharmacokinetic assessment for Part B
timeFrame: within 15 min prior to dosing on Day 1, 6, 9, 13&14. Post-dose blood samples at 0.25, 0.50, 1, 2, 3, 3.50, 4, 4.50, 5, 5.50, 6, 8, 10, 12, 16& 24 hrs following drug administration on Day 1 & Day 14 and 48 hrs post-dose on Day 16
measure: Pharmacokinetic assessment for Part D
timeFrame: within 15 min prior to dosing. Post-dose blood samples of at 0.50, 1, 2, 3, 3.50, 4, 4.50, 5, 5.50, 6 and 8 hrs following drug administration
Other outcomes:
Locations:
Study officials:
affiliation: Veeda Clinical research private limited
name: Dr. Dharmesh Domadia
role: PRINCIPAL_INVESTIGATOR
References: