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Low-Dose Naltrexone (LDN) and Acetaminophen Combination and Its Components in the Acute Treatment of Migraine (ANODYNE-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03061734
Recruitment Status : Completed
First Posted : February 23, 2017
Last Update Posted : January 2, 2020
Sponsor:
Information provided by (Responsible Party):
Allodynic Therapeutics, LLC

Brief Summary:

Low-Dose Naltrexone and Acetaminophen (LDNA) combines two well-established none-addictive medications, at lower doses than the doses used for the approved indications.

The combination is a First-in-Class drug for the treatment of migraine due to its unique mechanism of action.

Naltrexone 50 mg, is approved for the treatment of opioid and alcohol addiction, based on its opioid antagonist properties. Yet, the underlying mechanism of naltrexone 's analgesic properties is attributable to its antagonism of Toll-Like Receptor-4 (TLR4). Naltrexone reversed acute and chronic neuropathic pain and migraine in animal studies (led by Dr. Linda Watkins). Toll-like Receptor-4 activation leads to an intracellular signaling pathway and inflammatory cytokine production which is responsible for activating the innate immune system. TLR4 signaling has emerged as a major pathway that mediates neuropathic pain.

Naltrexone inhibits TLR4-induced pro-inflammatory cytokine production, [i.e., nitric oxide (NO), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS)].

Blocking TLR4 also leads to blocking of TLR4-induced cyclooxygenase-2 (COX-2) expression.

The biological rationale for LDNA is through naltrexone's inhibition of the TLR4-induced pro-inflammatory cytokine production and the inhibition of the TLR4-induced cyclooxygenase-2 (COX-2) activation. Acetaminophen provides additional COX-2 blockage, delivering a one-two punch to COX-2 expression.

Activators of TLR4 include endogenous Damage-Associated Molecular Patterns (DAMP), which may consist of extracellular degradation products or dead cell components such as DNA, RNA, or plasma proteins.

The resulting neuroinflammation in the spinal nerve roots and the trigeminal pathway leads to pain.

Clinically, acetaminophen has been commonly used to yield synergy in analgesic combinations (e.g., Vicodin) and is meant to create synergy with naltrexone. Combining an optimal dose of acetaminophen with an opioid produces an analgesic effect greater than that obtained by doubling the dose of either constituent administered alone.


Condition or disease Intervention/treatment Phase
Migraine With or Without Aura Drug: Naltrexon/Acetaminophen Drug: Naltrexone/Acetaminophen-High Dose Drug: Naltrexone Alone (regular dose) Drug: Acetaminophen Alone Drug: Matching Placebo Phase 2

Detailed Description:
The study consists of a screening visit, out-patient treatment of a migraine attack with a single dose of the study drug within 8 weeks, and End-of-Study Visit 2-7 days after treatment of a moderate or severe migraine attack.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 92 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Investigator-Initiated, Proof-of-Concept, Phase 2, Randomized Controlled Trial to Assess a Single Dose of Low-Dose Naltrexone and Acetaminophen (LDNA) Combination and Its Individual Components in the Acute Treatment of Migraine
Actual Study Start Date : February 18, 2017
Actual Primary Completion Date : February 8, 2018
Actual Study Completion Date : February 8, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Headache Migraine

Arm Intervention/treatment
Experimental: Naltrexon/Acetaminophen Capsules
Patients take one capsule containing naltrexone(regular dose) and one capsule containing acetaminophen together for a qualified Migraine
Drug: Naltrexon/Acetaminophen
Naltrexon (regular dose) plus acetaminophen

Experimental: Naltrexon/Acetaminophen-High Capsules
Patient take one capsule containing naltrexone (high dose) and one capsule containing acetaminophen together for a qualified Migraine
Drug: Naltrexone/Acetaminophen-High Dose
Naltrexon (high dose) plus acetaminophen

Active Comparator: Naltrexone Alone Capsules
Patient take one capsule containing naltrexone and one capsule containing placebo together for a qualified Migraine
Drug: Naltrexone Alone (regular dose)
Naltrexone Alone plus Placebo

Active Comparator: Acetaminophen Alone Capsules
Patient take one capsule containing naltrexone and one capsule containing placebo together for a qualified Migraine
Drug: Acetaminophen Alone
Acetaminophen Alone plus Placebo

Placebo Comparator: Placebo Capsules
Patient take two capsule containing placebo together for a qualified Migraine
Drug: Matching Placebo
Two Placebo capsules




Primary Outcome Measures :
  1. % of patients reporting no headache pain. [ Time Frame: 2 hours post-dose ]
    Self-reported headache pain on a four-point Likert scale.

