Study to Find Out the Optimal Dose of Caffeine in the Combination Tablet of Naproxen Sodium and Caffeine in Patients Experiencing Moderate to Severe Pain After Having Wisdom Teeth Removed

Bayer

Status and phase: Completed; Phase 2

Conditions: Pain, Postoperative

Treatments: Drug: Caffeine; Drug: Placebo; Drug: Naproxen sodium/Caffeine (BAY2880376); Drug: Naproxen sodium (Aleve)

Study type: Interventional

Funder types: Industry

Identifiers

NCT04132336

21069

2019-003513-33 (EudraCT Number)

Details and patient eligibility

About

The researchers in this study wanted to find out the optimal dose of Caffeine in the combination tablet of Naproxen Sodium and Caffeine that works in patients experiencing moderate to severe pain after having wisdom teeth removed. In the US, Naproxen has been marketed since 1976, and Naproxen Sodium has been approved for over-the-counter (OTC) use since 1994 for the temporary relief of minor aches and pains. Caffeine, which is generally consumed as coffee, tea or cocoa, has been shown to enhance the effectiveness of various pain relievers, and therefore is accepted as an additive to painkillers like aspirin and acetaminophen. Patients participating in this study underwent a surgery to remove 3 or 4 wisdom teeth. If the pain severity after the surgery met the study requirement, patients would receive oral tablet(s) of Naproxen Sodium and Caffeine, or Naproxen Sodium, or Caffeine, or placebo (drug with no active ingredient). Patients could also receive additional pain medication when needed. Researchers would also learn if the patients have any medical problems during the study.

Enrollment: 193 patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Healthy, ambulatory, male or female volunteers 16 years of age or older;
• Body mass index (BMI) 18.5 to 35.0 kg/m^2 inclusive as measured by the National Institutes of Health (NIH) BMI Calculator;
• Participants will undergo surgical extraction of three or four third molars, two of which must be mandibular molars. Maxillary third molars may be removed regardless of impaction level. The mandibular extractions must have a trauma rating of mild or moderate and meet one of the following scenarios: two full bony impactions; two partial bony impactions; one full bony impaction in combination with one partial bony impaction. supernumerary teeth present may also be removed at the discretion of the oral surgeon;
• Have not taken any form of medication, nutritional supplements with analgesic properties (e.g. gamma-Aminobutyric acid [GABA], turmeric) or herbal supplements (i.e., St. John's Wort) within 5 days of admission (except for oral contraceptives, prophylactic antibiotics, multivitamin supplements, or other routine medications to treat benign conditions (such as antibiotics to treat acne), and agree not to take any medication (other than that provided to them) throughout the study;
• Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) preoperatively, with or without a vasoconstrictor and nitrous oxide at the discretion of the Investigator;
• Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a score of at least 2 on a 4 point scale) and a score of ≥ 5 on the 0-10 pain intensity Numerical Rating Scale (NRS) within 4.5 hours post-surgery.

Exclusion criteria

• History of hypersensitivity to naproxen sodium, caffeine, ibuprofen, nonsteroidal anti-inflammatory drug (NSAIDS), aspirin, similar pharmacological agents, local anesthetics, rescue medication or components of the investigational products;
• Evidence or history of clinically significant (in the judgment of the investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including hypertension and cardiac arrhythmia), hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years;
• Participants with the following medical conditions may be eligible at the discretion of the investigator: attention deficit hyperactivity disorder (ADHD) on a stable dose regimen of methylphenidate/(dextro) amphetamine for at least 6 months; participants with hypothyroidism on a stable dose of synthetic thyroid hormone for at least 6 months;
• Have received any form of treatment in the form of medication for depression in the past 6 months or any form of psychotropic agent (including selective serotonin uptake inhibitors [SSRI] but excluding ADHD medications described above) within the last 6 months;
• Relevant concomitant disease such as asthma (exercise induced asthma is permitted);
• Current or past history of gastrointestinal ulceration, gastrointestinal bleeding or other bleeding disorder(s);
• Acute illness or active local infection prior to surgery that can interfere with the conduct of the study in the judgment of the investigator;
• Use of any over-the-counter (OTC) or prescription medications with which the administration of naproxen, acetaminophen, ibuprofen, any other NSAID, (e.g., tramadol) or if a medication is contraindicated;
• Use of any medications within 5 days of surgery until discharge from the study site (except oral contraceptives, prophylactic antibiotics, synthetic thyroid hormones, methylphenidate or medications to treat benign conditions such as antibiotics to treat acne);
• Use of caffeine within 2 days prior to the study;
• Habits of high consumption of caffeine (>400 mg/day equivalent to about 3-4 cups of coffee per day);
• Habituation to analgesic drugs including opioids (i.e., routine use of oral analgesics 5 or more times per week for greater than 3 weeks within the past 2 years);
• Surgeon's trauma rating of severe following surgery.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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193 participants in 7 patient groups, including a placebo group

Naproxen sodium/caffeine - Dose 1

Experimental group

Description:

Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars

Treatment:

Drug: Naproxen sodium/Caffeine (BAY2880376)

Naproxen sodium/caffeine - Dose 2

Experimental group

Description:

Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars

Treatment:

Drug: Naproxen sodium/Caffeine (BAY2880376)

Naproxen sodium/caffeine - Dose 3

Experimental group

Description:

Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars

Treatment:

Drug: Naproxen sodium/Caffeine (BAY2880376)

Naproxen sodium/caffeine - Dose 4

Experimental group

Description:

Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars

Treatment:

Drug: Naproxen sodium/Caffeine (BAY2880376)

Naproxen sodium

Active Comparator group

Description:

Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars

Treatment:

Drug: Naproxen sodium (Aleve)

Caffeine

Active Comparator group

Description:

Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars

Treatment:

Drug: Caffeine

Placebo

Placebo Comparator group

Description:

Participants received a single dose of two tablets of matching placebo after extraction of third molars

Treatment:

Drug: Placebo