  2. % of patients having absence of most bothersome migraine-associated symptom (MBS). [ Time Frame: 2 hours post-dose ]
    MBS was prospectively identified at baseline. Self-reported MBS as present or absent.

  3. % of patients who have "sustained pain freedom" [ Time Frame: 24-hour post-dose. ]
    Defined as having no headache pain at 2 hours after dose, with no use of rescue medication and no relapse of headache pain within 24 hours after administration of the investigational drug.


Secondary Outcome Measures :
  1. % of patients having absence of nausea, photophobia, phonophobia, and neck/shoulder pain [ Time Frame: 24-hour post-dose. ]
    Self-reported the current status of their associated symptom as present or absent.

  2. % of patients who used rescue medications [ Time Frame: 2-24 hours ]
  3. % of patients who had headache pain relapse. [ Time Frame: 2-48 hours ]
    Defined as the return of headache of any severity within 48 hours after administration of the investigational drug, when the patient was pain-free at 2 hours after the administration of the investigational drug.


Other Outcome Measures:
  1. % of patients who experienced adverse events [ Time Frame: 48 hours ]
    treatment related Adverse Events



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female 18 years of age or older.
  2. History of migraine with or without aura according to the International Classification of Headache Disorders (ICHD)-3rd edition (beta version) for at least one-year with first migraine prior to age 50.
  3. Migraine-associated nausea with ≥half of migraine attacks.
  4. 2 - 8 migraines per month in each of the previous 3 months.
  5. The patient is able to complete study questionnaires, comply with the study requirements and restrictions, and willing to provide written informed consent and authorize HIPAA.
  6. The female patient who is premenopausal or postmenopausal less than 1 year, or have not had surgical sterilization (i.e., tubal ligation, partial or complete hysterectomy) must have a negative urine pregnancy test, be non-lactating, and commit to using adequate and reliable contraception throughout the study (e.g., barrier with additional spermicidal, intra-uterine device, hormonal contraception). The male patient must be surgically sterile or commit to the use of 2 different methods of birth control during the study and for 28 days after taking the study drug.

Exclusion Criteria:

  1. The patient in the opinion of the investigator, may have medication-overuse headache pain (as defined by ICHD - 3 beta criteria for medication-overuse headache), (analgesic, opioid, ergotamine or triptan overuse) during the 3 months preceding screening.
  2. The patient in the opinion of the investigator has chronic migraine (as defined by ICHD - 3 beta criteria for chronic migraine).
  3. History of cluster headache or neurologically complicated migraine (hemiplegic, basilar, retinal, ophthalmoplegic migraine).
  4. Initiation or change in medications with possible migraine prophylactic effects during 3 months before inclusion into the trial (E.g., calcium channel blockers, tricyclic antidepressants, beta-blockers, selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine re-uptake inhibitors (SNRIs), or Botox).
  5. Any concurrent medical or psychiatric condition, this includes, but is not limited to chronic unstable debilitating diseases, significant renal or hepatic impairment.
  6. A history within the previous 3 years of abuse of any drug, prescription, illicit, or alcohol.
  7. The Female patient is pregnant or breast-feeding. The Male patient is not practicing 2 different methods of birth control with their partner during the study, and for 28 days after the investigational drug last dose or will not remain abstinent during the study, and for 28 days after the last dose.
  8. Use of opiates or barbiturates more than 3 days per month.
  9. Known-hypersensitivity reaction to any of the components of the investigational drug.
  10. Consumption of analgesic medication for other conditions on a regular basis, (nonsteroidal anti-inflammatory drugs, or acetaminophen, or muscle relaxants).
  11. Use of emergency care treatment more than 3 times in the previous 6 months.
  12. Participation in another study with an investigational drug within 30 days prior to randomization and/or a plan to participate during the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03061734


Locations
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United States, Florida
Annette C. Toledano MD
North Miami, Florida, United States, 33181
Sponsors and Collaborators
Allodynic Therapeutics, LLC
Investigators
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Study Director: Annette C Toledano, M.D. Allodynic Therapeutics, LLC
Additional Information:
Publications of Results:

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Responsible Party: Allodynic Therapeutics, LLC
ClinicalTrials.gov Identifier: NCT03061734    
Other Study ID Numbers: ANODYNE-1
First Posted: February 23, 2017    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Allodynic Therapeutics, LLC:
Migraine Disorders
Headache Disorders
Migraine with Aura
Migraine without Aura
Additional relevant MeSH terms:
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Migraine Disorders
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Acetaminophen
Naltrexone
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Alcohol Deterrents
Narcotic Antagonists